Conditions: Multiple Myeloma
Keywords: Radium-223 dichloride Bortezomib Dexamethasone Relapsed multiple myeloma Combination therapy multiple myeloma
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This study will be conducted in 2 parts. The phase 1b part will be an international, phase 1b, open-label, dose-escalation assessment of radium-223 dichloride administered with bortezomib and dexamethasone in subjects with relapsed multiple myeloma. The primary endpoint is to determine the optimal dose of radium-223 dichloride in combination with bortezomib/dexamethasone for the Phase 2 portion of the study.

The phase 2 part will be an international, phase 2, double-blind, randomized, placebo-controlled assessment of radium-223 dichloride versus placebo administered with bortezomib and dexamethasone, in subjects with relapsed multiple myeloma.

Up to 12 subjects in all dose cohorts combined will be treated in the phase 1b part of the study. Up to approximately 100 subjects will be enrolled in the phase 2 part of the study.

Detailed description:

Arms:
arm 1: Phase 1: Radium-223 dichloride; 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses plus SOC (standard of care) bortezomib/ dexamethasone. arm 2: Phase 1: Radium-223 dichloride; 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride doses plus SOC bortezomib/ dexamethasone. arm 3: Phase 2: Matching placebo (isotonic saline) every 6 weeks for a total of 6 doses plus SOC bortezomib/dexamethasone. arm 4: Phase 2: Phase 1b-selected dose of radium-223 dichloride every 6 weeks for 6 doses plus SOC bortezomib/dexamethasone

Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY88-8223) intervention 2: Placebo intervention 3: Bortezomib intervention 4: Dexamethasone
Intervention descriptions: intervention 1: Sequential dose escalation in Intravenous (IV) injection intervention 2: Matching placebo intervention 3: Bortezomib is administered subcutaneous (SC) (per Investigator choice ) at 1.3 mg/m2/dose intervention 4: Dexamethasone is administered orally at 40 mg

Protocol document:
Prot_001.pdf: 
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A phase 1b/2 trial to evaluate the safety of radium-223 dichloride (BAY 88-8223) in 
combination with bortezomib and dexamethasone in patients with relapsed multiple 
myeloma.
For this study, the protocol and subsequent protocol amendments were released as
follows:
Original protocol, Version 1.0, dated 11 JUL 2016
Amendment no. 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 08 AUG 2017
Amendment no. 2 (described in Section 15.2)
forming integrated protocol Version 3.0, dated 18 MAY 2018
This document integrates the original protocol and all global amendments.


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1.
Title page
A phase 1b/2 trial to evaluate the safety of radium-223 dichloride (BAY 88-8223) in 
combination with bortezomib and dexamethasone in patients with relapsed multiple 
myeloma.
Short title:
Phase 1b/2 study testing radium-223 dichloride in relapsed 
multiple myeloma
Test drug:
BAY 88-8223 / radium-223 dichloride / Xofigo
Study purpose:
Safety and early signals of anti-multiple myeloma activity 
Clinical study phase:
1b/2
Date:
18 MAY 2018
Registration:
EudraCT: 2016-002438-58
Version no.:
3.0
Sponsor’s study no.:
18987   
Sponsor:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc., 
                     100 Bayer Boulevard, P.O. Box 915,
                     Whippany, NJ 07981-0915, USA
Sponsor’s medical expert:
 
Bayer S.p.A.
20156 Milano, Italy
Phone: 
Mobile: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation. Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
Sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD
PPD


PPD
PPD


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Signature of Principal Investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the Sponsor’s study file and in the 
respective center’s Investigator Site File.


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2.
Synopsis
Title
A phase 1b/2 trial to evaluate the safety of radium-223 dichloride 
(BAY 88-8223) in combination with bortezomib and dexamethasone in 
patients with relapsed multiple myeloma.
Short title
Phase 1b/2 study evaluating radium-223 dichloride in relapsed multiple 
myeloma
Clinical study phase
Phase 1b/2
Study objective(s) 
Phase 1b part (open-label) 
Primary objectives:

To evaluate the safety of the combination of radium-223 
dichloride plus bortezomib (BOR) and dexamethasone (DEX)

To determine the dose of radium-223 dichloride that will be used 
in the phase 2 part of the study (maximum tolerated dose [MTD]
or recommended phase 2 dose [RP2D]) 
Secondary objectives:

To evaluate the combined complete response (CR) + very good 
partial response (VGPR), as determined by International 
Myeloma Working Group (IMWG) uniform response criteria
Phase 2 part (double-blind, randomized) 
Primary objectives:

To compare radium-223 dichloride versus placebo in addition to 
background treatment with BOR plus DEX in terms of combined 
CR+VGPR rate in relapsed multiple myeloma subjects, as 
determined by International Myeloma Working Group (IMWG) 
uniform response criteria.
Secondary objectives:

To evaluate safety

To evaluate the objective response rate (ORR), as determined by 
IMWG uniform response criteria

To evaluate overall survival (OS) 

To evaluate progression-free survival (PFS)

To evaluate duration of response (DOR)
Exploratory objectives:

To evaluate time to first on-study symptomatic skeletal event 
(SSE)

To evaluate bone biomarkers

To evaluate change in bone lesions

To evaluate change in MM disease markers

To evaluate circulating tumor DNA (ctDNA) and circulating 


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tumor cells (CTCs)

To evaluate time to opioid use for cancer pain in subjects without 
opioid use at baseline

To evaluate time to pain progression
Test drug(s)
BAY 88-8223
Name of active ingredient
Radium-223 dichloride
Dose(s) 
For the Phase 1b open-label part of the study, 2 dose levels of radium-223 
dichloride may be administered, following sequential dose escalation 
using  a ‘3 + 3’ design: 

Cohort 1: 33 kiloBecquerel (kBq)/kg body weight every 6 weeks 
for a total of 6 radium-223 dichloride doses in combination with 
BOR and DEX

Cohort 2: 55 kBq/kg body weight every 6 weeks for a total of 6 
radium-223 dichloride doses in combination with BOR and DEX
For the Phase 2 double-blind randomized part of the study, the 
MTD/RP2D, as determined by the phase 1b part of the study, will be 
administered once every 6 weeks for a total of 6 radium-223 dichloride 
doses.
Route of administration
Intravenous (IV) injection (slow bolus) 
Duration of treatment
Approximately 36 weeks: 6 doses; 1 dose every 6 weeks
Reference drug(s)
Matching placebo (isotonic saline) for the phase 2 part of the study
Name of active ingredient
Not applicable
Dose(s)
One dose every 6 weeks for a total of 6 doses
Route of administration
Intravenous (IV) injection (slow bolus)
Duration of treatment
Approximately 36 weeks: 6 doses; 1 dose every 6 weeks
Background treatment 
(Applicable to both phase 1b and 2 parts of the study)
Bortezomib will be administered subcutaneous (SC) at 1.3 mg/m2/dose, 
on Days 1, 4, 8, and 11 in a 21-day cycle, for 8 cycles. 
For extended therapy beyond 8 cycles, BOR will be administered on Days 
1 and 15 of a 28-day cycle for up to 2 years after the first dose of study 
treatment, or until progression-free survival (PFS) event occurs, the 
subject withdraws consent or unacceptable toxicity develops, whichever 
occurs first. 
Dexamethasone will be administered orally at 40 mg, on Days 1, 4, 8, and 
11 in a 21-day cycle, for 8 cycles. DEX administration may be split over 
2 days (on the day of BOR administration and the day after BOR
administration) at the discretion of the Investigator.
For extended therapy beyond 8 cycles, DEX will be administered orally at 
20 mg/dose, on Days 1 and 15 of a 28-day cycle along with BOR for up to 


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2 years after the first dose of study treatment or until a progression-free
survival (PFS) event occurs, the subject withdraws consent or 
unacceptable toxicity develops, whichever occurs first.
Indication
Relapsed multiple myeloma
Diagnosis and main criteria 
for inclusion /exclusion 
Inclusion criteria
Subjects must meet all the following criteria for inclusion in the study:
1.
Males or females ≥18 years of age 
2.
Have provided written informed consent. Subjects must be able to 
understand and be willing to sign the written informed consent, 
expressing their willingness and ability to comply with 
protocol-required treatment and assessment schedule, including 
follow-up visits. A signed informed consent form (ICF) must be 
appropriately obtained prior to the conduct of any trial-specific 
procedure.
3.
Subject must have documented monoclonal plasma cells in the bone 
marrow of ≥10%, as defined by their institutional standard at some 
point in their disease history or the presence of a biopsy proven 
plasmacytoma 
4.
Subjects must have received at least 1 and not more than 3 previous 
lines of treatment and have had a response to at least 1 prior treatment 
in the past (i.e., achieved a minimal response [MR] or better) 
according to the IMWG uniform response criteria
5.
Subject must be non-refractory to bortezomib (Refractory is 
defined: progression of disease while receiving bortezomib therapy or 
within 60 days of ending bortezomib therapy)
6.
Subjects must have documented evidence of progressive disease
according to the IMWG uniform response criteria following the last 
multiple myeloma treatment
7.
Subjects must have measurable disease defined as at least 1 of the 
following:
o
Serum M-protein defined by the following:

IgG multiple myeloma: Serum monoclonal paraprotein 
(M-protein) level ≥1.0 g/dL (measured by protein 
electrophoresis [PEP])

IgA, IgD, IgE, IgM multiple myeloma: serum M-
protein level ≥0.5 g/dL (measured by  PEP)
o
Urine M-protein ≥200 mg/24 hours (any immunoglobulin 
heavy chain type measured by PEP)
o
Serum free light chain (FLC) ≥10 mg/dL with abnormal ratio
in subjects with unmeasurable disease by serum or urine PEP 
8.
≥1 bone lesion identifiable by radiograph, computed tomography
(CT), positron emission tomography – computed tomography 
(PET-CT), or magnetic resonance imaging (MRI)
9.
Life expectancy of at least 3 months
10. Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 2
11. For subjects experiencing toxicities resulting from a previous therapy 
(including peripheral neuropathy), the toxicities must be resolved or 
stabilized to ≤Grade 1
12. Adequate hepatic function, with total bilirubin ≤1.5 x upper limit of 
normal (ULN) (except for Gilbert Syndrome: total bilirubin < 3.0 x 
ULN), and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤3.0 x ULN


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13. Absolute neutrophil count (ANC) ≥1.5 × 109/L, hemoglobin (Hb) 
≥9.0 g/dL, and platelet count ≥75.0 × 109/L independent of 
transfusion of red blood cells (RBC) or platelet concentrates and 
independent of granulocyte colony-stimulating factor (G-CSF) or 
granulocyte-macrophage colony-stimulating factor (GM-CSF) 
Note: Transfusion of RBC or platelet concentrates, use of G-CSF or 
GM-CSF within 21 days from ICF signature is not allowed.
14. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin 
time (PTT) ≤ 1.5 x ULN. Prothrombin time (PT) may be used instead 
of INR if ≤ 1.5 x ULN
15. Estimated creatinine clearance of ≥30 mL/minute, according to the 
Cockcroft and Gault formula
16. Serum potassium levels >3.0 mEq/L
17. Corrected serum calcium <14.0 mg/dL (3.5 mmol/L)
18. Female subjects of child-bearing potential must have a negative urine
pregnancy test within 72 hours before the first dose. Postmenopausal 
females (age ≥55 years and 1 year or more of amenorrhea; or age 
<55 years and 1 year or more of amenorrhea with an estradiol assay 
<20 pg/mL; or bilateral oophorectomy) and surgically sterilized 
females are exempt from a pregnancy test.
a) Female subjects of child-bearing potential who are sexually active 
must agree to utilize 2 reliable and acceptable methods of 
contraception used simultaneously: a barrier method such as 
(i) condoms (male or female) with spermicidal agent, or 
(ii) diaphragm or cervical cap with spermicide, combined with a 
highly effective non-hormonal birth control method such as intra-
uterine device, during treatment with and for 6 months following the 
last dose of radium-223 dichloride/placebo or 3 months after the last 
administration of bortezomib/dexamethasone, whichever occurs later.
b) Male subjects with partners of child-bearing potential must be 
willing to use 2 reliable and acceptable methods of birth control 
(including adequate barrier protection) used simultaneously as 
determined to be acceptable by the principal investigator and the 
sponsor during the study and for 6 months following completion of 
treatment with radium-223 dichloride/placebo or 3 months after the
last administration of bortezomib /dexamethasone, whichever occurs 
later. The contraception measures must be discussed with the subject. 
Suitable contraception could be, for example, the use of condoms 
combined with an oral contraceptive taken by the female partner of a 
study subject.
Exclusion criteria
Subjects must not meet any of the exclusion criteria listed below:
1.
Systemic glucocorticoid therapy (prednisone >10 mg/day orally or 
equivalent) within the last 4 weeks prior to first dose, unless tapered 
and on a stable dose (prednisone ≤10 mg/day orally or equivalent) for 
at least 1 week
2.
Subjects with known POEMS syndrome (polyneuropathy, 
organomegaly, endocrinopathy, monoclonal protein, and skin 
changes) or light-chain (AL) amyloidosis
3.
Plasma cell leukemia (defined by plasma cell >20%, and/or an 
absolute plasma cell count of >2 x 109/L in peripheral blood)
4.
Subject has received anti-myeloma treatment within 2 weeks or 5 
pharmacokinetic (PK) half-lives (t1/2) of the treatment, whichever is 
longer, before the date of start of treatment. 


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5.
Radiation therapy in the previous 4 weeks prior to first dose. 
Note: Subjects treated with local radiotherapy which is recommended 
to be limited fields for pain control are eligible.
6.
Administration of an investigational therapeutic study drug (including 
investigational vaccines) within 4 weeks or within 5 PK (t1/2) of the 
treatment, whichever time is greater, before the date of start of 
treatment
7.
Prior treatment with radium-223 dichloride or any experimental 
radiopharmaceutical
8.
Major surgery within 4 weeks prior to first dose (central line 
placement and kyphoplasty are not considered major surgery)
9.
Congestive heart failure (New York Heart Association [NYHA] class 
III to IV), symptomatic cardiac ischemia, unstable angina or 
myocardial infarction in the previous 6 months prior to first dose, or 
with a known left ventricular ejection fraction (LVEF) <40%, 
cardiomyopathy, pericardial disease, clinically relevant cardiac 
arrhythmia (CTCAE version 4.03 Grade 2 or higher), clinically 
significant ECG abnormalities, or screening 12-lead ECG showing a 
baseline prolonged QT interval (baseline QT interval as corrected by 
Fridericia’s formula > 470 msec).
Note: LVEF values will not be collected, however the investigator 
must verify and subjects must be excluded if LVEF <40% at study 
entry.
10. Acute diffuse infiltrative pulmonary disease
11. Acute active infection requiring systemic antibiotics, antivirals or 
antifungals within 2 weeks prior to first dose
12. Known HIV infection or subjects who are known to be HIV 
seropositive
13. Subjects with active hepatitis B or C infection at screening. Subjects 
with a known history of occult hepatitis B virus (HBV) infection 
(defined as positive hepatitis B core antibody [HBcAb] and negative 
hepatitis B surface antigen [HBsAg]), but who have undetectable 
HBV DNA at screening may be included. Subjects with a history of 
positive hepatitis C virus (HCV) antibody must be negative for HCV 
RNA by polymerase chain reaction (PCR) assessment or similar 
technology to be included.
14. Any history of malignancy within the past 3 years except adequately
treated a) basal cell or squamous cell skin cancer, b) carcinoma in situ 
of the cervix, c) prostate carcinoma in situ < Gleason Score 6 with 
stable prostate-specific antigen (PSA), or d) breast carcinoma in situ 
15. Neuropathy ≥ Grade 2 
16. Subjects with pleural effusions requiring thoracentesis or ascites 
requiring paracentesis 
17. Subjects with known meningeal and/or extramedullary involvement of 
MM
18. Known allergies, hypersensitivity or intolerance to radium-223 
dichloride, bortezomib, or dexamethasone or their excipients. 
19. Any clinically significant medical disease or condition that, in the 
Investigator's opinion, may interfere with protocol adherence or a 
subject's ability to give informed consent
20. Female subjects who are pregnant or lactating
21. Serious psychiatric condition that could interfere with compliance of 
treatment
22. Close affiliation with the investigational site (e.g., a close relative of 
the Investigator, dependent person [e.g., employee or student of the 
investigational site])


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23. Previous assignment to treatment during this study
Study design 
Phase 1b part: International, open-label, dose-escalation study consisting 
of up to 2 cohorts at different dose levels to determine maximum tolerated 
dose/recommended phase 2 dose for phase 2.
Phase 2 part: International, double-blind, randomized, placebo-controlled 
efficacy and safety study. 
Methodology 
This phase 1b study will evaluate 2 dose levels of radium-223 dichloride 
in combination with BOR and DEX (Cohort 1 and Cohort 2) in subjects 
with relapsed MM. Subjects will be treated at 2 different dose levels with 
radium-223 dichloride following sequential dose escalation using a “3+3” 
design.
The starting dose of 33 kBq/kg body weight will be combined in Cohort 1
with BOR and DEX every 6 weeks for a total of up to 6 doses of radium-
223 dichloride, which is a lower dose than the dose of radium-223 
dichloride monotherapy approved for CRPC (55 kBq/kg body weight). 
The next dose level of 55 kBq/kg body weight will be evaluated with BOR
and DEX in Cohort 2.
The dose escalation will follow a ‘3 + 3’ design for all evaluated 
combinations in Cohort 1 and Cohort 2. No intra-subject dose escalation or 
overlapping recruitment of cohorts will be permitted.
All subjects enrolled in the study, must be evaluated for the occurrence of 
dose-limiting toxicities (DLTs) during the DLT observation window, 
which is defined as the time from the first dose of study treatment through 
3 weeks after administration of the second dose of radium-223 dichloride. 
Subjects not evaluable for assessment of DLT due to early discontinuation 
for reasons other than DLT or subjects who have not completed 2 doses of 
radium-223 dichloride and 2 cycles of BOR/DEX will be replaced until 
the MTD/RP2D has been determined.
Dose-limiting toxicities, using Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 for the severity grade, are defined as 
follows: 
1. Grade 4 neutropenia for > 7 days, or febrile neutropenia with or 
without supportive care*
2. Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with 
≥Grade 2 bleeding, or Grade 3 thrombocytopenia lasting 
> 2 weeks with or without supportive care*
3. Grade 3 to 4 anemia lasting > 2 weeks with or without supportive 
care*
4. Grade 3 non-hematological toxicity, except:

diarrhea, vomiting, and fatigue that resolve within 
72 hours with or without supportive care

neuropathy
5. Any Grade 4 non-hematological toxicity (lab abnormalities of any 
grade will not be considered toxicity unless deemed clinically 
significant by the investigator)
* Any toxicity can be treated according to the institutional guidelines 
which may include G-CSF, RBC and platelet transfusions. In order to 
determine the DLT, such supportive care measures should not be given 
prophylactically during the DLT assessment period but are allowed to start 


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after cycle 3 of BOR/DEX.
Decisions on whether to step up to the next dose level will follow the rules 
described below: 

If 0 out of 3 experience DLT: proceed to next dose level 

If 1 out of 3 experience DLT: enter 3 more subjects at this dose 
level

If 1 out of the 6 subjects experience a DLT: proceed to next dose 
level

If 2 or more subjects experience a DLT: do not proceed to next 
dose level and the current dose level will be declared as the non-
tolerable dose. The dose level immediately below will be the 
MTD/RP2D. 

If 2 subjects experience a DLT at 33 kBq/kg body weight with 
any combination, the study will be terminated.

Alternatively, once the safety and tolerability of the non-tolerable 
dose level are reviewed, the investigators and the sponsor may 
decide to investigate an appropriate dose level.
Safety monitoring will occur by telephone conferences (safety calls)
between the Investigators and Sponsor. Dose escalation meetings (DEM) 
involving the Steering Committee, Investigators, and the Sponsor will be 
organized after all subjects of each dose cohort have been sufficiently 
observed for the DLT assessment. If no DLTs are experienced in any dose 
cohort, MTD/RP2D will be based on a safety data summary review 
(including, but not limited to, AEs, dose modifications, and laboratory 
changes) conducted by the Steering Committee, participating 
Investigators, and the Sponsor. All subjects will stay in the study and 
continue receiving study drug at the assigned dose level until the 
withdrawal criteria are met or the subjects complete the study.
The Phase part 2 of the study will evaluate the activity and safety of 
radium-223 dichloride in combination with BOR and DEX versus placebo 
in combination with BOR and DEX. For the phase 2 part of the study, an 
Independent Data Monitoring Committee (IDMC) will review the safety 
data once 20 and 50 subjects have completed 2 doses of radium-223 
dichloride or placebo in combination with BOR/DEX (plus a follow-up of 
at least 3 weeks after the second radium-223 dichloride/placebo dose) 
treatment, and every 6 months thereafter. 
After the first IDMC meeting, the following events will initiate ad-hoc 
IDMC meetings: 

≥ 33% of subjects discontinue study treatment due to TEAEs or  

≥ 33% of subjects experience Grade 4 treatment-related 
hematologic toxicities. 
The IDMC members will provide recommendations about the continuation 
of study with or without any modifications based on safety data and if any 
of the stopping criteria have been observed with an absolute increase of 
≥33 percentage points in the active arm over the placebo controlled arm of 
the study (using CTCAE version 4.03 for the severity grade). Stopping 
criteria are defined as follows in alignment with the Phase 1b portion of 
the trial if they occurred within the time from the first dose of study 
treatment through 2 doses of radium-223 administration + 3 weeks after 
2nd radium-223 administration: 

Grade 4 neutropenia for > 7 days, or febrile neutropenia with or 


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without supportive care

Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with 
≥Grade 2 bleeding, or Grade 3 thrombocytopenia lasting 
> 2 weeks with or without supportive care

Grade 3 to 4 anemia lasting > 2 weeks with or without supportive 
care

Grade 3 non-hematological toxicity, except:
o
diarrhea, vomiting, and fatigue that resolve within 
72 hours with or without supportive care
o
neuropathy
Any Grade 4 non-hematological toxicity (lab abnormalities of any grade 
will not be considered a toxicity unless deemed clinically significant by 
the investigator).
The study participation for each subject in both study phases will comprise 
3 periods: screening, treatment, and the follow up period (active follow-up 
with clinic visits, as per local standard of care and long-term follow-up 
with telephone calls). A randomization step is planned for phase 2 only.
Subjects will stay in the study until they have completed the 2 year active 
follow up period after the last administration of radium-223 dichloride. 
Subjects who have completed the 2 year active follow-up will be followed 
with a telephone call every 6 months (±28 days) for up to 5 years. 
A separate long-term follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of Bayer-
sponsored clinical trials. All subjects will be asked to transition into this 
separate study to complete their long-term follow-up. The long-term 
follow-up may start in the current trial and subjects will then be asked to 
transition into the separate roll-over study.
Screening period:
Applicable to Phase 1b and Phase 2.
All trial-related procedures and evaluations will only be performed after 
the subject has agreed to participate and has signed the Informed Consent 
Form (ICF). The screening period will consist of multiple evaluations that 
will take place within 21 days starting from the time of ICF signature, to 
ensure that all eligibility criteria are met. 
Bone marrow biopsy or aspirate, skeletal survey and local blood and urine 
protein-M tests (as well as any other specific multiple myeloma tumor 
assessment blood and urine tests) previously done as part of routine care 
will be accepted for eligibility confirmation purposes even if done prior to 
ICF signature, as long as these tests have been performed up to 14 days 
prior to ICF signature. If logistical reasons require, local lab results for 
blood and urine protein-M and other specific multiple myeloma tumor 
assessment tests ordered after ICF signature can also be used for eligibility 
assessment only, to ensure that eligibility confirmation timelines are met. 
If any local lab samples are used to run tumor assessment tests for 
eligibility confirmation, blood and urine samples for central lab analysis 
will still be collected and used as the final baseline value for data analysis. 
Given the complexity of screening assessments, investigators are 
encouraged to have subjects sign ICF on the same day in which protocol 
procedures will be undertaken, to avoid starting the screening period too 
early and reducing the number of screening days actually available in 


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practice.
After eligibility has been confirmed and documented, an additional period 
of up to a total of 21 days may take place before the administration of the 
first study drug, to account for all logistical needs related to radium-223 
dichloride dose preparation and transportation. All efforts will be made to 
shorten this period as much as possible.
Randomization step (only for phase 2):
Once eligibility is confirmed and documented, eligible subjects will be 
randomized in a ratio of 1:1 to treatment with radium-223 dichloride plus 
BOR and DEX (Arm A) or placebo (isotonic saline) plus BOR and DEX
(Arm B).
Treatment period:
Phase 1b part: Treatment consists of up to 6 doses of radium-223 
dichloride (1 dose every 6 weeks) at 2 different planned dose levels 
administered to ascending dose cohorts, in combination with 10 cycles
(3 weeks per cycle for the first 8 cycles, then 4 weeks per cycle) of BOR
and DEX, followed by ongoing maintenance treatment with BOR and 
DEX (4 weeks per cycle) up to 2 years after the first dose of study 
treatment or until a PFS event occurs (death or MM progression as per 
IMWG uniform criteria), unacceptable toxicity develops, or the subject 
withdraws consent, whichever occurs first. 
Phase 2 part: Treatment consists of up to 6 doses (1 dose every 6 weeks) 
of radium-223 dichloride (Arm A) or placebo (Arm B) in combination 
with 10 cycles (3 weeks per cycle for the first 8 cycles, then 4 weeks per 
cycle) of BOR and DEX, followed by ongoing maintenance treatment with 
BOR and DEX (4 weeks per cycle) up to 2 years after the first dose of 
study treatment or until a PFS event occurs (death or MM progression as 
per IMWG uniform criteria), unacceptable toxicity develops, or the subject 
withdraws consent, whichever occurs first.
All subjects must have safety evaluations for 30 days after the last dose of 
study treatment. If the subject does not return for a 30-day safety follow-
up visit regardless of the reason, the site should at a minimum contact the 
subject for the 30-day safety follow-up by telephone, email, or letter.
Active follow-up period: 
Subjects who have discontinued study treatment for any reason including 
progressive disease (PD) will be followed with a clinical visit every 8 
weeks (±7 days) up to 2 years after the last dose of radium-223 
dichloride/placebo treatment or until death occurs, or the subject 
withdraws consent, whichever occurs first. 
During active follow-up subjects will be followed for response/disease 
progression (in case not progressed), treatment-related AEs/SAEs, any 
anti-cancer treatment and bone health agent (BHA), and SSEs.
Particularly: new primary malignancy (including AML) or hematological 
conditions (e.g., MDS, aplastic anemia, myelofibrosis) must be reported as 
SAEs at any time and regardless of the investigator’s causality assessment;
all bone fractures and bone associated events (e.g., osteoporosis) need to 
be reported as either AEs or SAEs if the criteria of SAE were met, 
regardless of the investigator’s causality assessment, through the active
follow-up. Radium-223 dichloride-related occurrences of febrile 
neutropenia or hemorrhage will also be collected.


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In addition to protocol requirements, subjects will be treated and followed 
as per the institutional standard of care and/or according to the physician’s 
clinical judgment.
Long-term follow-up period: 
Subjects who have completed the 2 year active follow-up will be followed 
with a telephone call every 6 months (±28 days) for up to 5 years. 
A separate long-term follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of Bayer-
sponsored clinical trials. All subjects will be asked to transition into this 
separate study to complete their long-term follow-up. The long-term 
follow-up may start in the current trial and subjects will then be asked to 
transition into the separate roll-over study.
During long-term follow-up subjects will be followed for survival status, 
treatment-related AEs/SAEs, any anti-cancer treatment and bone health 
agent (BHA). Particularly: new primary malignancy (including AML) or 
hematological conditions (e.g., MDS, aplastic anemia, myelofibrosis) must 
be reported as SAEs at any time and regardless of the investigator’s 
causality assessment; all bone fractures and bone associated events (e.g.,
osteoporosis) need to be reported as either AEs or SAEs if the criteria of 
SAE were met, regardless of the investigator’s causality assessment, 
through the long-term follow-up. Radium-223 dichloride-related 
occurrences of febrile neutropenia or hemorrhage will also be collected.
Subject management, unless defined otherwise in this protocol, will be in 
accordance with routine clinical practice, at the discretion of the 
Investigator. 
Type of control
Placebo in combination with bortezomib/dexamethasone (for the phase 2 
part of the study only)
Steering Committee/Data 
Monitoring Committee 
For the phase 1b part of the study, decisions involving dose escalation, 
dose de-escalation, cohort expansion, or the MTD/RP2D will be 
determined by the Steering Committee, participating Investigators, and the 
Sponsor. The Steering Committee (SC) will be established comprising 
investigators participating in the trial and external experts in the treatment 
of multiple myeloma. For the phase 2 part of the study, decisions 
involving how to proceed with blinded randomized study will be 
determined by an Independent Data Monitoring Committee (IDMC)
responsible for safety data review. 
The SC role includes providing input on study design and conduct, 
decisions during dose escalation meetings and recommendations to 
continue, modify or to stop the study. The IDMC role is to periodically 
monitor the study for safety, study progress, and protocol compliance, as 
well as to assess the risk/benefit of the trial. 
Number of subjects 
Phase 1b part: Up to approximately 12 total subjects in all dose cohorts 
combined 
Phase 2 part: Approximately 100 subjects in total (with 1:1 randomization)


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Primary variable(s)
For phase 1b part: Number of subjects with DLTs
For phase 2 part: Combined CR/VGPR rate after 6 cycles of radium-223 
dichloride, as per the IMWG uniform response criteria.
Time point/frame of 
measurement for primary 
variable(s) 
The final analysis of phase 1b data will be conducted when all subjects in 
the phase 1b part have completed 6 doses of radium 223 with the required 
safety follow up of study treatment, or have discontinued early.
For the phase 2 part, the primary analysis of combined CR/VGPR rate will 
be conducted after all subjects have completed the end of radum-223 
dichloride visit and the final analysis of combined CR/VGPR rate will be 
conducted when all subjects enrolled have completed the end of treatment 
visit (also including the maintenance therapy).
The expected study duration starts with the first study treatment and 
continues up to 2 years after last patient first treatment (LPFT), followed 
by an additional 1 month of safety follow-up.
Plan for statistical analysis
All the analyses will be performed separately for the phase 1b part and the 
phase 2 part of the study. 
For Phase 1b part, the statistical summary for the safety and efficacy 
parameters will be provided by dose level cohort.
Phase 2 part:
Safety variables will be analyzed using frequency tables and descriptive 
statistics by treatment arm.
Fisher’s exact test will be used for evaluating response rate difference 
between treatment groups. Response rate difference and its exact 95% CI 
will be provided. The descriptive statistics will also be used to summarize 
response rates (combined CR+VGPR, ORR [CR+VGRP+PR]), and anti-
multiple myeloma response assessment, as determined by International 
Myeloma Working Group (IMWG) uniform response criteria. The number 
of responders, percentage of responders and 95% confidence interval 
[CIs]) will be presented by treatment arm. 
Time to event endpoints (e.g., PFS, OS, DOR, time to SSE, time to pain 
progression and time to opioid use) will be summarized by treatment arm 
using Kaplan-Meier estimates. Kaplan-Meier curves will be generated and 
median survival time together with the 25th and 75th percentiles and 
associated Brookmeyer-Crowley 95% CIs will be presented. 
There is no formal interim analysis planned for the primary efficacy
endpoint. In the event that enrollment is halted by the IDMC after the 
review of safety data, an interim analysis may be performed on all 
randomized subjects during the phase 2.


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Table of contents
1.
Title page ............................................................................................................................2
Signature of the Sponsor’s medically responsible person.....................................................3
Signature of Principal Investigator.........................................................................................4
2.
Synopsis...............................................................................................................................5
Table of contents .....................................................................................................................16
Table of Tables........................................................................................................................20
Table of Figures.......................................................................................................................20
List of abbreviations ...............................................................................................................21
Definitions of terms.................................................................................................................25
3.
Introduction......................................................................................................................26
3.1
Background.....................................................................................................................26
3.2
Study treatments .............................................................................................................28
3.2.1
Radium-223 dichloride (BAY 88-8223, Xofigo)........................................................28
3.2.2
Bortezomib in combination with dexamethasone.......................................................29
3.2.3
Dosing rationale ..........................................................................................................30
3.2.3.1
Radium-223 dichloride ............................................................................................30
3.2.3.2
Bortezomib/dexamethasone.....................................................................................32
3.3
Study rationale................................................................................................................32
3.3.1
Benefit-risk assessment...............................................................................................34
4.
Study objectives................................................................................................................35
5.
Study design......................................................................................................................36
5.1
Design overview.............................................................................................................36
5.1.1
Study design schematic...............................................................................................37
5.1.2
Study periods and duration..........................................................................................38
5.1.3
Study endpoints...........................................................................................................43
5.2
Primary variable .............................................................................................................44
5.3
End of study....................................................................................................................45
6.
Study population..............................................................................................................45
6.1
Inclusion criteria.............................................................................................................45
6.2
Exclusion criteria............................................................................................................47
6.3
Withdrawal of subjects from study.................................................................................48
6.3.1
Withdrawal..................................................................................................................48
6.3.1.1
Withdrawal from study treatment (continue with collection of follow-up 
data)..........................................................................................................................50
6.3.1.2
Withdrawal from active and/or long-term follow-up period (no further 
data collection).........................................................................................................53
6.3.2
Replacement................................................................................................................53
6.4
Subject identification......................................................................................................53
7.
Treatment(s).....................................................................................................................54


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7.1
Treatments to be administered........................................................................................54
7.2
Identity of study treatment..............................................................................................55
7.3
Treatment assignment (phase 2 only).............................................................................55
7.4
Dosage and administration .............................................................................................56
7.4.1
Radium-223 dichloride................................................................................................56
7.4.1.1
Dose calibration .......................................................................................................57
7.4.1.2
Dose handling ..........................................................................................................58
7.4.1.3
Dose calculation.......................................................................................................58
7.4.1.4
Dose preparation......................................................................................................59
7.4.1.5
Dose administration .................................................................................................60
7.4.2
Bortezomib..................................................................................................................61
7.4.3
Dexamethasone ...........................................................................................................62
7.4.4
Dose modification, delays and treatment discontinuation guidance...........................63
7.4.4.1
Dosing criteria to administer radium-223 dichloride/placebo:................................63
7.4.4.2
Dosing criteria to administer bortezomib and dexamethasone at the start of 
a bortezomib cycle...................................................................................................63
7.4.5
Supportive care guidelines ..........................................................................................66
7.5
Blinding..........................................................................................................................67
7.6
Drug logistics and accountability...................................................................................68
7.7
Treatment compliance ....................................................................................................69
8.
Non-study therapy ...........................................................................................................69
8.1
Prior and concomitant therapy........................................................................................69
8.1.1
Prohibited concomitant therapy ..................................................................................70
8.1.2
Permitted concomitant therapy ...................................................................................70
8.1.3
Interaction potential of bortezomib with other medicinal products............................71
8.2
Post-study therapy ..........................................................................................................72
9.
Procedures and variables................................................................................................72
9.1
Tabular schedule of evaluations .....................................................................................72
9.2
Visit description..............................................................................................................83
9.2.1
Screening period..........................................................................................................83
9.2.1.1
Study Procedures .....................................................................................................83
9.2.2
Randomization ............................................................................................................86
9.2.3
Treatment period .........................................................................................................86
9.2.3.1
Day of administration of radium-223 dichloride/placebo (total of 6 doses 
to be given once every 6 weeks)..............................................................................88
9.2.3.2
Day 1 of bortezomib/dexamethasone Cycles 1 through 8 (±7 days).......................90
9.2.3.3
Days 4, 8, and 11 of bortezomib/dexamethasone Cycles 1 through 8 
(±3 days) ..................................................................................................................92
9.2.3.4
End of radium-223 dichloride/placebo visit ............................................................92
9.2.3.5
Maintenance treatment with bortezomib/dexamethasone........................................93
9.2.3.6
End of treatment visit (30 days[+7 days] post-last study treatment 
administration).........................................................................................................94
9.2.4
Active follow-up period ..............................................................................................96
9.2.5
Long-term follow-up (telephone call every 6 months [±28 days]).............................97
9.3
Population characteristics...............................................................................................98
9.3.1
Demographic...............................................................................................................98


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9.3.2
Medical history............................................................................................................98
9.3.3
Other baseline characteristics......................................................................................98
9.4
Anti-multiple myeloma activity (phase 2)......................................................................99
9.4.1
Anti-multiple myeloma activity endpoints (phase 2)..................................................99
9.4.2
Anti-multiple myeloma activity evaluation ..............................................................101
9.5
Pharmacokinetics / pharmacodynamics .......................................................................102
9.6
Safety............................................................................................................................102
9.6.1
Adverse events ..........................................................................................................103
9.6.1.1
Definitions..............................................................................................................103
9.6.1.2
Classifications for adverse event assessment.........................................................105
9.6.1.3
Assessments and documentation of adverse events...............................................107
9.6.1.4
Reporting of serious adverse events ......................................................................108
9.6.1.5
Expected adverse events ........................................................................................109
9.6.2
Pregnancies ...............................................................................................................109
9.6.3
Further safety ............................................................................................................109
9.6.3.1
Laboratory safety assessments...............................................................................109
9.6.3.2
Vital signs ..............................................................................................................109
9.6.3.3
Body weight...........................................................................................................110
9.6.3.4
Physical examination .............................................................................................110
9.7
Other procedures and variables ....................................................................................110
9.7.1
Resource utilization...................................................................................................110
9.7.2
Biomarkers ................................................................................................................110
9.7.2.1
Circulating Bone Biomarkers ................................................................................110
9.7.2.2
Circulating DNA....................................................................................................110
9.7.2.3
Circulating Tumor Cells ........................................................................................110
9.7.2.4
Tumor biomarkers..................................................................................................111
9.8
Appropriateness of procedures/measurements.............................................................111
10. Statistical methods and determination of sample size................................................111
10.1
General considerations .................................................................................................111
10.2
Analysis sets .................................................................................................................111
10.2.1
Phase 2 ......................................................................................................................111
10.3
Variables and planned statistical analyses....................................................................111
10.3.1
Phase 1b ....................................................................................................................111
10.3.2
Variables ...................................................................................................................112
10.3.3
Statistical and analytical plans ..................................................................................112
10.3.3.1
Demographics and other baseline characteristics ..................................................112
10.3.3.2
Safety analysis .......................................................................................................112
10.3.3.3
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D)...............113
10.3.3.4
Anti-multiple myeloma activity analysis...............................................................113
10.3.3.5
Biomarker analysis.................................................................................................113
10.3.4
Missing data / drop outs ............................................................................................114
10.4
Determination of sample size.......................................................................................114
10.5
Planned interim analyses ..............................................................................................115
11. Data handling and quality assurance...........................................................................115
11.1
Data recording ..............................................................................................................115
11.2
Monitoring....................................................................................................................116


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11.3
Data processing ............................................................................................................117
11.4
Missing data..................................................................................................................117
11.5
Audit and inspection.....................................................................................................117
11.6
Archiving......................................................................................................................117
12. Premature termination of the study.............................................................................118
13. Ethical and legal aspects................................................................................................119
13.1
Investigator(s) and other study personnel.....................................................................119
13.1.1
Sponsor’s medical expert ..........................................................................................119
13.1.2
External data evaluation bodies ................................................................................119
13.1.2.1
Steering Committee ...............................................................................................119
13.1.2.2
Independent Data Monitoring Committee .............................................................120
13.2
Funding and financial disclosure..................................................................................121
13.3
Ethical and legal conduct of the study..........................................................................121
13.4
Subject information and consent ..................................................................................122
13.5
Publication policy and use of data................................................................................123
13.6
Compensation for health damage of subjects/insurance ..............................................123
13.7
Confidentiality..............................................................................................................124
14. Reference list ..................................................................................................................125
15. Protocol amendments ....................................................................................................129
15.1
Amendment 1 - 08 AUG 2017 .....................................................................................129
15.1.1
Overview of changes to the study .............................................................................129
15.1.2
Changes to the protocol text......................................................................................131
15.2
Amendment 2 - 18 MAY 2018.....................................................................................132
15.2.1
Overview of changes to the study .............................................................................132
15.2.2
Changes to the protocol text......................................................................................137
16. Appendices......................................................................................................................138
16.1
National Cancer Institute-Common Terminology Criteria, version 4.03.....................138
16.2
International Myeloma Working Group (IMWG) uniform response criteria...............139
16.3
Calculation for glomerular filtration rate .....................................................................141
16.4
New York Heart Association (NYHA) functional classification.................................142
16.5
Eastern Cooperative Oncology Group (ECOG) performance status............................143
16.6
Resource Utilization Questionnaire..............................................................................144
16.7
Brief Pain Index-Short Form (BPI-SF) ........................................................................146
16.8
Interaction potential of bortezomib with other medicinal products .............................148
16.8.1
CYP3A clinical inhibitors for P450-mediated metabolisms (for concomitant 
use clinical DDI studies and/or drug labeling) (9/26/2016)......................................148
16.8.2
CYP2C19 clinical inhibitors or P450-mediated metabolisms (for 
concomitant use clinical DDI studies and/or drug labeling) (9/26/2016).................148
16.8.3
CYP3A inducers for P450-mediated metabolisms (for concomitant use 
clinical DDI studies and/or drug labeling) (9/26/2016) ............................................148


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Table of Tables
Table 7–1:  Dose modification for management of toxicities...................................................64
Table 7–2:  Recommended starting dose of bortezomib for hepatic impairment.....................65
Table 7–3: Dose modifications for neuropathy ........................................................................65
Table 9–1:  Schedule of assessments for screening and treatment period for Phase 1b and 
Phase 2 ...................................................................................................................73
Table 9–2: Schedule of assessments for maintenance period and follow-up periods (Phase 
1b and Phase 2) ......................................................................................................79
Table of Figures
Figure 5–1: Study design schematic .........................................................................................37
Figure 9–1: Schedule of drug administration for radium-223 dichloride/placebo, 
bortezomib, and dexamethasone............................................................................82


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List of abbreviations
AE
Adverse event
ADL
Activities of daily living
AL
Light-chain amyloidosis
ALP
Alkaline phosphatase
ALSYMPCA
Alpharadin in Symptomatic Prostate Cancer
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AP
Antero-posterior
APEX
Assessment of Proteosome Inhibition for Extending Remissions
AQA
Analgesic Quantification Algorithm
AST
Aspartate aminotransferase
BHA
Bone health agents
BOR
Bortezomib
BPI-SF
Brief Pain Index-Short Form 
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
con med
Concomitant medication
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CRO
Contract Research Organization
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
ctDNA
Circulating tumor DNA
CTCs
Circulating tumor cells
CTCAE 
Common Terminology Criteria for Adverse Events; version 4.03
D
Day
DEM 
Dose escalation meeting 
DES
Dose evaluable set
DEX
Dexamethasone
DK
Decay correction factor
DL
Dose level
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
EAP
Early Access Program
EBRT
External beam radiotherapy
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic case report form
EDC
Electronic data capture


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EMD
Extramedullary disease
EOS
End of study
EOT
End of treatment
EU
European Union
FDA
United States Food and Drug Administration
FEV
Forced expiratory volume 
FLC
Free light chain
G-CSF
Granulocyte colony-stimulating factor
GCP
Good clinical practice
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
HR
Hazard ratio
IC
Investigator’s choice
ICF
Informed consent form
ICH
International Conference on Harmonization
ICTP
Type I collagen telopeptide
ID
Identification number
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee 
IF
Immunofixation
IMiDs
Immunomodulatory drugs 
IMP
Investigational medicinal product
IMWG
International Myeloma Working Group
INR
International normalized ratio of prothrombin time
IRB
Institutional Review Board
ISS
International Staging System for Multiple Myeloma
ITT
Intent-to-treat
IV
Intravenous
IxRS
Interactive Voice/Web Response System
kBq
KiloBecquerel; SI unit of radioactivity
kg
Kilogram
LDH
Lactate dehydrogenase
LET
Linear energy transfer
mAbs
Monoclonal antibodies
Maint
Maintenance
mCi
Millicurie
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MR
Minimal response


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MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NIST
National Institute of Standards and Technology
NYHA
New York Heart Association
OME
Oral morphine equivalents
ORR
Objective response rate
OR
Overall response
OS
Overall survival
PA
Postero-anterior
PCP
Pneumocystis carinii pneumonia
PCR
Polymerase chain reaction 
PD
Progressive disease
PEP
Protein electrophoresis
PET-CT
Positron emission tomography – computed tomography
PFS
Progression-free survival
PI
Proteasome inhibitor
PINP
Procollagen type I N-propeptide
PK
Pharmacokinetics
POEMS
Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, 
and skin changes
PR
Partial response
PRD
Patient-ready dose
PS
Performance status
PSA
Prostate-specific antigen
PT(-INR)
Prothrombin time(-international normalized ratio)
PTT
Partial thromboplastin time
Q/q
Every
RANKL
Receptor activator for nuclear factor–κB ligand
RAVE
Medidata Rave; electronic data capture tool
RBC
Red blood cell
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
RUQ
Resource Utilization Questionnaire
SAE
Serious adverse event
SAF
Safety Set
SAP
Statistical analysis plan
SC
Subcutaneous
sCR
Stringent complete response
SCTx
Serum C-terminal cross-linking telopeptide of type-I collagen
SLAM
Signaling lymphocytic activation molecule
SD
Stable disease
SPEP
Serum protein electrophoresis
SRE
Skeletal-related event
SSE
Symptomatic skeletal event


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SUMMIT
Study of Uncontrolled Myeloma Management with proteasome 
Inhibition Therapy
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Drug half-lives
TTP
Time to progression
ULN
Upper limit of normal
UNTx
Urine N-terminal cross-linking telopeptide of type-I collagen
UPEP
Urine protein electrophoresis
US
United States
Vd
Bortezomib, dexamethasone 
VGPR
Very good partial response
WBC
White blood cell
wk
Week


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Definitions of terms
Radium-223 
dichloride 
The investigational product, a targeted alpha particle-emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous (IV) 
injection containing the drug substance radium-223 dichloride. The 
active moiety is the alpha particle-emitting nuclide radium-223, present 
as a divalent cation (223Ra2+). 
Dose 
Doses are given as kiloBecquerel (kBq) per kilogram body weight. The 
term “dose” is used to describe the quantity of radioactivity from 
radium-223 administered. 
Line of 
treatment
A line of treatment is defined as 1 or more cycles of a planned treatment 
program. This may consist of 1 or more planned cycles of single-agent 
therapy or combination therapy, as well as a sequence of treatments 
administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous stem cell 
transplantation, followed by maintenance is considered 1 line of 
treatment. A new line of treatment starts when a planned course of 
therapy is modified to include other treatment agents (alone or in 
combination) as a result of disease progression, relapse, or toxicity. A 
new line of treatment also starts when a planned period of observation 
off treatment is interrupted by a need for additional treatment for the 
disease.(1)
Study drug
For this study, the term “study drug” specifically refers to radium-223 
dichloride.
Study 
treatment
For this study, the term “study treatment” can refer to any or all of the 
drugs being investigated in this study for therapeutic intent: radium-223 
dichloride, bortezomib, and dexamethasone.


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3.
Introduction
3.1
Background
Multiple myeloma (MM) or plasma cell myeloma, globally, resulted in about 74,000 
deaths in 2010, up from 49,000 in 1990. In 2014, there were approximately 118,539 people 
in the United States (US) living with plasma cell myeloma, and according to Surveillance,
Epidemiology, and End Results data, an estimated 30,280 new cases of myeloma were 
diagnosed in 2017 in the US. The age-adjusted incidence rate for plasma cell myeloma is
6.6 per 100,000 per year.(2)
It is the third most prevalent blood cancer after non-Hodgkin's lymphoma and leukemia, 
and represents approximately 1.8% of all cancers and 2.1% of all cancer deaths.(3) Recent 
statistics indicate that the incidence has been increasing 0.8% per year based on 2011-2013 
data , while 5-year relative survival rates have also increased (from 26.3% in 1973 to 
49.6% in 2007-2013).(2)
The median age at diagnosis is 69 years. MM affects more men than women in all racial 
groups, and Afro-Caribbeans have the highest prevalence rate. The incidence of myeloma 
is reported to be 1.5 times higher in men than women, and 2 times higher among 
African-Americans than among Caucasians.(4) 
MM is a cancer of plasma cells, differentiated B-cell lymphocytes normally responsible for 
producing antibodies. In MM, collections of abnormal plasma cells accumulate in the bone 
marrow, where they interfere with the production of normal blood cells. Most cases of 
MM also feature the production of a paraprotein, an abnormal antibody which can cause 
kidney problems. Bone lesions and hypercalcemia are also often encountered.
MM is diagnosed with blood tests (serum protein electrophoresis [SPEP], serum-free 
kappa/lambda light chain [FLC] assay), bone marrow examination, urine protein 
electrophoresis (UPEP), and X-rays of commonly involved bones.
MM bone lesions are due to increased osteoclast activity and reduced osteoblast function, 
resulting from the overexpression of receptor activator for nuclear factor-κB ligand 
(RANKL) by bone marrow stroma.(5) The RANKL activates osteoclasts, which reabsorbs
bone. The resultant bone lesions are lytic in nature (cause breakdown) and are best seen in 
plain radiographs, which may show "punched-out" reabsorptive lesions (including the 
"pepper pot" appearance of the skull on radiography). Radiation therapy is sometimes used 
to reduce pain from bone lesions. Bone pain affects more than 70% of subjects and is the 
most common symptom. Myeloma bone pain usually involves the spine and ribs, and 
worsens with activity. Persistent localized pain may indicate a pathological bone fracture. 
Involvement of the vertebrae may lead to spinal cord compression. The breakdown of bone 
also leads to release of calcium into the blood, leading to hypercalcemia and its associated 
symptoms. 
The natural history of myeloma is of relapse following treatment. Multiple myeloma is 
clinically characterized beyond plasma cells abnormalities by infiltration of the bone 
marrow with differentiated plasma cells that cause lytic lesions in large bones and 
vertebrae, leading to skeletal-related events (SREs). 


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MM is considered to be incurable, but treatable. Remissions may be induced with steroids, 
chemotherapy, proteasome inhibitors (PIs), immunomodulatory drugs (IMIiDs), 
monoclonal antibodies (mAbs) and stem cell transplants. Radiation therapy is sometimes 
used to reduce pain from bone lesions. Depending on the patient's condition, the prior 
treatment modalities used and the duration of remission, options for relapsed disease 
include re-treatment with the original agent (if relapse >6 months) or use of other
alternative agents, alone or in combination. Later in the course of the disease, "treatment 
resistance" occurs. This may be a reversible effect, and some new treatment modalities 
may re-sensitize the tumor to standard therapy. 
Since 2003, bortezomib (Velcade®), the first generation proteasome inhibitor, is 
considered an important background therapy for all stages of MM, including new 
diagnosed subjects, relapsed and relapsed/refractory disease, maintenance therapy, high 
risk, and renal failure. The thalidomide derivatives, lenalidomide (Revlimid) and 
pomalidomide (Pomalyst) as well as the proteasome inhibitor carfilzomib (Kyprolis), and a 
pan-deacetylase inhibitor, panobinostat (Farydak), may be used for relapsed and refractory 
multiple myeloma. Very recently, positive data have been demonstrated with monoclonal 
antibodies (mAbs), such as elotuzumab (anti-SLAMF7 antibody) in combination with 
lenalidomide and dexamethasone and daratumumab (anti-CD38 antibody) in combination 
with bortezomib and dexamethasone.
Due to the certainty of relapse of nearly 100% subjects, relapsed/refractory MM represent 
an unmet medical need despite the new treatment options available. An established 
effective double combination treatment in early relapsed disease was
bortezomib/dexamethasone (Assessment of Proteasome Inhibition for Extending 
Remissions [APEX] study).(5;7;8). 
Most recently several phase III trials have demonstrated that triplet combinations are 
associated with a deeper response and a longer duration of response compared to doublet 
standard treatments, which may better control the emerging drug resistant clones leading to 
progression. (9)  
Monoclonal antibodies are an important new class of agents with marked activity either as 
single agent and/or in combination with in relapsed/refractory MM (6). Recently, two 
phase III trials have demonstrated that adding daratumumab to bortezomib and 
dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) (8), markedly improved 
PFS, ORR, CR and VGPR with manageable toxicities (10;11) leading to an approval of 
these two regimens as primary option for the treatment of relapsed/refractory MM subjects 
who received at least one prior line of therapy.
Overall despite the introduction of new classes of compounds in the past decade leading to 
significant PFS improvements, the use of multiple lines of therapy is limited by the 
overlapping mechanisms of action of the available agents. Therefore, there is a need for 
new agents with different mechanisms of action for subjects with relapsed or relapsed and 
refractory MM.
The infiltration of the bone marrow with differentiated plasma cells that cause lytic lesions 
in large bones and vertebrae, leading to skeletal-related events (SREs) is a characteristic of 
relapsed MM. The investigation of radium-223 dichloride in an in vivo MM model has 


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shown promising bone-targeting effects as monotherapy and in combination with 
bortezomib (12).
All together these data support the evaluation of radium-223 dichloride in the clinical 
myeloma setting 
3.2
Study treatments
3.2.1
Radium-223 dichloride (BAY 88-8223, Xofigo)
Radium-223 dichloride solution for injection is a targeted alpha particle-emitting 
radiopharmaceutical. The bone-targeting property of radium-223 is similar to that of other 
alkaline earth elements, like calcium or strontium-89. However, the radiation 
characteristics of an alpha particle-emitting radionuclide appear to be more advantageous 
than that of a beta-emitting radionuclide. Radium-223, with a physical half-life (t½) of 
11.4 days, emits high linear energy transfer (LET) alpha radiation, with a range limited to 
less than 100 micrometers. The high LET of alpha emitters (80 keV/micrometer) leads to a 
high frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor 
effect on bone metastases.(13)
Biodistribution studies have shown that radium-223 is selectively concentrated in bone 
compared to soft tissues, and that radium-223 is retained in the bone matrix.(14;15) Due to 
increased bone metabolism in skeletal metastases, preferential uptake in these lesions 
compared to normal bone is observed. Significant radium-223 anti-tumor effects have been 
demonstrated in experimental osteoblastic prostate cancer in mice (13) and osteolytic 
breast cancer skeletal metastases models in mice (16), and in rats.(14)
The clinical development of radium-223 dichloride was initiated in 2001 and consists of a 
total of 26 studies, including two Expanded Access Programs, and two Managed Access 
Programs in subjects with bone metastases from prostate cancer, breast cancer and other 
solid tumors or MM, up to the cut-off date of 14 NOV 2016. Nineteen studies, considering 
also two Expanded Access Programs and two Managed Access Programs, included only 
subjects with prostate cancer with bone metastases; three studies included only subjects 
with metastatic breast cancer (MBC) with bone metastases; while one study included 
subjects with bone metastases from prostate cancer or from breast cancer; one study 
included subjects with solid tumors and this Study included subjects with Myeloma.
Subjects who have completed treatment with radium-223 dichloride in selected clinical 
studies are included in the long-term follow-up program. The initial focus of development 
for radium-223 dichloride is metastatic prostate cancer in which eight studies have been 
conducted. 
A phase III study was conducted to evaluate the efficacy and safety of radium-223 
dichloride. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) was a 
multinational, randomized, double-blind, placebo-controlled study in subjects with 
symptomatic castration-resistant prostate cancer (CRPC) with bone metastases.(17;18;19).
The trial started in 2008 and results have been published in 2013. A total of 922 subjects 
were randomized 2:1 to receive 6 intravenous (IV) doses of either radium-223 dichloride 
or placebo every 4 weeks. Subjects were followed until 3 years from the first dose of study 
drug. The Independent Data Monitoring Committee recommended to unblind the 
ALSYMPCA trial based on results of a pre-planned interim analysis that evaluated OS.


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Based on the positive results of the ALSYMPCA study, radium-223 dichloride was 
approved in the US in May 2013 and in the European Union (EU) in November 2013 for 
the treatment of subjects with CRPC with bone metastases, and is currently marketed for 
this indication.  
Radium-223 dichloride is under clinical development for breast cancer with bone 
metastases. Further detail can be found in the IB, which contains comprehensive 
information on the study drug.
Based on the data generated in the clinical development program with radium-223 
dichloride it appeared that the safety profile of radium-223 dichloride and the treatment 
effect on bone metastases was consistent throughout the studies. 
In this study, it is proposed to investigate radium-223 dichloride for the treatment of 
relapsed multiple myeloma.
Interaction potential with other medicinal products
Radium-223 is an isotope which decays and is not metabolized by any enzyme. No impact 
on radium-223 is, therefore, expected by polymorphic enzymes. Radium-223 dichloride is 
administered intravenously; therefore, absorption-related differences are not applicable for 
this compound. Given these properties of radium-223 dichloride, it is unlikely that 
pharmacokinetic (PK) interaction may occur.
Further details regarding radium-223 dichloride can be found in the latest available version 
of the Investigator's Brochure, which contains comprehensive information on the study 
drug.
3.2.2
Bortezomib in combination with dexamethasone
Bortezomib
Bortezomib is a small, cell permeable molecule that specifically and selectively inhibits 
the proteasome by binding tightly with the enzyme’s active sites. This is the first-in-class 
of proteasome inhibitors. 
Bortezomib is indicated for treatment of subjects with multiple myeloma via subcutaneous 
(SC) or intravenous (IV) administration routes only.
According to the bortezomib prescribing information, bortezomib is contraindicated in 
subjects with hypersensitivity to the active substance, to boron, or any of the excipients.
Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include 
nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, 
neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and 
anorexia.
Overall, safety data were similar for the subcutaneous (SC) and intravenous (IV) treatment 
groups; differences were observed in the rates of some Grade ≥3 adverse reactions. 
Differences of ≥5% were reported in neuralgia (3% SC versus 9% IV), peripheral 
neuropathies (6% SC versus 15% IV), neutropenia (13% SC versus 18% IV), and 
thrombocytopenia (8% SC versus 16% IV). The incidence of Grade ≥2 peripheral 
neuropathy was 24% for SC versus 39% for IV administration and Grade ≥3 was 6% in the 
SC treatment group and 15% in the IV group. A local reaction was reported in 6% of 


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subjects in the SC group, mostly redness, resolved in a median of 6 days. Dose reductions 
occurred due to adverse reactions in 31% of subjects in the SC treatment group compared 
with 43% in the IV treatment group. (20;29)
For further details regarding bortezomib please consult specific product labeling.  
Dexamethasone
According to the dexamethasone prescribing information, risks for treatment with 
dexamethasone are summarized as follows: allergic reactions, cardiovascular events, 
dermatologic events, endocrine events, fluid and electrolyte disturbances, gastrointestinal 
events, metabolic events, musculoskeletal events, neurologic/psychiatric events, 
ophthalmic events and other such as decreased resistance to infection. (21)
The safety data of dexamethasone in subjects with relapsed multiple myeloma were 
reported from a randomized phase III trial comparing bortezomib (n=331) to 
dexamethasone (n=332) in subjects with relapsed multiple myeloma. (6;20) 
Among the bortezomib-treated subjects, the most commonly reported (>20%) adverse 
reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral 
neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and 
anorexia (21%). The most commonly reported (>20%) adverse reaction reported among 
the subjects in the dexamethasone group was fatigue (25%). Eight percent of subjects in 
the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common 
reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent of 
dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual 
dexamethasone-related Grade 4 adverse reactions were less than 1%. (20)
For further details regarding dexamethasone please consult specific product labeling.  
3.2.3
Dosing rationale
3.2.3.1
Radium-223 dichloride
In the completed phase 1 clinical study (ATI-BC-1; Study 15522), safety, tolerability, and 
PK of radium-223 dichloride have been evaluated in subjects diagnosed with prostate or 
breast carcinoma and skeletal metastases. Radium-223 dichloride was administered in 
single doses of 46, 93, 163, 213, or 250 kBq/kg body weight (n=25) or multiple doses of 
5 administrations of 50 kBq/kg body weight at 3-week intervals (n=3) or 2 administrations 
of 125 kBq/kg body weight at 6-week intervals (n=3). 
In the completed phase 2 study (BC1-02; Study 15280), 64 subjects with CRPC and 
painful skeletal metastases received 4 injections of 50 kBq/kg body weight radium-223 
dichloride (n=33) or placebo (n=31) at 4-week intervals, to examine the effects of 
radium-223 dichloride on biomarkers of disease progression, SSEs, pain palliation, 
survival, and safety parameters. 
The completed phase 3 trial, ALSYMPCA (BC1-06; Study 15245), enrolled 921 subjects 
diagnosed with CRPC and symptomatic bone metastases who received 6 injections of 
radium-223 dichloride (50 kBq/kg body weight) in 4-week intervals. Endpoints included 
OS, time to disease-related events, time to progression (TTP) as measured by serum 
prostate-specific antigen (PSA), total alkaline phosphatase (ALP) concentrations, pain 


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palliation, acute and long-term safety profile, and health-related quality of life. (Note: The 
radium-223 dichloride treatment in the ALSYMPCA CSR was calculated as 50 kBq/kg per 
NIST 2010, and would be approximately 55 kBq/kg per NIST 2015 standard.)
After discussions with the Steering Committee it was decided to administer radium-223 
dichloride every 6 weeks in the proposed trial in order to better align with the 21-day 
cycles for bortezomib and to synchronize treatment related effects from both agents and to 
allow the recovery from resulting toxicity. Furthermore, modeling simulations done for 
exposure to radium-223 in combination with chemotherapy revealed slightly less bone 
marrow suppression with 6-week intervals compared to 4-week intervals. Finally, the 
potentially longer treatment duration (6 x 6 weeks instead of 6 x 4 weeks) may be 
beneficial especially in tumor indications with relatively long time to progression.
Study 18987: Phase 1b
The phase 1b part of the study has the following dose cohorts, which will be implemented 
sequentially. The initial dose cohort utilizes a dose lower than the dose of radium-223 
dichloride monotherapy approved for CRPC (33 kBq/kg body weight ) every 6 weeks. The 
second dose level will be the approved dose 55 kBq/kg body weight). 

Cohort 1: 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 
6 radium-223 dichloride doses 

Cohort 2: 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223
dichloride doses (standard dose)
The dose escalation to the next higher dose cohort will follow a ‘3 + 3’ design as described 
in Section 5.1.2 and decisions regarding dose escalation and the MTD/RP2D will be based 
on the defined DLT. If no DLTs are experienced in any dose cohort, the MTD/RP2D will 
be based on a safety data summary review (including, but not limited to, AEs, dose 
modifications, and laboratory changes) conducted by the Steering Committee, participating 
Investigators, and Sponsor. All subjects enrolled in the Phase 1b part of the study must be 
evaluated for occurrence of DLTs during the DLT observation window, which is defined 
as the time from the first dose of study treatment through  3 weeks after second radium-
223 administration. Subjects not evaluable for assessment of DLT due to early 
discontinuation for reasons other than DLT or subjects who have not completed 2 doses of 
radium-223 dichloride and 2 cycles of bortezomib will be replaced until the MTD/RP2D
has been determined. 
Study 18987: Phase 2
The dosing regimen for the phase 2 part of the study will be selected, based on DLT and 
the safety evaluation as well as a benefit/risk evaluation of the Phase 1 doses, after the last 
subject in the phase 1b part of the study has received the first 2 doses of radium-223 
dichloride in combination with bortezomib and dexamethasone (plus a follow up of at least 
3 weeks) as described (Section 5.1.2). In the phase 2 part, subjects will be randomly 
assigned (1:1) to receive either the selected dose of radium-223 dichloride or matching 
placebo once every 6 weeks for a total of 6 doses. 


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3.2.3.2
Bortezomib/dexamethasone
The proposed background treatment for subjects both the Phase 1b and Phase 2 parts of the 
study is bortezomib (1.3 mg/m2/dose) administered SC on Days 1, 4, 8, and 11 and 
dexamethasone administered orally at 40 mg, on Days 1, 4, 8, and 11 in a 21-day cycle for 
8 cycles. For extended therapy beyond 8 cycles, bortezomib/dexamethasone will be 
administered on Days 1 and 15 of a 28-day cycle at the same dose for bortezomid and 
dexamethasone will be administered at 20 mg for up to 2 years after the first dose of study 
treatment. The maintenance bortezomib injection schedules are based upon dosing 
schedules cited in the IMWG consensus on maintenance therapy in MM as tolerable and 
effective. (22;23)
Bortezomib initially received approval in Europe based on the results of the large phase 2
SUMMIT (Study of Uncontrolled Myeloma Management with proteasome Inhibition 
Therapy) trial, which evaluated bortezomib monotherapy in subjects with multiple 
myeloma who were refractory to prior therapies. The trial enrolled 202 subjects and 
bortezomib produced a 35% overall response rate, including 10% complete or near-
complete responses. Median TTP was 7 months, and median OS was 16 months.(24)
These results gained bortezomib approval for use in third-line treatment or later. The
confirmatory phase 3 APEX trial compared bortezomib with dexamethasone in 
669 subjects with relapsed/refractory multiple myeloma.(6) More than one-third of these 
subjects had received only 1 previous regimen. The combined response rate and complete 
response (CR) rates induced by bortezomib were statistically superior. Median times to 
disease progression in the bortezomib and dexamethasone groups were 6.2 and 3.5 months, 
respectively. Median OS for subjects receiving bortezomib was 29.8 months compared 
with 23.7 months for those receiving dexamethasone; this remained statistically significant 
despite the fact that 62% of subjects in the dexamethasone arm crossed over to bortezomib
upon progression. (25).
Studies comparing bortezomib alone versus bortezomib combined with dexamethasone 
have shown an advantage for the combined treatment. The addition of dexamethasone to 
bortezomib treatment in 22 subjects with relapsed and/or refractory MM with less than 
optimal response to bortezomib treatment alone resulted in improved response without 
increased AEs.(26) A recent retrospective matched-pairs analysis of 109 pairs of subjects 
with relapsed MM from 3 trials (MMY-2045, APEX, and DOXIL-MMY-3001) showed 
significantly higher response rates and longer median TTP and PFS for bortezomib/ 
dexamethasone combination versus bortezomib-alone.(27)
3.3
Study rationale
Over the last decade, the survival of MM patients has significantly improved due to the 
autologous stem cell transplantation in younger patients and the introduction of drugs such 
as the immunomodulatory agents (IMiDs) thalidomide, lenalidomide and pomalidomide, 
and the proteasome inhibitors (PI) bortezomib, carfilzomib and ixazomib. However, the 
majority of patients relapse even when intensive therapy is combined with IMiDs and PIs.
(28) In patients who had progressive MM after at least one previous treatment the median 
OS is about 30 months (25). In this population the median time to progression (TTP)/ PFS 
is in the range of 6 to 9 months with doublet combinations such as: iv bortezomib ± 
dexamethasone (25), 10.4 months for sc bortezomib ± dexamethasone (29) and 11.1 to 


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11.3 months for lenalidomide+dexamethasone (30;31). The duration of response (DOR)
has been reported to decrease with each relapse from 9.9 months from diagnosis to first 
relapse, to 3.2 months from diagnosis to sixth relapse. (32)
Recently novel agent-based triplet combinations demonstrated superior response rates and 
prolonged disease control when compared with two-drug regimens in several randomized 
clinical trials. (33) The median PFS with triplet PI/IMiDs/dexamethasone combinations 
was 26 months for lenalidomide/dexamethasone (Rd) ± carfilzomib; (34) 20.6 months for 
Rd ± ixasomib (35) and with panobinostat/bortezomib/dexamethasone 12 months for Vd± 
panobinostat. (36)
Most recently monoclonal antibodies (mAbs) emerged as promising therapeutic options in 
MM. Elotuzumab, (anti-SLAMF7 antibody) is the first mAb approved based on PFS 
improvement in combination with lenalidomide/dexamethasone (19.4 months) compared 
to lenalidomide/dex (14.9 months) (37). 
The anti-CD38 mAb daratumumab is the second mAb approved in MM. Two phase III 
trials have demonstrated that adding daratumumab to bortezomib/dexamethasone (DVd) or 
lenalidomide/dexamethasone (DRd), markedly improved PFS, ORR, complete response 
(CR) and very good partial response (VGPR) for patients with recurrent/refractory MM 
with manageable toxicities leading to an accelerate approval. The median PFS was 
16.7 months for DVd, while in the control group it was 7.2 months for bortezmib/
dexamethasone. (10;11) 
Bone involvement represented by osteolytic bone disease is one of the main characteristics 
of MM. Bone marrow infiltration by neoplastic plasma cells causes irreversible alteration 
in structure and function of microenvironment components. Osteolytic bone disease is a 
consequence of increased osteoclast activation via cytokine deregulation along with 
osteoblast inhibition, resulting in altered bone remodeling. (5) As a consequence of altered 
bone remodeling, 80% to 90% of patients with multiple myeloma develop bone lesions 
that can cause skeletal-related events (SREs) such as bone pain, fractures, spinal cord 
compression, and hypercalcemia.(38) The occurrence of SREs has been linked to inferior 
survival, reduced quality of life and increased healthcare costs for MM patients. (5; 39;40;
41;42;43) 
Bisphosphonate therapy is the main treatment for bone disease in multiple myeloma for 
reduction of SREs; however, this treatment comes with risk of decreased renal function in 
patients with renal impairment and osteonecrosis of the jaw.(44;45)  
Therefore an optimal drug targeting the metastatic bone niche would have dual activity, on 
tumor cells and the microenvironment, leading to both direct and indirect antitumor 
effects. One such class, a mainstay of myeloma treatment, is proteasome inhibitors; 
particularly bortezomib has been shown direct toxicity on both tumor and bone cells. 
Bortezomib-related bone effects are due to enhanced osteoblastogenesis by negatively 
regulating RANKL, and impaired osteoclast differentiation/ survival by reducing NF-kB.
Bortezomib also appears to decrease the serum levels of DKK-1 and RANKL in MM 
patients. (46;47)
The use of radium-223 dichloride for patients with MM is of interest due to its effects on 
bone lesions, including in combination with bortezomib as demonstrated in  preclinical 


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study. Radium-223 dichloride has shown significant anti-tumor activity in phase 2 and 3 
trials in subjects with bone metastatic CRPC.(48) Data derived from the systemic, 
syngeneic 5TGM1 mouse model support the development of radium-223 dichloride in 
combination with bortezomib. Single-agent treatment with radium-223 dichloride, as well 
as with bortezomib reduced osteolysis, and additive/synergistic effects were observed from 
combination treatment with bortezomib. In addition, concurrent treatment with bortezomib 
increased radium-223 dichloride uptake in MM-bearing bone. The strong additive effects 
of the combined radium-223 dichloride/bortezomib treatment led to an eradication of 
osteoclasts at the tumor-bone interface, thereby addressing a key pathological mechanism 
of MM. Furthermore, the combination treatment was well tolerated (12;13). 
The potential benefits in radium-223 dichloride treatment in combination with bortezomib/
dexamethasone in MM patients include:

May increase the response rate 

Long-term local disease control through internal-focused radiation exposure of 
multiple myeloma lesions, resulting in cellular damage of the tumor and re-
activation of antigen exposure and immunological response seen in earlier disease 
settings

Improved quality of life through reduced pain and bone structural decompensation 
as a result of the reversal of bone/bone marrow progressive disease (PD)

Further follow-up treatment and potentially extended PFS and/or OS
Although both radium-223 dichloride and bortezomib may cause gastrointestinal adverse 
reactions and myelosuppression, no major overlapping toxicities from the combination are 
expected. As it is possible that an increase of hematologic toxicities could be also observed 
due to pre-treatment options and the disease focus in the bone marrow, close monitoring of 
hematologic parameters (complete blood count, etc.) and the dose-escalation part of the 
study is planned to identify potential exacerbation of hematologic AEs due to the disease 
setting and/or co-treatment. Dose modification guidelines for each study agent are 
provided in Section 7.4.
As an optimal dose of radium-223 dichloride in combination with bortezomib and 
dexamethasone has not yet been established in MM patients, a dose-escalation part has 
been included in this study. Two dose levels have been selected: 33 and 55 kBq/kg. 
Dose escalation will follow a 3+3 design as described in Section 5.1. The MTD/RP2D
dose defined from the review of safety data and DLT events will be implemented in the
future phase 2/3 studies. 
3.3.1
Benefit-risk assessment
Preclinical data with radium-223 dichloride in combination with bortezomib showed an 
almost complete eradication of MM-associated osteoclasts in a mouse model. Adding 
radium-223 dichloride to the established therapy of relapsed MM patients is expected to 
positively impact patient outcomes (i.e., PFS, pain, SSEs, OS). Transient hematologic 
Grade 3 or 4 AEs (anemia, leukocytopenia, and thrombocytopenia) are possible due to 
synergistic effects from the disease setting, pre-treatment options, and radium-223 
dichloride and bortezomib-related side effects.


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Based on preclinical data and the known safety profile of radium-223 dichloride observed 
to date in studies for prostate cancer and the need to improve PFS and OS in relapsed 
multiple myeloma patients, the potential benefits of the combination of radium-223 
dichloride with bortezomib exceed the potential risks in this patient population. The 
expected AE profile for this combination is expected to be within the scope of the current 
treatments available for this patient population.
Therefore, the sponsor considers the overall benefit-risk profile of the proposed 
combination to be favorable for this clinical study.
4.
Study objectives
Phase 1b part (open-label) 
Primary objectives:

To evaluate the safety of the combination of radium-223 dichloride plus 
bortezomib (BOR) and dexamethasone (DEX)

To determine the dose of radium-223 dichloride that will be used in the phase 2 
part of the study (maximum tolerated dose [MTD] or recommended phase 2 dose 
[RP2D]) 
Secondary objectives:

To evaluate the combined complete response (CR) + very good partial response 
(VGPR), as determined by International Myeloma Working Group (IMWG) 
uniform response criteria
Phase 2 part (double-blind, randomized) 
Primary objectives:

To compare radium-223 dichloride versus placebo in addition to background 
treatment with BOR plus DEX in terms of CR+VGPR rate in relapsed multiple 
myeloma subjects, as determined by International Myeloma Working Group 
(IMWG) uniform response criteria.
Secondary objectives:

To evaluate safety

To evaluate the objective response rate (ORR), as determined by IMWG uniform 
response criteria

To evaluate overall survival (OS) 

To evaluate progression-free survival (PFS)

To evaluate duration of response (DOR)
Exploratory objectives:

To evaluate time to first on-study symptomatic skeletal event (SSE)

To evaluate bone biomarkers


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
To evaluate change in bone lesions

To evaluate change in MM disease markers

To evaluate circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs)

To evaluate time to opioid use for cancer pain in subjects without opioid use at 
baseline

To evaluate time to pain progression
5.
Study design
5.1
Design overview
This study will be conducted in 2 parts. The phase 1b part will be an international, phase 
1b, open-label, dose-escalation assessment of radium-223 dichloride administered with 
bortezomib and dexamethasone in subjects with relapsed MM. The phase 2 part will be an 
international, phase 2, double-blind, randomized, placebo-controlled assessment of 
radium-223 dichloride versus placebo administered with bortezomib and dexamethasone, 
in subjects with relapsed MM.
Up to approximately 12 total subjects in the 2 dose cohorts combined will be treated in the 
phase 1b part of the study and approximately 100 subjects will be enrolled in the phase 2 
part of the study.


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5.1.1
Study design schematic
Figure 5–1: Study design schematic
Abbreviations: IV=intravenous; DLT=Dose-limiting toxicity; DEM=dose escalation meeting BOR=bortezomib; 
DEX=dexamethasone; MTD=maximum tolerated dose; RP2D=recommended phase 2 dose; w=weeks
Dose escalation will follow a ‘3 + 3’ design based on defined DLT. The DLT observation window is defined as 
the time from the first dose of study treatment through 21 days after administration of the second dose of 
radium-223 dichloride. Decisions on whether to step up to the next dose level will follow the conventional 
3 + 3 rules. 
*The maintenance treatment for Cohort 1 and Cohort 2 will consist of bortezomib and dexamethasone 
administered on Days 1 and 15 of a 28-day cycle for up to 2 years after the first dose of study treatment
or until a PFS event occurs, unacceptable toxicity develops, or the subject withdraws consent, whichever 
occurs first.
Cohort 1: Radium-223 dichloride 
33 KBq/Kg  +  BOR/DEX 
DLT window ≥ 9 weeks (2 injections Xofigo +3w) 
DEM 3 subjects evaluable for DLT
≤1 DLT in 3- 6 subjects
Cohort 2: Radium-223 dichloride 
55 KBq/Kg  +  BOR/DEX 
DLT window ≥ 9 weeks (2 injections Xofigo +3w) 
DEM 3 subjects evaluable for DLT
Randomized Phase 2: 
Radium-223 dichloride at the MTD/RP2D) + BOR/DEX 
versus Placebo +BOR/DEX
≤1 DLT in 3- 6 subjects
Arm A Treatment Period:
Radium-223 dichloride +
Bortezomib and Dexamethasone 
Maintenance Treatment:
Bortezomib and Dexamethasone * for up 
to 2 years from first dose
Arm B Treatment Period:
Placebo (saline) + 
Bortezomib and Dexamethasone 
Maintenance Treatment:
Bortezomib and Dexamethasone * for up 
to 2 years from first dose
Long-term Follow-up Period
Subjects who completed active follow-up 
Telephone call every 6 months (± 28 days) up to 5 years or death or consent withdrawal. 
The long-term follow-up will start in the current trial and may be pursued in a separate roll-over 
study; the overall duration of the active and long-term follow-up is up to 7 years or until death 
occurs, or the subject withdraws consent, whichever occurs first.
Active Follow-up Period
Subjects who discontinued treatment 
Clinic visit every 8 weeks (± 7 days) up to 2 years after last Radium-
223 dichloride dose or death or consent withdrawal.


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5.1.2
Study periods and duration
The phase 1b part of the study will evaluate 2 dose levels of radium-223 dichloride in 
combination with bortezomib and dexamethasone in subjects with relapsed multiple 
myeloma. Subjects will be treated at the different dose levels of radium-223 dichloride 
sequentially. The starting dose is 33 kBq/kg body weight every 6 weeks, which is a dose 
lower than the dose of radium-223 dichloride monotherapy approved for CRPC 
(55 kBq/kg body weight). The dose of 55 kBq/kg body weight every 6 weeks for up to a 
total of 6 doses is evaluated in the Cohort 2.
The dose escalation will follow a ‘3 + 3’ design. No intra-subject dose escalation or 
overlapping recruitment of cohorts will be permitted. 
All subjects enrolled in the Phase 1b part of the study must be evaluated for the occurrence 
of DLTs during the DLT observation window, which is defined as the time from the first 
dose of study treatment through 3 weeks after second radium-223 administration
(approximately 9 weeks). Subjects not evaluable for assessment of DLT due to early 
discontinuation for reasons other than DLT or subjects who have not completed 2 doses of 
radium-223 dichloride and 2 cycles of bortezomib will be replaced until the MTD/RP2D
has been determined. 
Dose-limiting toxicities, using CTCAE version 4.03 for the severity grade, are defined as 
follows:
1. Grade 4 neutropenia for > 7 days, or febrile neutropenia with or without supportive 
care*
2. Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, or 
Grade 3 thrombocytopenia lasting > 2 weeks with or without supportive care*
3. Grade 3 to 4 anemia lasting > 2 weeks with or without supportive care*
4. Grade 3 non-hematological toxicity, except:

diarrhea, vomiting, and fatigue that resolve within 72 hours with or without 
supportive care

neuropathy
5. Any Grade 4 non-hematological toxicity (lab abnormalities of any grade will not be 
considered toxicity unless deemed clinically significant by the investigator)
* Any toxicity can be treated with supportive care according to the institutional 
guidelines which may include G-CSF, RBC and platelet transfusions. In order to 
determine the DLT, such supportive care measures should not be given 
prophylactically during the DLT assessment period but are allowed to start after 
cycle 3 of BOR/DEX.


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Decisions on whether to step up to the next dose level will follow the rules described 
below: 

If 0 out of 3 subjects experience DLT: proceed to next dose level 

If 1 out of 3 subjects experience DLT: enter 3 more subjects at this dose level

If 1 out of the 6 subjects experience a DLT: proceed to next dose level

If 2 or more subjects experience a DLT: do not proceed to next dose level and the 
current dose will be declared as the non-tolerable dose. The dose level immediately 
below will be the MTD/RP2D. If this occurs during the first dose cohort, the study 
will be terminated. 
Safety monitoring will occur by telephone conferences between the Investigators and 
Sponsor on a regular basis. If no DLTs are experienced in any dose cohort, MTD/RP2D
will be based on a safety data summary review (including, but not limited to, AEs, dose 
modifications, and laboratory changes) conducted by the Steering Committee, participating 
Investigators, and the Sponsor.  
All Phase 1b subjects will stay in the study and continue receiving study drug at the 
assigned dose level until withdrawal criteria are met.
The Phase 2 part of the study will evaluate the activity and safety of radium 223 dichloride
in combination with bortezomib and dexamethasone versus placebo in combination with 
bortezomib and dexamethasone. For the phase 2 part of the study, an Independent Data 
Monitoring Committee (IDMC) will review the safety data once 20 and 50 subjects have 
completed 2 doses of radium-223 dichloride or placebo in combination with 
bortezomib/dexamethasone (plus a follow-up of at least 3 weeks after the second 
radium 223 dichloride/placebo dose) treatment, and every 6 months thereafter. 
After the first IDMC meeting, the following events will initiate ad-hoc IDMC meetings: 

≥ 33% of subjects discontinue study treatment due to TEAEs or  

≥ 33% of subjects experience Grade 4 treatment-related hematologic toxicities. 
The IDMC members will provide recommendations about the continuation of study with 
or without any modifications based on safety data and if any of the stopping criteria have 
been observed with an absolute increase of ≥ 33 percentage points in the active arm over 
the placebo controlled arm of the study (using CTCAE version 4.03 for the severity grade). 
Stopping criteria are defined as follows in alignment with the Phase 1b portion of the trial
if they occurred within the time from the first dose of study treatment through 2 doses of 
radium-223 administration + 3 weeks after 2nd radium-223 administration: 

Grade 4 neutropenia for > 7 days, or febrile neutropenia with or without supportive 
care

Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with ≥ Grade 2 bleeding, or 
Grade 3 thrombocytopenia lasting > 2 weeks with or without supportive care

Grade 3 to 4 anemia lasting > 2 weeks with or without supportive care

Grade 3 non-hematological toxicity, except:


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o
diarrhea, vomiting, and fatigue that resolve within 72 hours with or without 
supportive care
o
neuropathy

Any Grade 4 non-hematological toxicity (lab abnormalities of any grade will not be 
considered toxicity unless deemed clinically significant by the investigator)
The study participation for each subject in both study parts will comprise 3 periods: 
screening, treatment, and the follow up period (active follow-up with clinic visits and long-
term follow-up with telephone calls). A randomization step is planned for phase 2 only.
Subjects will stay in the study until they completed the 2 year active follow-up period after 
the last administration of radium-223 dichloride.
Subjects who have completed the 2 year active follow-up will be followed with a 
telephone call every 6 months (±28 days) for up to 5 years. 
A separate long-term follow-up study has been set up to follow subjects who received 
radium-223 dichloride or placebo in the course of Bayer-sponsored clinical trials. All 
subjects will be asked to transition into this separate study to complete their long-term 
follow-up. The long-term follow-up may start in the current trial and subjects will then be 
asked to transition into the separate roll-over study.
Screening period:
All trial-related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the Informed Consent Form (ICF). 
The screening period will consist of multiple evaluations that will take place within 
21 days starting from the time of ICF signature to ensure that all eligibility criteria are met.
Bone marrow biopsy or aspirate, skeletal survey and local blood and urine protein-M tests 
(as well as any other specific MM tumor assessment blood and urine tests) previously done 
as part of routine care will be accepted for eligibility confirmation purposes even if done 
prior to ICF signature, as long as these tests have been performed up to 14 days prior to 
ICF signature. If logistical reasons require, local lab results for blood and urine protein-M 
and other specific MM tumor assessment tests ordered after ICF signature can also be used 
for eligibility assessment only, to ensure that eligibility confirmation timelines are met. If 
any local lab samples are used to run tumor assessment tests for eligibility confirmation, 
blood and urine samples for central lab analysis will still be collected and used as the final 
baseline value for data analysis. Given the complexity of screening assessments, 
investigators are encouraged to have subjects sign ICF on the same day in which protocol 
procedures will be undertaken, to avoid starting the screening period too early and 
reducing the number of screening days actually available in practice. 
After eligibility has been confirmed and documented, an additional period of up to a total 
of 21 days may take place before the administration of the first study drug, to account for 
all logistical needs related to radium-223 dichloride dose preparation and transportation. 
All efforts will be made to shorten this period as much as possible.


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Randomization step (phase 2 only):
Once eligibility is confirmed and documented, eligible subjects in phase 2 part of the study 
will be randomized in a ratio of 1:1 to treatment with radium-223 dichloride plus 
bortezomib and dexamethasone (Arm A) or placebo (isotonic saline) plus bortezomib and 
dexamethasone (Arm B). 
Treatment period:
Treatment consists of:

Phase 1 b part: up to 6 doses (1 dose every 6 weeks) of radium-223 dichloride at 
2 different doses administered to ascending dose cohorts, in combination with 
10 cycles (dosing on Days 1, 4, 8, and 11 of a 3-week cycle for the first 8 cycles, 
then dosing on Day 1 and 15 of a 4-week cycle) of bortezomib and dexamethasone, 
followed by ongoing maintenance treatment with bortezomib and dexamethasone
(dosing on Day 1 and 15 of a 4-week cycle) up to 2 years after the first dose of 
study treatment or until a PFS event occurs(death or MM progression as per IMWG 
uniform criteria), unacceptable toxicity develops, or the subject withdraws consent, 
whichever occurs first. 

Phase 2 part: up to 6 doses (1 dose every 6 weeks) of radium-223 dichloride 
(Arm A) or placebo (Arm B) in combination with 10 cycles (dosing on Days 1, 4, 
8, and 11 of a 3-week cycle for the first 8 cycles, then dosing on Day 1 and 15 of a 
4-week cycle) of open label bortezomib and dexamethasone, followed by ongoing 
maintenance treatment with bortezomib and dexamethasone (dosing on Day 1 and 
15 of a 4-week cycle) up to 2 years after the first dose of study treatment or until a 
PFS event occurs (death or MM progression as per IMWG uniform criteria), 
unacceptable toxicity develops, or the subject withdraws consent, whichever occurs 
first.
Subjects will be evaluated for AEs, serious AEs (SAEs), and SSEs at every visit. Subjects 
will be assessed for response/disease progression and pain endpoints on Day 1 of Cycle 1 
and every 3 weeks (±7 days) through Cycle 8 and every 4 weeks thereafter.
Subjects will start treatment with bortezomib and dexamethasone on the same day as the 
first dose of radium-223 dichloride/placebo. All subjects receive supportive care, as per 
local standard of practice.
Subjects who experience disease progression per IMWG criteria will discontinue all study 
treatment. Subjects should not discontinue treatment if they experience a new skeletal 
event not due to PD (e.g., spontaneous fracture based on existing bone lesion). If, however, 
the start of a new anti-cancer treatment is required, all study treatment will be permanently 
discontinued, and the subject should enter the long-term follow-up period.
Subjects who discontinue radium-223 dichloride/placebo treatment prior to experiencing 
an SSE or a PFS event can continue to receive bortezomib/dexamethasone treatment if 
considered by the Investigator to be in the subject’s best interest and will be followed up 
for SSEs and response/disease progression.


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Subjects who discontinue bortezomib/dexamethasone treatment prior to experiencing an 
SSE or a PFS event should also discontinue radium-223 dichloride/placebo treatment and 
be followed up for SSEs and response/disease progression.
Subjects who discontinue only DEX may continue with the other treatment (radium-223
dichloride/placebo and/or BOR).
The treatment period extends from the day of the first dose of radium-223 dichloride/ 
placebo to 30 days (+7-day window) after the last dose of study treatment (i.e., radium-223 
dichloride/placebo, bortezomib, or dexamethasone, whichever occurs last). All subjects 
must have safety evaluations for 30 days after the last dose of study treatment. If the 
subject does not return for a 30-day safety follow-up visit regardless of the reason, the site 
should at a minimum contact the subject for the 30-day safety follow-up by telephone, 
email, or letter.
Background treatment
Bortezomib will be administered subcutaneous (SC) at 1.3 mg/m2/dose, on Days 1, 4, 8,
and 11 in a 21-day cycle, for 8 cycles.
For extended therapy beyond 8 cycles, BOR will be administered on Days 1 and 15 of a
28-day cycle for up to 2 years after the first dose of study treatment, or until a progression-
free survival (PFS) event occurs, the subject withdraws consent or unacceptable toxicity 
develops, whichever occurs first.
Dexamethasone will be administered orally at 40 mg, on Days 1, 4, 8, and 11 in a 21-day
cycle, for 8 cycles. DEX administration may be split over 2 days (on the day of BOR
administration and the day after BOR administration) at the discretion of the Investigator.
For extended therapy beyond 8 cycles, DEX will be administered orally at 20 mg/dose, on 
Days 1 and 15 of a 28-day cycle along with BOR for up to 2 years after the first dose of 
study treatment, or until a progression-free survival (PFS) event occurs, the subject 
withdraws consent or unacceptable toxicity develops, whichever occurs first.
Radium-223 dichloride/placebo
Radium-223 dichloride/placebo will be administered concomitantly with BOR/DEX. Only 
for Cycle 1 on Day 1, radium-223 dichloride/placebo will be administered before 
BOR/DEX.
Subjects with radium-223 dichloride/placebo administration delayed from the date of the 
intended dose may receive the subsequent cycles of radium-223 dichloride/placebo at 
another day other than Day 1 of BOR/DEX planned schedule.
All subjects must have safety evaluations for 30 days after the last dose of study treatment. 
If the subject does not return for a 30-day safety follow-up visit regardless of the reason, 
the site should at a minimum contact the subject for the 30-day safety follow-up by 
telephone, email, or letter.
Active follow-up period: 
Subjects who have discontinued study treatment for any reason including PD will be 
followed with a clinic visit every 8 weeks (±7 days) up to 2 years after the last dose of 


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radium-223 dichloride/placebo treatment or until death occurs or the subject withdraws 
consent, whichever occurs first. 
During active follow-up subjects will be followed for response/disease progression (in case 
not progressed), treatment-related AEs/SAEs, any anti-cancer treatment and bone health 
agent (BHA), and SSEs.
Particularly: new primary malignancy (including AML) or hematological conditions (e.g.,
MDS, aplastic anemia, myelofibrosis) must be reported as SAEs at any time and regardless 
of the investigator’s causality assessment; all bone fractures and bone associated events 
(e.g., osteoporosis) need to be reported as either AEs or SAEs if the criteria of SAE were 
met, regardless of the investigator’s causality assessment, through the long-term follow-up. 
Radium-223 dichloride-related occurrences of febrile neutropenia or hemorrhage will also 
be collected. 
In addition to protocol requirements, subjects will be treated and followed as per the 
institutional standard of care and/or according to the physician’s clinical judgment. 
Long-term follow-up period: 
Subjects who have completed the 2 year active follow-up will be followed with a 
telephone call every 6 months (±28 days) up to 5 years. 
A separate long-term follow-up study has been set up to follow subjects who received 
radium-223 dichloride or placebo in the course of Bayer-sponsored clinical trials. All 
subjects will be asked to transition into this separate study to complete their long-term 
follow-up. The long-term follow-up may start in the current trial and subjects will then be 
asked to transition into the separate roll-over study.
During long-term follow-up subjects will be followed for survival status,  treatment-related 
AEs/SAEs, any anti-cancer treatment and bone health agent (BHA). Particularly: new 
primary malignancy (including AML) or hematological conditions (e.g., MDS, aplastic 
anemia, myelofibrosis) must be reported as SAEs at any time and regardless of the 
investigator’s causality assessment; all bone fractures and bone associated events (e.g.,
osteoporosis) need to be reported as either AEs or SAEs if the criteria of SAE were met, 
regardless of the investigator’s causality assessment, through the long-term follow-up.
Radium-223 dichloride-related occurrences of febrile neutropenia or hemorrhage will also 
be collected.
Subject management, unless defined otherwise in this protocol, will be in accordance with 
routine clinical practice, at the discretion of the Investigator.
5.1.3
Study endpoints
Phase 1b
Primary endpoint:

Number of subjects with DLTs treated with radium-223 dichloride in combination 
with BOR/DEX.

Maximum tolerated dose/recommended phase 2 dose of radium-223 dichloride in 
combination with BOR/DEX


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Secondary endpoints:

Combined number of complete response (CR) + very good partial response (VGPR) 
evaluation
Phase 2
Primary endpoint

Combined CR+VGPR rate as determined by IMWG uniform response criteria
Secondary endpoints

Number of subjects with adverse events

Objective response rate (ORR), as determined by IMWG uniform response criteria

Overall survival (OS)

Progression-free survival (PFS)

Duration of response (DOR)
Exploratory endpoints:

Time to first on-study SSE

Bone biomarkers, including but not limited to urine N-terminal cross-linking 
telopeptide of type-I collagen (UNTx), serum C-terminal cross-linking telopeptide 
of type-I collagen (SCTx), total alkaline phosphatase (ALP), bone-ALP (B-ALP), 
procollagen type I N-propeptide (PINP), and type I collagen telopeptide (ICTP)

Change in the number of active bone lesions (for PET-CT, X-ray, MRI, or low-dose 
CT) and/or the intensity of PET uptake (for PET-CT) from baseline to the follow-up 
evaluation.

Change in MM disease markers:

Change in M-protein 

Evaluate potentially predictive biomarker candidates (ctDNA, CTCs, MM 
related citokines)

Time to opioid use for cancer pain in subjects without opioid use at baseline

Time to pain progression
5.2
Primary variable
Phase 1b:
Safety
o
The incidence of DLTs will be used to determine the MTD/RP2D.
o
The incidence of treatment-emergent adverse events (TEAEs), drug-related 
TEAEs, and treatment-emergent serious adverse events.


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Phase 2:
o
CR/VGPR rate, as per the IMWG uniform response criteria
5.3
End of study
For each participating EU country, the end of study (EOS) according to the EU Clinical 
Trial Directive will be reached when the last visit of the last subject in any site in the EU 
has occurred.
The EOS as a whole will be reached as soon as the EOS according to the above definition 
has been reached in all participating countries (EU and non-EU).
The primary completion of this study will be conducted when all subjects enrolled in 
Phase 2 part have completed the end of radum-223 dichloride visit and the final analysis 
will be conducted when all subjects enrolled have completed the end of treatment visit 
(including the maintenance therapy).
6.
Study population
All the inclusion and exclusion criteria below have to be fulfilled 
6.1
Inclusion criteria
Subjects must meet all the following criteria for inclusion in the study:
1. Males or females ≥18 years of age
2. Have provided written informed consent. Subjects must be able to understand and be 
willing to sign the written informed consent, expressing their willingness and ability to 
comply with protocol-required treatment and assessment schedule, including follow-up 
visits. A signed informed consent form (ICF) must be appropriately obtained prior to 
the conduct of any trial-specific procedure.
3. Subject must have documented monoclonal plasma cells in the bone marrow of ≥10%, 
as defined by their institutional standard at some point in their disease history or the 
presence of a biopsy proven plasmacytoma.
4. Subjects must have received at least 1 and not more than 3 previous lines of treatment 
and have had a response to at least 1 prior treatment in the past (i.e., achieved a 
minimal response [MR] or better) according to the IMWG uniform response criteria
Section 16.2.
5. Subject must be non-refractory to bortezomib (Refractory is defined: progression of 
disease while receiving bortezomib therapy or within 60 days of ending bortezomib 
therapy)
6. Subjects must have documented evidence of progressive disease according to the 
IMWG uniform response criteria following the last multiple myeloma treatment.
7. Subjects must have measurable disease defined as at least 1 of the following:
-
Serum M-protein defined by the following:


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o
IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level 
≥1.0 g/dL (measured by protein electrophoresis [PEP])
o
IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL
(measured by PEP)
-
Urine M-protein ≥200 mg/24 hours (any immunoglobulin heavy chain type
measured by PEP)
-
Serum free light chain (FLC) ≥10 mg/dL with abnormal ratio in subjects with 
unmeasurable disease by serum or urine PEP.
8. ≥1 bone lesion identifiable by radiograph, computed tomography (CT), positron 
emission tomography – computed tomography (PET-CT), or magnetic resonance 
imaging (MRI).
9. Life expectancy of at least 3 months.
10. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2.
11. For subjects experiencing toxicities resulting from a previous therapy (including 
peripheral neuropathy), the toxicities must be resolved or stabilized to ≤Grade 1.
12. Adequate hepatic function, with total bilirubin ≤1.5 x upper limit of normal (ULN) 
(except for Gilbert Syndrome: total bilirubin <3.0 x ULN), and aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x ULN.
13. Absolute neutrophil count (ANC) ≥1.5 x 109/L, hemoglobin (Hb) ≥9.0 g/dL, and 
platelet count ≥75.0 x 109/L independent of transfusion of red blood cells (RBC) or 
platelet concentrates and independent of granulocyte colony-stimulating factor 
(G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
Note: Transfusion of RBC or platelet concentrates, use of G-CSF or GM-CSF within 
21 days from ICF signature are not allowed.
14. International normalized ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤1.5 x 
ULN. Prothrombine time (PT) may be used instead of INR if ≤1.5 x ULN.
15. Estimated creatinine clearance of ≥30 mL/minute, according to the Cockcroft and 
Gault formula.
16. Serum potassium levels >3.0 mEq/L
17. Corrected serum calcium <14.0 mg/dL (3.5 mmol/L)
18. Female subjects of child-bearing potential must have a negative urine pregnancy test 
within 72 hours before the first dose. Postmenopausal females (age ≥55 years and 1 
year or more of amenorrhea; or age <55 years and 1 year or more of amenorrhea with 
an estradiol assay <20 pg/mL; or bilateral oophorectomy) and surgically sterilized 
females are exempt from a pregnancy test.
a) Female subjects of child-bearing potential who are sexually active must agree to 
utilize 2 reliable and acceptable methods of contraception used simultaneously: a 
barrier method such as (i) condoms (male or female) with spermicidal agent, or (ii) 
diaphragm or cervical cap with spermicide, combined with a highly effective non 
hormonal birth control method such as intra-uterine device, during treatment with 


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and for 6 months following the last dose of radium 223 dichloride/placebo or 3 
months after the last administration of bortezomib/dexamethasone, whichever 
occurs later.
b) Male subjects with partners of child-bearing potential must be willing to use 2 
reliable and acceptable methods of birth control (including adequate barrier 
protection) used simultaneously as determined to be acceptable by the principal 
investigator and the sponsor during the study and for 6 months following 
completion of treatment with radium-223 dichloride/placebo or 3 months after the 
last administration of bortezomib/dexamethasone, whichever occurs later. The 
contraception measures must be discussed with the subject. Suitable contraception 
could be, for example, the use of condoms combined with an oral contraceptive 
taken by the female partner of a study subject.
6.2
Exclusion criteria
Subjects must not meet any of the exclusion criteria listed below:
1. Systemic glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within 
the last 4 weeks prior to first dose, unless tapered and on a stable dose (prednisone ≤10 
mg/day orally or equivalent) for at least 1 week
2. Subjects with known POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes) or light chain (AL) 
amyloidosis
3. Plasma cell leukemia (defined by plasma cell >20%, and/or an absolute plasma cell 
count of >2 x 109/L in peripheral blood)
4. Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic 
(PK) half-lives (t1/2) of the treatment, whichever is longer, before the date of start of 
treatment.
5. Radiation therapy in the previous 4 weeks prior to first dose. Note: Subjects treated 
with local radiotherapy which is recommended to be limited fields for pain control are 
eligible.
6. Administration of an investigational therapeutic study drug (including investigational 
vaccines) within 4 weeks or within 5 PK (t1/2) of the treatment, whichever time is 
greater, before the date of start of treatment.
7. Prior treatment with radium-223 dichloride or any experimental radiopharmaceutical.
8. Major surgery within 4 weeks prior to first dose (central line placement and 
kyphoplasty are not considered major surgery).
9. Congestive heart failure (New York Heart Association [NYHA] class III to IV), 
symptomatic cardiac ischemia, unstable angina or myocardial infarction in the previous 
6 months prior to first dose, or with a known left ventricular ejection fraction (LVEF) 
<40%, cardiomyopathy, pericardial disease, clinically relevant cardiac arrhythmia 
(CTCAE version 4.03 Grade 2 or higher), clinically significant ECG abnormalities, or 
screening 12-lead ECG showing a baseline prolonged QT interval (baseline QT 
interval as corrected by Fridericia’s formula > 470 msec).


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Note: LVEF values will not be collected, however the investigator must verify and 
subjects must be excluded if LVEF < 40% at study entry.
10. Acute diffuse infiltrative pulmonary disease.
11. Acute active infection requiring systemic antibiotics, antivirals or antifungals within 
2 weeks prior to first dose.
12. Known HIV infection or subjects who are known to be HIV seropositive.
13. Subjects with active hepatitis B or C infection at screening. Subjects with a known 
history of occult hepatitis B virus (HBV) infection (defined as positive hepatitis B core 
antibody [HBcAb] and negative hepatitis B surface antigen [HBsAg]), but who have 
undetectable HBV DNA at screening may be included. Subjects with a history of 
positive hepatitis C virus (HCV) antibody must be negative for HCV RNA by
polymerase chain reaction (PCR) assessment or similar technology to be included.
14. Any history of malignancy within the past 3 years except adequately treated 
a) basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, 
c) prostate carcinoma in situ < Gleason Score 6 with stable prostate-specific antigen 
(PSA), or d) breast carcinoma in situ.
15. Neuropathy ≥Grade 2 
16. Subjects with pleural effusions requiring thoracentesis or ascites requiring 
paracentesis.
17. Subjects with known meningeal and/or extramedullary involvement of MM.
18. Known allergies, hypersensitivity or intolerance to radium-223 dichloride, bortezomib 
or dexamethasone or their excipients.
19. Any clinically significant medical disease or condition that, in the Investigator's 
opinion, may interfere with protocol adherence or a subject's ability to give informed 
consent. 
20. Female subjects who are pregnant or lactating.
21. Serious psychiatric condition that could interfere with compliance of treatment.
22. Close affiliation with the investigational site (e.g., a close relative of the Investigator, 
dependent person, employee or student of the investigational site).
23. Previous assignment to treatment during this study.
6.3
Withdrawal of subjects from study
6.3.1
Withdrawal
Study treatment discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study. Every effort should be made to retain subjects who 
discontinue treatment for any reason and encourage them to remain in the study for follow 
up of primary, secondary and other objectives (i.e., continue in safety follow-up, active 
follow-up and/or long-term follow up for up to 5 years).


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Subjects qualifying for follow-up are expected to participate in the follow-up unless they 
explicitly object. Withdrawal of consent to treatment should be documented in the 
subject’s medical file. If subjects do not wish to be followed up further, they should sign 
the “Declaration of Objection to Collection of Study Data after Withdrawal of Consent” 
form as an additional consent withdrawal for follow up. 
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records (consent withdrawal [due to AE or for other 
reason], lost to follow-up, or death).
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below.
Screening failure
A subject who, for any reason (e.g., failure to satisfy the selection criteria) terminates the 
study before the first dose of radium-223 dichloride for phase 1b or before randomization 
for Phase 2 is regarded as a “screening failure”. 
If one or more screening laboratory tests do not support eligibility, laboratory re-test is 
permitted only once and after Sponsor approval has been documented. Only the laboratory 
tests with results which are out of range of eligibility need to be repeated. However 
absolute neutrophil, hemoglobin, and platelet count must be in the range of eligibility 
criteria independently of transfusion of red blood cells (RBC) or platelet concentrates and 
independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage 
colony stimulating factor (GM-CSF). 

The laboratory re-tests must be completed within 21 days of the original ICF 
signature. If the tests cannot be performed or their results will not be available 
within 21 days of the original ICF signature subject is considered a screen failure. 
These subjects can still undergo a new full re-screening after signing a new ICF.

The re-testing of blood and urine M-protein, β2 microglobulin, cytogenetic and 
bone marrow MM assessment due to their original test results being outside of 
protocol required limits is not allowed.
Re-screening of screen-failed subjects may only be allowed once after discussion with the 
medical monitor of the Sponsor and after his/her approval. Sponsor approval of 
re-screening must be documented. Re-screening may be considered under the following 
circumstances:

Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired may need the screening procedures to be repeated in order to be within the 
window required prior to enrollment. 

Re-screening is also permitted when the screening procedures for subject's 
eligibility expired due to completion of wash-out periods as per protocol, in case of 
expiry of investigational product that requires replacement, or for extraordinary 
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
Re-screening is also permitted when the screening failure was due to intercurrent 
infection if not >45 days from date of screen failure AND subject has been off of 
treatment for infection for at least 7 days or M-protein not meeting the criterion of 
measurable disease during screening

Subjects who need to repeat the screening procedures have to sign a new ICF. 
Screening procedures will be repeated again, as necessary, to meet the timeframe 
required per protocol and the eligibility criteria. Such subjects will obtain a new 
subject number after signing their 2nd ICF.  
In any case, the Investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk. 
Rescreening of a subject as per the rules outlined above can only be attempted once.
Once the number of subjects screened and enrolled is likely to ensure target enrollment, 
the Sponsor may close the study to further screening. In this case, the subjects who screen 
failed will not be permitted to rescreen.
Information to be collected on screening failures
Subjects who sign an ICF but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered 
eCRF. The demographic information, informed consent, and Inclusion/Exclusion pages 
must also be completed for Screen Failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a 
Serious Adverse Event during the Screening Phase. 
Dropout
A “dropout” is defined as a subject who has received the first dose of study treatment and 
discontinues study participation prematurely for any reason.
General procedures
The subject may object to the generation and processing of post-withdrawal data as 
specified in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.3.1.1
Withdrawal from study treatment (continue with collection of 
follow-up data)
The total treatment period is defined from the initiation of treatment until 30 days 
(+7 days) after the last administration of study treatment (radium-223 dichloride/placebo, 
BOR and DEX, whichever occurs last).


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Subjects must be withdrawn from the radium-223 dichloride/placebo treatment for the 
following reasons:

If, in the Investigator's opinion, continuation of the radium-223 dichloride/placebo
treatment would be harmful to the subject's well-being

If the subject experiences a DLT (phase 1b) defined as follows:
•Grade 4 neutropenia for > 7 days, or febrile neutropenia with or without 
supportive care *
•Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with Grade 2 
bleeding, or Grade 3 thrombocytopenia lasting > 2 weeks with or 
without supportive care *
•Grade 3 to 4 anemia lasting > 2 weeks with or without supportive care *
•Grade 3 non-hematologic toxicity, except: 

diarrhea, vomiting, and fatigue that resolve within 72 hours with or 
without supportive care

neuropathy
•Any Grade 4 non-hematological toxicity (lab abnormalities of any grade will 
not be considered toxicity unless deemed clinically significant by the 
investigator) (For laboratory-related Grade 4 toxicities, refer to Section 
7.4.4)
* Any toxicity can be treated with supportive care according to the institutional 
guidelines which may include G-CSF, RBC and platelet transfusions. In order to 
determine the DLT, such supportive care measures should not be given 
prophylactically during the DLT assessment period but are allowed to start after cycle 
3 of BOR/DEX.

Delay in radium-223 dichloride/placebo administration of >28 days due to toxicity 
from the intended dosing date (maximum of 10 weeks between 2 consecutive doses 
of radium-223 dichloride/placebo). 
Note: If the delay in radium-223 dichloride/placebo administration of >28 days from 
the intended dosing date (maximum of 10 weeks between 2 consecutive doses of 
radium 223 dichloride/placebo) is due to logistics supplying, for subjects with clear 
benefit (based on the IMWG criteria) the investigator will evaluate on an individual 
basis whether the study treatment may be continued or discontinued in agreement 
with the Sponsor.
Subjects with radium-223 dichloride/placebo administration delayed from the date of 
the intended dose may receive the subsequent cycles of radium 223 
dichloride/placebo at another day other than Day 1 of BOR/DEX planned schedule.
Subjects may be withdrawn from the radium-223 dichloride/placebo treatment for the 
following reason*:

If within the time from the first dose of study treatment through 2 dose of radium-
223 administration + 3 weeks after 2nd radium-223 administration the subject 


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experiences one of the stopping criteria, defined as follows in alignment with the 
Phase 1b portion of the trial:
•Grade 4 neutropenia for > 7 days, or febrile neutropenia with or without 
supportive care **
•Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with Grade 2 
bleeding, or Grade 3 thrombocytopenia lasting > 2 weeks with or 
without supportive care **
•Grade 3 to 4 anemia lasting > 2 weeks with or without supportive care **
•Grade 3 non-hematologic toxicity, except: 

diarrhea, vomiting, and fatigue that resolve within 72 hours with or 
without supportive care

neuropathy
•Any Grade 4 non-hematological toxicity (lab abnormalities of any grade will 
not be considered toxicity unless deemed clinically significant by the 
investigator) (For laboratory-related Grade 4 toxicities, refer to Section 
7.4.4) 
* If a subject experiences a clinical benefit from treatment, the subject can continue to 
receive radium-223 dichloride treatment if considered by the Investigator to be in the 
subject’s best interest. 
** Any toxicity can be treated with supportive care according to the institutional 
guidelines which may include G-CSF, RBC and platelet transfusions. In order to 
determine the DLT, such supportive care measures should not be given 
prophylactically during the DLT assessment period but are allowed to start after cycle 
3 of BOR/DEX.
The subject can continue to receive bortezomib/dexamethasone treatment if considered by 
the Investigator to be in the subject’s best interest and will continue to be followed as per 
protocol up to 5 years after the last dose of radium-223 dichloride/placebo, or death, or the 
subject withdraws consent, whichever occurs first. 
Subjects must be withdrawn from all study treatment for the following reasons:

If, in the Investigator's opinion, continuation of study treatment would be harmful to 
the subject's well-being including unacceptable toxicity related to study treatment

Delay in BOR administration of >28 days due to toxicity from the intended day of 
the next scheduled dose.

If the subject starts a new systemic anti-cancer treatment (Section 8.1.1)

At her/his own request or at the request of her/his legally acceptable representative. 
At any time during the study and without giving reasons, a subject may decline to 
participate further. The subject will not suffer any disadvantage as a result.

At the specific request of the Sponsor and in liaison with the Investigator 
(e.g., obvious non-compliance, safety concerns)


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6.3.1.2
Withdrawal from active and/or long-term follow-up period (no 
further data collection)
Subjects must be withdrawn from the follow-up procedures and no further data will be 
collected for the following reasons:

Subject withdraws consent from study and objects to any further data collection or 
study-related procedures. A subject must be removed from the study at her/his own 
request or at the request of her/his legally acceptable representative. At any time 
during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result. In this case, the 
subject has to expressively inform the Investigator and sign the Declaration of 
Objection to the Collection of Study Data after Withdrawal of Consent as an 
additional consent withdrawal for follow up. The objection is also valid, if the 
declaration is not in place for any reason, but the Investigator documented the 
objection in the files.

Subject is lost to follow-up

Death
6.3.2
Replacement
During the phase 1 b part of the study, any subject who terminates treatment before 
administration of the first 2 doses of radium-223 dichloride, for reasons other than DLT, 
will be replaced until the MTD/RP2D has been determined. Subjects in the Phase 2 will 
not be replaced.
Replacement of subjects will ensure collection of data on the safety profile of radium-223 
dichloride in combination with BOR/DEX in accordance with the dose escalation ‘3 + 3’ 
design based on defined DLT.
6.4
Subject identification
A subject number (a unique identification number) will be assigned via an Interactive 
Voice/Web Response System (IxRS) when a subject signs the ICF and is evaluated for 
inclusion into the study. When the subject is eligible for the trial, the study site will send 
an order (using the IxRS) to the manufacturer for drug shipment based on the planned visit 
date of the subject. See Section 7.3.
Subjects who meet re-screening eligibility and are re-screened will be assigned a new 
subject number in IxRS. See Section 6.3.1.
The subject number is a 9-digit number consisting of:
Digits 1 to 5 = Unique center number
Digits 6 to 9 = Current subject number within the center.


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7.
Treatment(s)
7.1
Treatments to be administered
Investigational medicinal product (IMP): Radium-223 dichloride at the specified dose 
will be administered IV as a slow bolus injection for a total of up to 6 doses at intervals of 
6 weeks. Please refer to Section 7.4.1 for details regarding radium-223 dichloride dosage 
and administration. Please refer to Section 7.4.4 for dose reduction, dose interruption, and 
discontinuation.
For the phase 1b part of the study, up to 2 dose levels of radium-223 dichloride may be 
administered, following sequential dose escalation using a ‘3 + 3’ design: 

Cohort 1: 33 kBq/kg body weight every 6 weeks for a total of 6 radium-223 
dichloride doses in combination with BOR and DEX

Cohort 2: 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 
dichloride doses in combination with BOR and DEX
Phase 2 part (double-blinded, randomized)

For the phase 2 part of the study, the MTD/RP2D of radium-223 dichloride, as 
determined by the phase 1b part of the study, will be administered once every 
6 weeks for a total of 6 doses.
Reference therapy:
Phase 2 part (double-blinded, randomized)
During the phase 2 part of the study, a placebo solution of isotonic saline (0.9% sodium 
chloride solution for injection) will be administered IV as a slow bolus injection 6 times, at 
intervals of 6 weeks. The isotonic saline will be provided by the study center. Traceability 
of the respective manufacturers and batches will be maintained in the respective 
preparation documentation and drug accountability logs.
It is important to note that, in general (unless otherwise agreed; e.g., for sites using 
patient-ready dose [PRD] depots [Section 7.4.1.2]), in cases where study drug has been 
ordered, the time window for administration should be within 3 days of the scheduled 
treatment visit. If administration must be postponed more than 3 days after the scheduled 
treatment visit, replacement of the drug order may be required. 
Background treatment:
Phase 1b and Phase 2 parts
Bortezomib will be administered subcutaneous (SC) at 1.3 mg/m2/dose, on Days 1, 4, 8, 
and 11 in a 21-day cycle, for 8 cycles. 
For extended therapy beyond 8 cycles, BOR will be administered on Days 1 and 15 of a 
28-day cycle for up to 2 years after the first dose of study treatment, until a progression-
free survival (PFS) event occurs, or the subject withdraws consent or unacceptable toxicity 
develops, whichever occurs first.
Please refer to Section 7.4.2 for details regarding BOR dosage and administration.


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Dexamethasone will be administered orally at 40 mg, on Days 1, 4, 8, and 11 in a 21-day 
cycle, for 8 cycles. DEX administration may be split over 2 days (on the day of BOR
administration and the day after BOR administration) at the discretion of the Investigator.
For extended therapy beyond 8 cycles, DEX will be administered orally at 20 mg/dose, on 
Days 1 and 15 of a 28-day cycle along with BOR for up to 2 years after the first dose of 
study treatment, or until a progression-free survival (PFS) event occurs, the subject 
withdraws consent or unacceptable toxicity develops, whichever occurs first.
Please refer to Section 7.4.3 for details regarding DEX dosage and administration.
Radium-223 dichloride/placebo will be administered concomitantly with BOR and DEX. 
Subjects with radium-223 dichloride/placebo administration delayed from the date of the 
intended dose may receive the subsequent cycles of radium 223 dichloride/placebo at 
another day other than Day 1 of BOR/DEX planned schedule.
Only for Cycle 1 on Day 1, radium-223 dichloride/placebo will be administered before 
BOR/DEX.
Please refer to Section 7.4.4 for dose reduction, dose interruption, and discontinuation for 
BOR and DEX. Dose modifications and administration of BOR and DEX must be in 
compliance with the local labels in each of the participating countries and in line with 
standard practice guidelines.
7.2
Identity of study treatment
The Sponsor will supply radium-223 dichloride, and may supply BOR and DEX which
will be labeled according to the requirements of local law and legislation. Label text will 
be approved according to the Sponsor’s agreed procedures, and a copy of the respective 
local labels will be made available to the study site upon request.
Local sourcing of the background treatments BOR, and DEX might be considered. Locally 
sourced medication will be handled according to the local procedures and will not be 
labelled study specific.
For radium-223 dichloride, a system of numbering in accordance with all requirements of 
Good Manufacturing Practice (GMP) will be used, ensuring that each dose of study 
treatment can be traced back to the respective bulk batch of the ingredients. Lists linking 
all numbering levels will be maintained by the Sponsor’s clinical supplies Quality 
Assurance group. 
Placebo (isotonic saline) will be provided by the study site.
A complete record of batch numbers and expiry dates of all centrally or locally sourced 
study treatment as well as the labels for the centrally supplied study treatments needs to be 
filed in the Sponsor’s study file.
7.3
Treatment assignment (phase 2 only)
To accomplish random assignment of radium-223 dichloride/placebo treatment, a 
computer generated randomization list will be prepared by the Sponsor and provided to the 
IXRS. The IXRS will assign each eligible subject a randomization number and the 
respective treatment in a ratio of 1:1 to radium-223 dichloride:placebo. 


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The IXRS will provide only the randomization number to the caller (i.e., blinded 
personnel), but not the assigned treatment. A confirmation e-mail containing 
randomization number and treatment will be sent to the unblinded staff member who will 
be responsible for preparing the study drug for the subject for the first administration. 
When the subject is allocated to radium-223 dichloride, the unblinded person will use 
IXRS to send an order to the manufacturer for drug shipment. The timing for the drug 
order should be based on the planned subject visit date. If the subject is allocated to 
placebo, the unblinded person at the study site will be responsible for providing isotonic 
saline corresponding to the IXRS treatment day. This should not be made available before 
to avoid unblinding the subject and blinded study personnel. 
Subsequent orders for each study drug administration will be made by accessing the IXRS 
from the study site on the date of the previous dose. If, after ordering, the order needs to be 
cancelled or amended, the Investigator should contact their monitor immediately.
7.4
Dosage and administration
7.4.1
Radium-223 dichloride
The Sponsor will provide radium-223 dichloride, which is manufactured by Bayer AG. 
Radium-223 dichloride is produced according to GMP and will be delivered with a 
certified activity. This alpha particle-emitting radiopharmaceutical is shipped in a lead 
container and a Type A radioactive package according to international transportation 
guidelines for radioactive materials. 
Radium-223 dichloride should be received, used and administered only by authorized 
personnel in designated clinical settings. The receipt, storage, use, transfer and disposal of 
radium-223 dichloride is subject to the regulations and/or appropriate licenses of the 
competent official organization. 
The volume per vial is 6 mL, corresponding to 6.6 MBq, at the calibration reference day. 
Radium-223 dichloride has a shelf-life of 28 days from production day, when stored at 
ambient temperature. The shelf-life is valid for all climate zones I to IV. In addition, it has 
been shown that the product quality is not jeopardized upon freezing. 
The dose should be ordered through IxRS as soon as possible prior to the planned date of 
administration. The subject’s weight taken 3 to 5 days (for US sites) or within 3 days (for 
ex-US sites) before radium-223 dichloride dosing will be submitted with the dose request. 
The site is not required to assess safety labs prior to placing the order.
It is important to note that, in general (unless otherwise agreed; e.g., for sites using PRD 
depots [Section 7.4.1.2]), in cases where study drug has been ordered, the time window for 
administration should be within 3 days of the scheduled treatment visit. If administration 
must be postponed more than 3 days after the scheduled treatment visit, replacement of the 
drug order may be required.
Written information about radium-223 dichloride and instruction about storage, handling,
and injection of radioactive material will be provided to study personnel. 
In general, the administration of radioactive drugs involves a potential risk for third 
parties, due to radiation from the subject and due to possible contamination by spilling 


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urine or feces or vomit. When radium-223 dichloride has been injected intravenously into 
a subject, the risk for external radiation exposure to third parties is extremely low, due to 
the short range of the alpha particles (<100 μm) and the low portion of beta and gamma 
radiation. For these reasons the product can be administered on an outpatient basis. 
To minimize the risk of contamination, the subject and her/his caregivers will be provided 
with instructions regarding hygiene precautions to abide by after receiving the radioactive 
drug according to the investigational study site radiation protection guidelines. 
These instructions will be given to all subjects, as neither the Principal Investigator nor 
subject will know the subject’s assignment to radium-223 dichloride or placebo doses.
7.4.1.1
Dose calibration
Radium-223 dichloride can be measured in a normal dose calibrator instrument. When all 
the required written approvals for the use and handling of radium-223 dichloride from the 
Radiation Protection Agency/Agencies for the specific site have been received by the 
Sponsor, a vial of radium-223 dichloride for technical use may be sent to the study site, if 
the site is not already a qualified user of radium-223 dichloride.
Different clinical study sites possess dose calibrators from various suppliers; thus, the 
isotope calibration factor may differ from site to site. Consequently, each site must 
perform the radium-223 dial-setting on their relevant dose calibrator(s) if no isotope 
calibration factor for radium-223 is being provided by the vendor of the dose calibrator. 
For dial-setting, the clinical study site will receive a sealed vial or a prefilled syringe 
containing a radium-223 solution for calibration only. The vial or syringe is identical to the 
vials/syringes used for study treatment. The amount of radium-223 in the vial/syringe will 
be stated on the label. Instructions for the dial-setting, including the calibration log form, 
will be enclosed with the dispatch of the calibration sample.
As of 2015, NIST has established an updated standardization for radium-223 dichloride, 
which indicates that an approximately 10 % difference existed between activity values 
obtained using the former standard and the updated standardization. The updated 
standardization was implemented in April 2016. (49)
The change in the NIST radium-223 standard has no impact on subjects; subjects are 
receiving, and will continue to receive, the same actual dose and volume that was studied 
in ALSYMPCA and is associated with the proven safety and efficacy of radium-223 
dichloride, though the stated nominal radiation dose received is being updated to reflect 
the new standard. 


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7.4.1.2
Dose handling
At least 2 unblinded personnel should be nominated at each study site (Section 7.5). The 
primary dedicated unblinded person (“the unblinded person”), who has the responsibility 
delegated from the Principal Investigator, will be responsible for the safe handling and 
storage of radium-223 dichloride and placebo control. The unblinded person also has the 
responsibility of correctly receiving and recording the delivery of radium-223 dichloride in 
accordance with this protocol. At least one deputy unblinded person should also be 
nominated. Radium-223 dichloride should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides.
The radium-223 dichloride vials or PRDs must be stored inside their lead container in a 
secure facility. The study drug should be used within 28 days of production or prior to the 
expiry date specified for PRDs. 
Control measurements of both the radium-223 dichloride vial (before and after dispensing) 
and syringes (before and after administration) are performed as part of the clinical trial 
documentation. Since PRDs will be prepared at the country depot, relevant procedures are 
recorded by the country depot staff. All administrations of radium-223 dichloride will be
based on the certified activity of radium-223 at the reference date. Please note that all 
documentation that contains unblinded information must be kept by the unblinded 
person(s) and not shared with the other study site personnel during the conduct of the 
study.
7.4.1.3
Dose calculation
For this study, two dose levels of radium-223 dichloride are planned:

33 kBq/kg body weight 

55 kBq/kg body weight 
The total activity to be injected will be calculated volumetrically using the subject’s body 
weight (kg) within 3 days prior to the dose for ex-US sites or 3 to 5 days prior to the dose
for US sites, the dosage level, and the decay correction factor (DK) to correct for physical 
decay of radium-223 (ex-US sites only). A table with DKs according to physical decay of 
the study medication will be provided with each vial of radium-223 dichloride (ex-US sites 
only). The total amount (volume to be drawn into the syringe) to be administered to a 
subject should be calculated according to the recommended formula below for each dose 
group:

33 kBq/kg 
Body Weight (kg) x 33 kBq/kg
= volume to be injected (mL)
DK x 1,100 kBq/mL

55 kBq/kg 
Body Weight (kg) x 55 kBq/kg
= volume to be injected (mL)
DK x 1,100 kBq/mL


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Site specific volume calculation methods are acceptable as well, provided that the subject 
dose is as indicated above. 
For the phase 2 part of the study, the most appropriate dose level will be selected based on 
the safety results of the phase 1b part of the study. The dosing calculation above that 
corresponds to the dose level chosen will be used.
Data regarding activity, calculations (ex-US sites only), and volume to be injected must be 
recorded in the IMP preparation log and in the study electronic data capture (EDC) tool 
(Medidata Rave [RAVE]) by the unblinded person. This applies to both doses that are 
prepared at the study site and doses that are prepared by an off-site vendor. 
In the US, applicable documentation is required for the country PRD depot. The subject’s 
weight will be obtained only once for each dose. To ensure time for the country PRD depot 
to prepare and deliver the PRDs to the sites:

The subject’s weight will be obtained 3 to 5 days before the planned dosing date

This weight will be communicated to the country PRD depot for preparation of the 
current dose along with a prescription and any other details required by the PRD 
depot; a record of this information transfer will be retained at the site

Documentation by the PRD depot of the required activity and volume in the syringe 
will be retained at the depot with a copy provided to the site
Subjects at ex-US sites should be reweighed on the day of dose administration; the final 
dose to be administered should be determined using that weight. Subjects should not be 
weighed more than once or at different departments on the day of the administration to 
avoid the potential use of different weights. Subjects in the US will receive patient-ready 
doses based on the subject weight 3 to 5 days before the day of administration. Therefore, 
no other weight measurement is needed.
For subjects randomized to receive placebo, the volume of isotonic saline to be injected
will be provided by the IXRS based on the subject’s weight and the saline solution will be
prepared by the unblinded site staff. Data regarding the isotonic saline batch number and
the volume to be injected should be recorded in the eCRF by unblinded staff.
7.4.1.4
Dose preparation
To keep the treating physician blinded to the assignment of study medication, the 
unblinded person (e.g., from the hospital pharmacy or nuclear medicine department) will 
be responsible for blinding the syringe, and responsible for calculating the required 
dosage. Data regarding activity and volume to be injected should be recorded in the IMP 
preparation log and in the appropriate eCRF, both of which will not be available to the
treating physicians. Copies of the vial label and the syringe serial number are to be 
attached with each entry in the IMP preparation log. Additional written instructions for 
study drug administration, for blinded and unblinded personnel will be provided.
Personnel should use appropriate protective clothing and equipment during syringe filling 
and application to prevent contamination with the radioactive solution (lab coats, medical 
gloves, protective glasses) and to reduce radiation exposure. Sites should adhere to all 


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relevant radiation safety regulations as prescribed by local authorities administering their 
site radiation license, including as low as reasonably achievable principles. 
Filling of the syringe should take place in a safety bench or similar cabinet in the 
Radiopharmacy/Nuclear Medicine Department. The individual responsible for study drug 
preparation will draw the correct volume of study drug into a syringe. The size of the 
syringe should be chosen according to the applied volume to reach the required dosing 
accuracy. In some countries/study sites, a third party vendor will be used to prepare the 
injections to be used by the study site. 
Radium-223 dichloride should not be diluted or mixed with any solutions. If the vials have 
been stored in a refrigerator, they should be left at room temperature for 1 hour prior to 
use, since cold material should not be injected in a subject.
For subjects in the placebo arm, a syringe with isotonic saline will be prepared in the same
way as for the active treatment.
It is important to note that, in general (unless otherwise agreed, e.g., for sites using PRD 
depots [Section 7.4.1.2]), in cases where study drug has been ordered, the time window for 
administration should be within 3 days of the scheduled treatment visit. If administration 
must be postponed more than 3 days after the scheduled treatment visit, replacement of the 
drug order may be required. The same process must be followed, regardless of treatment
arm assignment, to maintain the study blind.
The study drug will be administered as a slow bolus IV injection. The actual radioactivity 
administered must be within the tolerance limits of 10% of the calculated radioactivity.
After administration, the equipment used in connection with the preparation and 
administration of drug, are to be treated as radioactive waste and should be disposed in 
accordance with hospital procedures for the handling of radioactive material and according 
to local laws. Written information about radium-223 dichloride and instructions for the 
handling and injection of radioactive material will be provided to study personnel.
7.4.1.5
Dose administration
Every effort will be made to administer the full dosing regimen (6 doses of radium-223 
dichloride or placebo). Dose adjustment of radium-223 dichloride/placebo is not permitted. 
The minimum time window between 2 doses of radium-223 dichloride/placebo must be 
6 weeks. 
Radium-223 dichloride/placebo administration may be delayed if medically necessary. 
Preferably, the next dose should be administered within a 2-week delay; however, a 
maximum of 28 days from the date of the intended dose is allowed (i.e., a maximum of 
10 weeks between 2 consecutive doses) for recovery of AEs. If administration is delayed 
beyond this window due to toxicity, the subject must permanently discontinue radium-223 
dichloride/placebo administration. Treatment delays or discontinuations of radium-223 
dichloride/placebo may be instituted as described in Section 7.4.4. 
Subjects with radium-223 dichloride/placebo administration delayed from the date of the 
intended dose may receive the subsequent cycles of radium 223 dichloride/placebo at 
another day other than Day 1 of BOR/DEX planned schedule.
BOR administration may be delayed if medically necessary.


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If BOR administration is delayed >28 days from the intended day of the next scheduled 
dose due to toxicity, the subject must be permanently discontinued from background 
treatment.
In case BOR have to be permanently discontinued, radium-223 dichloride/placebo will 
also be discontinued.
7.4.2
Bortezomib
Bortezomib (BOR) is part of background treatment in this study for subjects enrolled in all 
cohorts and may be provided with appropriate labelling by the Sponsor, where local 
sourcing is not applicable. Local sourcing might be considered. Locally sourced 
medication will be handled according to the local procedures and will not be labelled study 
specific. It is required, at minimum, that the batch numbers and expiry dates are recorded.
In case BOR is supplied centrally the IxRS allocates one vial per treatment to a subject. 
Subjects enrolled will start treatment with BOR on the same day as the first dose of 
radium-223 dichloride/placebo.
BOR is a small, cell permeable molecule that specifically and selectively inhibits the 
proteasome by binding tightly with the enzyme’s active sites. This is the first-in-class of 
proteasome inhibitors. It is supplied in single use vials of BOR as lyophilized powder for 
SC injection. Unopened vials may be stored at controlled room temperature 25ºC (77ºF); 
excursions permitted from 15°C to 30ºC (59°F to 86ºF). Retain in original package to 
protect from light. 
The dose of BOR administered in the study is 1.3 mg/m2/dose. Subjects previously treated 
with BOR can receive a starting dose at the last tolerated dose (minimum 0.7 mg/m2/dose).

The amount (in mg) of BOR administered will be determined based on body surface 
area (BSA). Body surface area should be calculated using a standard nomogram 
(this can be the site’s institutional standard formula). 
o
To calculate the BSA is recommended to use Gehan and George Equation: 
BSA (m2) = 0.0235 x height(cm)0.42246 x weight(kg)0.51456 However, the 
BSA can be calculated as per standard practice at site. 

The same formula/method should be consistently used for all BSA calculations of a 
subject.

The dose should be calculated on Day 1 of each cycle; the dose administered may 
remain the same throughout each cycle unless the subject experiences a ≥10% 
change in weight. The Investigator should also assess the cause of any rapid weight 
change for overall subject management and possible safety reporting. 

It is not required that the BOR dose be corrected for obese subjects.
BOR is administered SC, on Days 1, 4, 8, and 11 in a 21-day cycle for 8 cycles; the route 
of administration should remain consistent throughout the duration of treatment. For 
extended therapy beyond 8 cycles (subjects enrolled in Cohort 1 and Cohort 2), BOR will 
be administered on Days 1 and 15 of a 28-day cycle until disease progression, 


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unacceptable toxicity or consent withdrawal, whichever occurs first, or for up to 2 years 
after the first dose of study treatment.
Subjects who experienced severe skin /local toxicity related to the SC administration of 
BOR and have clinical benefit from study treatment may switch from the SC 
administration to intravenous maintaining the same dose and schedule of BOR.
The minimum time window between 2 BOR doses is 72 hours. Individual BOR doses can 
be delayed for a maximum of 3 days from the original scheduled day (calculated from Day 
1 of the respective cycle); omit if delay is >3 days. Treatment delays or discontinuations of 
BOR may be instituted as described in Section 7.4.4.
Follow special handling and disposal procedures for anti-cancer pharmaceuticals as 
directed in the respective local label. Dosage, administration, and treatment with BOR
must be in compliance with the respective local label in each of the participating countries 
and in line with standard practice guidelines. Treatment will be captured in the eCRFs.
7.4.3
Dexamethasone
Dexamethasone (DEX) is part of background treatment in this study for subjects enrolled 
in all the cohorts and may be provided with appropriate labeling by the Sponsor, where 
local sourcing is not applicable. Local sourcing might be considered. Locally sourced 
medication will be handled according to the local procedures and will not be labelled study 
specific. It is required at minimum that the batch numbers and expiry dates are recorded. 
In case DEX is supplied centrally, the IxRS allocates one kit every other cycle on day 1 to 
a subject. 
Subjects enrolled will start treatment with DEX on the same day as the first dose of 
radium-223 dichloride/placebo.
DEX is a synthetic adrenocortical steroid, primarily used for anti-inflammatory effects,
supplied as tablets for oral administration. Store at 20°C to 25°C (68°F to 77°F). Protect 
from moisture. Dispense in a well-closed, light-resistant container. 
DEX tablets (4 mg or 8 mg, dependent upon participating country) are administered orally. 
The dose of DEX administered in the study is 40 mg during cycles 1 through 8 (ten 4 mg 
tablets, or five 8 mg tablets).
DEX is administered on Days 1, 4, 8, and 11 in a 21-day cycle for 8 cycles; however, DEX
administration may be split over 2 days (on the day of BOR administration and the day 
after BOR administration) at the discretion of the Investigator. For subjects who are older 
than 75 years, underweight (BMI<18.5), have poorly controlled diabetes mellitus or prior 
intolerance/adverse event (AE) to steroid therapy, the DEX dose may administered at a 
dose of 20 mg weekly. 
During extended therapy beyond 8 cycles, DEX will be administered 20 mg/dose, on 
Days 1 and 15 of a 28-day cycle along with BOR until disease progression, unacceptable 
toxicity or consent withdrawal, whichever occurs first, or for up to 2 years after the first 
dose of study treatment. Treatment will be captured in the eCRFs.


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7.4.4
Dose modification, delays and treatment discontinuation guidance
7.4.4.1
Dosing criteria to administer radium-223 dichloride/placebo:
After first radium-223 dichloride/placebo administration, prior to each subsequent dose of 
radium-223 dichloride/placebo, subjects must meet the following criteria for study 
treatment administration:

Hb level ≥8.0 g/dL

Platelet count ≥75 × 109/L

ANC ≥1 x 109/L

All non-hematological toxicities resolved to Grade ≤1 or baseline
Radium-223 dichloride/placebo is recommended to be given on Day 1 of a cycle of 
BOR/DEX. 
Radium-223 dichloride/placebo administration may be delayed by no more than 28 days
from the date of the intended dose (maximum of 10 weeks between 2 consecutive doses) 
for recovery of AEs. 
Subjects with radium-223 dichloride/placebo administration delayed from the date of the 
intended dose may receive the subsequent cycles of radium-223 dichloride/placebo at 
another day other than Day 1 of BOR/DEX planned schedule. 
If administration is delayed beyond 28 days due to toxicity, permanently discontinue 
radium-223 dichloride/placebo administration. 
Continuation of BOR/DEX after stopping radium-223 dichloride/placebo can be 
considered after consultation with the medical monitor, if this is considered by the 
Investigator to be in the best interest of the subject.
7.4.4.2
Dosing criteria to administer bortezomib and dexamethasone at the 
start of a bortezomib cycle
Prior to initiating any cycle of BOR, subjects must meet the following criteria for study 
treatment administration on Day 1 of any BOR cycle:

Hb level ≥8.0 g/dL

Platelet count ≥75 x 109/L

ANC ≥1 x 109/L

All non-hematological toxicities resolved to Grade ≤1 or baseline
Initiation of a new cycle of BOR may be delayed up to 28 days to allow recovery of all 
toxicities. 
If BOR administration is delayed beyond 28 days from the intended day of the next 
scheduled due to toxicity, the subject should be permanently discontinued.
Supportive care per institutional guidelines, including blood product transfusions or 
growth factor support is allowed for treatment criteria to be met. 


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Management of toxicities during a cycle
Grade 1 to 2 AEs (excluding neuropathy)
No pre-specified dose modifications are required except for neurological toxicities (see 
below); however, an Investigator may interrupt, delay, or reduce BOR and/or DEX more 
conservatively if deemed medically necessary according to his or her clinical judgment. 
Grade 3 non-hematological AEs (excluding neuropathy) 
For Grade 3 non-hematological toxicities, hold the BOR until the toxicity has resolved to 
Grade ≤1 or baseline. Restart at a reduced dose.
Grade 4 non-hematological AEs
For Grade 4 non-hematological toxicities, discontinue study treatment (Note: decisions 
concerning laboratory-related Grade 4 toxicities should be based on the Investigator’s 
clinical judgment in discussion with the medical monitor).
Grade 3 hematological AEs
For Grade 3 hematological toxicities, except febrile neutropenia and thrombocytopenia 
with bleeding (see below), no pre-specified dose modifications are required. Institutional 
guidelines for supportive care and BOR dosing can be applied.
Grade 4 hematological AEs
For Grade 4 hematological toxicities or thrombocytopenia with bleeding or febrile 
neutropenia, hold the BOR until the toxicity has resolved to Grade ≤2. Restart at reduced 
dose.
Dose Reductions
If BOR is re-initiated, it will be at a 25% reduced dose. The first dose reduction is to 1 
mg/m2/dose; a second dose reduction is to 0.7 mg/m2/dose. If a third dose reduction is 
required for any toxicity, permanently discontinue all study treatment. If a dose delay of 
BOR lasts longer than 28 days, permanently discontinue BOR treatment. A table for 
recommended dose modification for management of toxicities is presented in Table 7–1.
Table 7–1:  Dose modification for management of toxicities
Toxicity
Dose modification
Hematological toxicity Grade 1, 2, or 3
Continue dosing and apply supportive care 
according to institutional guidelines; (For Day 1 
of each cycle, please follow minimum dosing 
criteria)
Grade 3 or 4 febrile neutropenia,
thrombocytopenia with bleeding
Grade 4 neutropenia, thrombocytopenia, 
anemia
Hold treatment until Grade 2 or less; restart at 
reduced dose (reduce 1 dose level); (For Day 1 
of each cycle, please follow minimum dosing 
criteria)
Grade 1 or 2 non-hematological toxicity
Continue dosing and apply supportive care per 
institutional guidelines;
Grade 3 Non-hematological toxicity (except 
neuropathy)
Hold treatment until Grade 1 or less; restart at 
reduced dose (reduce 1 dose level)


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Grade 4 non-hematological toxicity
Permanently discontinue bortezomib treatment
Source: adapted from Velcade - EMEA/H/C/000539 -IB/0083 Summary of product characteristics 
Hepatic Impairment (for starting dose of bortezomib only)
In subjects with hepatic impairment, for moderately elevated levels (>1.5 x to 3 x ULN) or 
severely elevated levels (>3 x ULN) of bilirubin, reduce BOR to 0.7 mg/m2/dose. 
Subsequent dose escalation to 1.0 mg/m2/dose or further dose reduction to 0.5 mg/m2/dose
is allowed based on subject tolerability. Note: this dose level of 0.5 mg/m2 is only 
applicable to hepatic impairment.
Modify BOR as indicated in Table 7–2. 
Table 7–2: Recommended starting dose of bortezomib for hepatic impairment
Bilirubin Level
SGOT (AST) 
Levels
Modification of Starting Dose 
Mild
Less than or equal to 
1.0x ULN 
More than ULN 
None 
Mild
More than 1.0x−1.5x 
ULN 
Any 
None 
Moderate
More than 1.5x−3x 
ULN 
Any 
Reduce bortezomib to 0.7 mg/m2 in the 
first cycle. Consider dose escalation to 1.0 
mg/m2 or further dose reduction to 0.5 
mg/m2 in subsequent cycles based on 
subject tolerability.
Severe
More than 3x ULN 
Any 
Abbreviations: AST = aspartate aminotransferase; SGOT = serum glutamic oxaloacetic 
transaminase; ULN = upper limit of the normal range
Source: adapted from Velcade - EMEA/H/C/000539 -IB/0083 Summary of product characteristics 
Neuropathy
Modify BOR as indicated in Table 7–3. 
Table 7–3: Dose modifications for neuropathy
Neuropathic pain and/or peripheral 
neuropathy
Dose modification
CTCAE Grade 1 (asymptomatic; loss of deep 
tendon reflexes or paresthesia) without pain or 
loss of function
CTCAE Grade 2 (moderate symptoms; limiting 
instrumental ADL [preparing meals, shopping 
for groceries or clothes, using telephone, 
managing money, etc.])
CTCAE Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self-care ADL [bathing, 
dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden])
CTCAE Grade 4 (life-threatening 
consequences; urgent intervention indicated)
No action
Reduce bortezomib to 1 mg/m2/dose
Withhold bortezomib until toxicity resolves. 
When toxicity resolves, re-initiate with reduced 
dose of bortezomib at 0.7 mg/m2/dose
Discontinue bortezomib permanently
Abbreviations: ADL=activities of daily living; CTCAE=Common Terminology Criteria for Adverse 


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events, version 4.03.
Source: adapted from Velcade - EMEA/H/C/000539 -IB/0083 Summary of product characteristics 
Other considerations
Delay of an individual BOR dose administration on Days 4, 8, or 11 is allowed up to 
3 days to investigate possible toxicity or to allow recovery from rapidly reversible toxicity 
or for logistical reasons (e.g., bank holiday); alternatively the dose may be omitted. There 
must be at least 72 hours between each injection of BOR. If toxicity has not resolved 
within a 3-day delay, the dose should be omitted.
As there have been reports of cardiopulmonary adverse reactions associated with BOR
administration, in the event of new or worsening cardiopulmonary symptoms, a prompt 
comprehensive diagnostic evaluation should be conducted, per the Investigator’s clinical 
judgment.
Diarrhea should be managed aggressively as a Grade 2 may progress to Grade 3, 
necessitating interruption in therapy. Consideration regarding the use of prophylactic 
and/or supportive care should be made upon the first observation of diarrhea. Consider 
giving the subject a prescription for anti-diarrheals (e.g., loperamide) to be used as needed 
and to maintain hydration. 
For subjects that experience any Grade 3 or 4 infection, therapy with BOR must be 
interrupted till resolved to Grade ≤1. For subjects with suspected infection, the subject
should undergo work-up for possible infection (e.g., chest XR, blood cultures, urinalysis, 
etc. as applicable) and dosing with BOR may be delayed for the work-up to occur. 
For situations where dose modification guidance is ambiguous or conflicting, the more 
conservative approach will be used.
Dexamethasone considerations
DEX can be adjusted as needed per standard of care. Subjects who cannot tolerate DEX
are permitted to continue study treatment without DEX. 
7.4.5
Supportive care guidelines
Supportive treatment should be provided as deemed necessary by the treating Investigator. 
Recommendations for supportive treatment are provided in the IMWG supportive care 
guidelines for multiple myeloma.(50) 
Supportive treatment may include anti-emetics, antidiarrheal medications, fluid and 
electrolyte replacement, anti-pyretics, antihistamines, analgesics, antibiotics, blood 
products, growth factors, focal external radio therapy if given for pain management, and 
others. 
Adequate hydration is recommended for the prevention of myeloma-related kidney 
disease. 
During treatment with bisphosphonates, the subjects may be administered an oral calcium 
supplement of 500 mg and 400 IU vitamin D daily
Antiviral prophylaxis to prevent herpes zoster infection or re-activation is recommended. 


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If surgery is required, the subject should continue with study treatment, if this is 
considered safe in the treating Investigator’s opinion. The surgeon needs to be notified that 
the subject has been given radioactive drug and needs to follow the guidelines for 
radioactive protection. The subject should continue with study treatment if it is considered 
safe in the treating Investigator’s opinion.
7.5
Blinding
Every effort will be made to keep the phase 2 part of the study blinded. In the phase 2 part, 
subjects will be randomized to receive radium-223 dichloride or placebo in a double-blind 
fashion. All subjects will also receive bortezomib and dexamethasone; this treatment will 
be provided by the Sponsor or locally sourced and will be administered in an open-label 
format.
All treating physicians, clinical staff, subjects, Contract Research Organization (CRO), and 
Sponsor personnel will be blinded as to the treatment to which a subject is randomized, 
except for named representatives who will perform the verification of the drug 
accountability at the study sites and drug ordering. Blinded and unblinded roles are not 
interchangeable during the study. Unblinded personnel must only perform unblinded tasks; 
blinded personnel must only perform blinded tasks.
Study personnel from the sponsor and the CRO responsible for drug supply and 
monitoring, who are not otherwise involved in the conduct of the study, will also be 
unblinded to study treatments.
Due to the nature of radium-223 dichloride, there must be at least 2 people in the study 
site’s nuclear medicine department who are unblinded to the treatment arms assigned to 
subjects. One of these unblinded individuals will serve as back-up for the other. To 
maintain the study blind for the hospital personnel who provide treatment to the subject, 
the unblinded person at the study site will be responsible for filling the syringe with the
correct amount of radium-223 dichloride/placebo (isotonic saline) and labeling it. Both 
radium-223 dichloride and placebo are clear solutions, thus syringes with radium-223 
dichloride and placebo cannot be distinguished from each other visually. The person 
performing the administration of study drug must be blinded to the treatment arm. The 
subject will not be told whether they have received radium-223 dichloride or placebo.
Treatment with bortezomib and dexamethasone is not blinded.
In compliance with applicable regulations, in the event of a Suspected Unexpected Serious 
Adverse Reaction (SUSAR; see Section 9.6.1.4) related to the blinded treatment, the 
subject’s treatment code will usually be unblinded before reporting to the health authorities 
and ethic committees. 
Emergency unblinding by the Investigator 
Investigators may only unblind subjects under emergency conditions. If a subject is 
unblinded by the Investigator, the subject must discontinue treatment with radium-223 
dichloride or placebo. The subject may continue treatment with bortezomib and 
dexamethasone if the Investigator considers continued treatment to be in the subject’s best 
interest.


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Investigators should note that the occurrence of an SAE or PD should not routinely 
precipitate the immediate unblinding of the label. 
If emergency unblinding is necessary for the treatment of a subject for an SAE, the study 
treatment can be unblinded via the IXRS system (refer to the IXRS manual for 
instructions). The participating site has unrestricted and immediate access to break the 
treatment code in IXRS. Should the blind code be broken for a subject, the medical 
monitor or designee should be contacted by the Principal Investigator within 1 working 
day of unblinding to discuss the rationale for the premature unblinding. It is the 
investigator’s responsibility to notify the medical monitor before placing a call to IXRS to 
unblind the subject.
7.6
Drug logistics and accountability
All study treatments will be stored at the investigational site in accordance with national 
regulations on radioactive materials, Good Clinical Practice (GCP) and GMP requirements 
and the instructions given by the clinical supplies department of the Sponsor (or its 
affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
Sponsor’s study file. All documents regarding drug logistics need to be filed in the 
Investigator Site File.
On the day of receipt, the responsible site personnel will confirm receipt of study drug via 
IxRS. The personnel will use the study drug only within the framework of this clinical 
study and in accordance with this protocol. Receipt, distribution, return and destruction (if 
any) of the study drug must be properly documented according to the sponsor´s agreed and 
specified procedures. Written instructions on medication destruction will be made 
available to affected parties as applicable. If performing drug accountability implies a 
potential risk of contamination, a safety process/guidance for handling returned drug will 
be provided. Locally sourced medication, is to be handled by the local standards. It is 
required at minimum that the batch numbers by subject and expiry dates are recorded.
In some countries/study sites, it will be required to use a third party vendor to prepare the 
injections to be used by the study site. Any labels or mandatory logs provided by the 
Sponsor are to be utilized according to instructions. A copy of study drug documentation 
will be collected for the Sponsor file.
For radium-223 dichloride: 
Radium-223 dichloride will be shipped to study site upon IxRS shipment request. Lead 
times differ per country but the shipment will arrive at the study site 1 day before the 
planned treatment at the latest. The responsible unblinded study site personnel will confirm 
receipt of Sponsor-supplied study drug via IxRS system.
The unblinded person at the study site is responsible for drug accountability. A dedicated 
unblinded person representing the Sponsor will monitor the drug accountability logs. 
Receipt, distribution, and destruction of the study drug must be properly documented 
according to the Sponsor’s agreed and specified procedures. An unblinded monitor will 
review overall drug accountability and destruction per the study site documentation only. 
The remains of radioactivity and contaminated material (i.e., vials, syringes, containers) 


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should be disposed of in accordance with the local regulations and the hospital procedure, 
respectively. A log of radium-223 dichloride (received, administered to subjects, and 
destroyed) must be maintained and signed and the appropriate eCRF pages completed by 
the unblinded person responsible for drug handling at each site.
For locally provided isotonic saline (placebo):
Isotonic saline (placebo) will be provided by the study site. Drug accountability for 
isotonic saline will also be performed. At a minimum, storage conditions, dispensing, 
batch numbers, and expiry dates will be retained in the study site files. A log of isotonic 
saline (administered to subjects, and destroyed) must be maintained and signed and the 
appropriate eCRF pages completed by the unblinded person responsible for drug handling 
at each site. The used vials must be stored until the drug accountability has been completed 
by the unblinded monitor.
For study treatment bortezomib and dexamethasone
In case BOR and DEX is supplied centrally, the medication will be shipped to the study 
center upon IxRS shipment request. The responsible site personnel will confirm receipt of 
Sponsor-supplied study treatment in writing and via IxRS.  
Locally sourced medication will be handled according to the local procedures and will not 
be labelled study specific. It is required, at minimum, that the batch numbers and expiry 
dates are recorded.
An accountability log of all study medication must be maintained and signed by the 
appropriately trained site personnel for drug handling at each site. All study treatment 
packages provided by the sponsor must be stored until drug accountability has been 
completed by the monitor. 
7.7
Treatment compliance
Subjects will receive treatment with radium-223 dichloride/placebo under supervision of a 
physician licensed in the administration of radioisotopes. Unblinded study personnel will 
check the administration volume and total radioactivity injected. The dose activity and the 
volume injected will be recorded in a study drug log and the eCRF pages, neither of which 
will be available to the treating physician or site personnel. Only the unblinded monitor 
will review overall drug accountability and destruction per the site documentation.
8.
Non-study therapy
8.1
Prior and concomitant therapy
At baseline screening, all prior cancer-related treatments are to be recorded.
All concomitant medications taken by the subject from signing of the ICF to 30 days after 
last study treatment administration must be recorded in the eCRF. 
The option of starting a bone health agent (BHA) including bisphosphonates or denosumab 
should be considered, taking into consideration applicable guidelines. Thereafter, until the 
end of the follow-up period, only medications given to treat any grade AEs related to the 


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study treatment, analgesic medication, and any subsequent anti-cancer treatment 
medication need to be recorded in the eCRF.
The generic name and trade name of each prior or concomitant medication, its indication, 
dosage, and when applicable, the start and stop dates will be recorded. 
The Sponsor’s representative will encode all therapy and medication according to well 
recognized dictionaries of medical codes.
It is not required to report the administration of contrast media or radioactive tracer in 
conjunction with protocol-specified radiological procedures (CT or PET-CT) on the 
concomitant medications eCRF page unless there is an AE related to the administration of 
the contrast agent (e.g., an allergic reaction related to the administration of a contrast 
agent) or the tracer.
8.1.1
Prohibited concomitant therapy
Other cancer treatment with established efficacy in multiple myeloma should not be used 
during the treatment period. If such treatments are considered to be the best standard of 
care during the treatment period, further radium-223 dichloride/placebo and BOR/DEX
administrations must be discontinued.
All supportive care for the subject may be provided at the discretion of the Investigator.
Note that all treatments for multiple myeloma, including other investigational drugs taken 
after withdrawal from treatment with radium-223 dichloride/placebo, will be recorded in 
the eCRFs until the end of the active follow-up period.
The following concomitant therapy is prohibited during the treatment phase:

Any marketed therapy with anti-myeloma effect including, but not limited to, 
chemotherapy, immunotherapy, and stem cell transplant

Radiopharmaceuticals with anti-cancer properties such as strontium-89, 
samarium-153, rhenium-186, or rhenium-188

Hemibody external radiotherapy

Any investigational drugs

All medications that are prohibited as per the local label instructions for BOR and 
DEX and the supportive treatment

Per FDA recommendation, biotin supplements over 30 mcg per day should be 
avoided as they may interfere with biomarker assays.
It is the site’s responsibility to ensure that the study treatment with BOR and DEX is 
administered in line with standard practice and local label instructions. 
8.1.2
Permitted concomitant therapy
The following supportive care medications are considered permissible during the study:

Conventional multivitamins, selenium, and soy supplements

All subjects are expected to have been on therapy with bone health agents (BHA)
including bisphosphonates or denosumab before the start of study treatment and to 
continue on this therapy without change during the course of the study, unless 


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unable to tolerate or contraindicated. If not already on treatment, the option of 
starting a BHA, including bisphosphonates or denosumab should be considered
during or after study drug treatment, taking into consideration applicable guidelines. 
Injection of bisphosphonates should be done at least 2 hours before or after study 
treatment administration.

Focal external radiotherapy if given for pain management

Blood transfusions and use of biologic response modifiers, such as G-CSF or 
GM-CSF, are allowed during the study per institutional guidelines, at the discretion 
of the Investigator, except during the DLT observation window when they are 
allowed only in a curative setting.

Analgesic use will be captured via the eCRF (analgesic concomitant medication,  
24-hour analgesic use and opioid use, see Table 9–1) , and the subject should be 
asked to record any pain medication they took that day. Any medication taken for 
pain, whether for palliation of bone pain or relief of other type of pain, and any 
changes should be recorded in the eCRF. The Brief Pain Index-Short Form (BPI-SF; 
Section 16.7) will also be dispensed according to the schedule of assessments. 

External beam radiotherapy (EBRT) treatment should be recorded in the eCRFs 
until end of the active follow-up period.

Antiviral prophylaxis is recommended as per the local standard of care.

Pneumocystis carinii pneumonia (PCP) prophylaxis is recommended as per the local 
standard of care.
8.1.3
Interaction potential of bortezomib with other medicinal products 
BOR is a substrate of cytochrome P450 enzyme 3A4, 2C19, and 1A2. Subjects taking 
BOR in combination with the below medicinal products should be closely monitored.
CYP3A4 inhibitors
Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of 
BOR by 35% in 12 subjects. Monitor subjects for signs of BOR toxicity and consider a 
BOR dose reduction if BOR must be given in combination with strong CYP3A4 inhibitors 
(e.g., ketoconazole, ritonavir).
CYP2C19 inhibitors
Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the 
exposure of BOR in 17 subjects.
CYP3A4 inducers
Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the 
exposure of BOR by at least 45%. Because the drug interaction study (n=6) was not 
designed to exert the maximum effect of rifampin on BOR PK, decreases greater than 45% 
may occur.


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Efficacy may be reduced when BOR is used in combination with strong CYP3A4 
inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in 
subjects receiving BOR.
St. John’s Wort (hypericum perforatum) may decrease BOR exposure unpredictably and 
should not be used. 
For more details on strong, moderate, and weak CYP3A4 inhibitors and inducers please 
refer to Section 16.8
8.2
Post-study therapy
Treatment with radium-223 dichloride/placebo will be halted following completion of the 
full assigned treatment (6 doses) or at early termination. Treatment with BOR or DEX will 
be terminated for disease progression or unacceptable toxicity or other reasons (Section 
6.3.1.1). 
Following discontinuation of all study treatments (radium-223 dichloride/placebo, BOR
and DEX), subjects will be treated and followed as per the institutional standard of care 
and/or according to the physician’s clinical judgment. The option of starting bone health 
agent (BHA) including bisphosphonates or denosumab should be considered, taking into 
consideration applicable guidelines. 
Once a subject enters the follow-up period, all protocol-related treatments must be 
stopped; all standard anti-cancer treatments a subject might receive during the follow-up 
period will be recorded as follow-up anti-cancer therapy.
If possible, cytotoxic chemotherapy, other systemic radioisotope, hemibody external 
radiotherapy, or other investigational drug should not be given prior to completing a 
4-week wash-out period after last administration of radium-223 dichloride/placebo, 
provided the subject is eligible for such therapy according to local physician’s assessment.  
Details of post-study anti-cancer treatment will be recorded on the appropriate eCRF page.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
All disease response analyses will be conducted by central laboratory (Section 9.4.2). 
Safety evaluations will be conducted locally (Section 9.6).
Safety measurements and data from the evaluation of the early signal of anti-MM activity 
obtained during the course of the study are summarized in the schedule of assessments 
(Table 9–1).
A diagram of dosing for is presented in Figure 9–1.


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Table 9–1:  Schedule of assessments for screening and treatment period for Phase 1b and Phase 2
Study
Period
Screening a
D-21 to D-1
Randomization
(Phase 2 only)
Treatment b,c
End of Radium-223 
dichloride/placebo 
visit d
(Placebo option for 
Phase 2 only)
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
BOR/DEX
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
Maintenance BOR/DEX
Cycle
1
2
3
4
5
6
7
8
9
10
Week
0
1
2
3
4
5
6-8
9-11
12-14
15-17
18-20
21-23
24
26
28
30
BOR/DEX e
D 0
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1, 4,
8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1
D 15
D 1
D 15
Radium-223 dichloride / 
placebo dosing f
(Placebo option for 
Phase 2 only)
Dose 1
(D1 only)g
Dose 2
(D1 only)
Dose 3
(D1 only)
Dose 4
(D1 only)
Dose 5
Dose 6
Informed consent h
X
Subject ID Assignment
X
Review of eligibility a
X
X
Demographics
X
Disease history
X
Medical history
X
Prior SRE i
X
Randomization
(Phase 2 only)
X
BPI-SF j(Day 1)
X
X
X 
X
X
X
X
RUQ j (Day 1)
X
X
X
X
X
X
X
24-hr analgesic use j
(Day 1)
X
X
X
X
X
X
X
X
Opioid use 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs, SAEs k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DLT assessment
(Phase 1 only)
X
X
X
X
X
X
X
X gg
Prior and con meds 
(+anti-cancer 
treatments) l,m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 9–1:  Schedule of assessments for screening and treatment period for Phase 1b and Phase 2
Study
Period
Screening a
D-21 to D-1
Randomization
(Phase 2 only)
Treatment b,c
End of Radium-223 
dichloride/placebo 
visit d
(Placebo option for 
Phase 2 only)
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
BOR/DEX
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
Maintenance BOR/DEX
Cycle
1
2
3
4
5
6
7
8
9
10
Week
0
1
2
3
4
5
6-8
9-11
12-14
15-17
18-20
21-23
24
26
28
30
BOR/DEX e
D 0
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1, 4,
8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1
D 15
D 1
D 15
Radium-223 dichloride / 
placebo dosing f
(Placebo option for 
Phase 2 only)
Dose 1
(D1 only)g
Dose 2
(D1 only)
Dose 3
(D1 only)
Dose 4
(D1 only)
Dose 5
Dose 6
Vital signs n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG o
X
Weight p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Physical examination q
X
X
X
X
X
X
X
X
X
X
X
X
ECOG-PS r
X
X
X
X
X
X
X
X
X
X
X
Hematology s, t
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test and 
estradiol assay u
X
X
X
X
X
X
X
X
Clinical chemistry v
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation panel w
X
Assessment for 
hepatitis B and C x
X
Blood and urine 
biomarkers y
X
X
X
X
X
X
X
X
Plasma for ctDNA 
analysis z
X
X
X
X
X
X
X
X
Whole blood for CTCs 
analysis aa
X
X
X
X
X
X
X


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Table 9–1:  Schedule of assessments for screening and treatment period for Phase 1b and Phase 2
Study
Period
Screening a
D-21 to D-1
Randomization
(Phase 2 only)
Treatment b,c
End of Radium-223 
dichloride/placebo 
visit d
(Placebo option for 
Phase 2 only)
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
BOR/DEX
Radium-223 dichloride or placebo
(Placebo option for Phase 2 only)
+
Maintenance BOR/DEX
Cycle
1
2
3
4
5
6
7
8
9
10
Week
0
1
2
3
4
5
6-8
9-11
12-14
15-17
18-20
21-23
24
26
28
30
BOR/DEX e
D 0
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1, 4,
8, 11
D 1,4
D 8, 11
D 1,4,
8, 11
D 1,4
D 8, 11
D 1,4
D 8, 11
D 1
D 15
D 1
D 15
Radium-223 dichloride / 
placebo dosing f
(Placebo option for 
Phase 2 only)
Dose 1
(D1 only)g
Dose 2
(D1 only)
Dose 3
(D1 only)
Dose 4
(D1 only)
Dose 5
Dose 6
Bone marrow biopsy bb
X
Performed according to IMWG criteria
EMD assessments cc
X
Performed according to IMWG criteria
M-protein 
measurements by 
SPEP, UPEP, Freelite 
essay IF (central lab) dd
X
X
X
X
X
X
X
X
X
X
X
β2-microglobulin
X
Disease assessment dd
X
X
X
X
X
X
X
X
X
X
X
SSEs i,dd,ee
X
X
X
X
X
X
X
X
X
X
X
Radium-223 dichloride
/ placebo dosing g
(Placebo option for 
Phase 2 only)
X
X
X
X
X
X
Skeletal survey ff
X
X


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Abbreviations: AE=adverse event; BOR=bortezomib; BPI-SF=Brief Pain Index-Short Form; con med=concomitant medication; CT=computed tomography; CTCs= circulating 
tumor cells; ctDNA= circulating tumor DNA; D=Day; DEX=dexamethasone; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG-PS=Eastern Cooperative Oncology 
Group Performance Status; eCRF=electronic case report form; EMD=extramedullary disease; EOT=end of treatment; Hb=hemoglobin; HBcAb=hepatitis B core antibody; 
HBV=hepatitis B virus; HCV-hepatitis C virus; HIV=human immunodeficiency virus; ID=identification number; IF=Immunofixation; IMWG=International Myeloma Working 
Group; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; PET=positron emission tomography; PFS=progression-free survival; PRD=patient-ready dose; 
q=every; RBC=red blood cell; RNA= ribonucleic acid; RUQ=Resource Utilization Questionnaire; SAE=serious adverse event; SPEP=serum protein electrophoresis; SRE= 
skeletal-related event, SSE=symptomatic skeletal event; UPEP=urine protein electrophoresis; US=United States; WBC=white blood cell; wk=week 
a.
All screening evaluations must be complete and reviewed prior to confirmation of eligibility (phase 1b) or randomization (phase 2). Screening evaluations must be 
complete within 21 days starting from the time of ICF signature. Bone marrow biopsy or aspirate, skeletal survey and local blood and urine protein-M tests (as well as 
any other specific multiple myeloma tumor assessment blood and urine tests) previously done as part of routine care will be accepted for eligibility confirmation 
purposes even if done prior to ICF signature, as long as these tests have been performed up to 14 days prior to ICF signature. If logistical reasons require, local lab 
results for blood and urine protein-M and other specific multiple myeloma tumor assessment tests ordered after ICF signature can also be used for eligibility assessment 
only, to ensure that eligibility confirmation timelines are met. If any local lab samples are used to run tumor assessment tests for eligibility confirmation, blood and 
urine samples for central lab analysis will still be collected and used as the final baseline value for data analysis.
b.
All assessments at treatment visits should be performed before study treatment administration.
c.
Subjects will continue in the treatment period until the occurrence of a PFS event, unacceptable toxicity develops, or the subject withdraws consent, whichever occurs 
first (Section 9.4.2). 
d.
The End of radium-223 dichloride/placebo visit should occur 30 days (+7 days) after radium-223 dichloride/placebo treatment is completed or discontinued.
e.
Bortezomib/dexamethasone will be given for eight 21-day cycles on Days 1, 4, 8, and 11. The minimum time window between 2 BOR injections is 72 hours; if an 
injection is delayed, this can be for a maximum of 3 days from original scheduled day (calculated from Day 1 of the respective cycle). Omit injection if delay is >3 
days. DEX may be administered over 2 days, at the discretion of the Investigator.
f.
A total 6 radium-223 dichloride/placebo doses are planned at 6-week intervals. The minimum time window between 2 doses of radium-223 dichloride/placebo must be 
6 wks. Radium-223 dichloride/placebo administration may be delayed if medically necessary. A maximum of 28 days from the date of the intended dose is allowed 
(i.e., a maximum of 10 weeks between 2 consecutive doses) for recovery of AEs is allowed. If administration is delayed beyond the 10 weeks window due to toxicity, 
the subject must permanently discontinue radium-223 dichloride/placebo administration. Subjects with radium-223 dichloride/placebo administration delayed from the 
date of the intended dose may receive the subsequent cycles of radium 223 dichloride/placebo at another day other than Day 1 of bortezomib/dexamethasone planned 
schedule.
g.
On Cycle 1 Day 1 only, radium-223 dichloride/placebo must be administered before BOR or DEX. Samples for M-protein must be collected before administration of 
radium-223 dichloride/placebo. The IxRS must be accessed for drug re-supply in preparation for the next study visit. This should be done on the day of the current 
treatment visit (where possible) to provide the maximum time in advance of the next scheduled subject visit date and in accordance with country-specific order lead-
times.
h.
Informed consent is to be collected before the initiation of any study related procedures. 
i.
Bone fractures / pathological fractures will be collected regardless disease relationship.
j.
Analgesic use (24-hr), BPI-SF, and RUQ will be provided to the subject at Screening, on Cycle 1 Day 1, and every 6 weeks thereafter until the end of Cycle 6 of 
radium-223 dichloride/placebo with a window of  ±7 days. During the Maintenance Period and until EOT visit, they will be provided at Day 1 every 28 days with a 
window of  ±7 days and during active follow-up, they will be provided every 8 weeks with a window of  ±7 days. Pain medication will also be assessed at each visits 
and analgesic use will be recorded in the appropriate eCRF page. 
k.
Window ±1 day for AEs. Adverse events will be collected through 30 days post-last study treatment administration. Investigator should check for occurrences of any 
new malignancy: new primary malignancy (including AML) or hematological conditions (e.g., MDS, aplastic anemia, myelofibrosis) must be reported as SAEs at any 
time and regardless of the investigator’s causality assessment.  All AEs and SAEs considered related to any agent of study treatment (radium-223 dichloride/placebo, 


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bortezomib, or dexamethasone) occurring during the active follow-up period will be collected. All bone fractures and bone associated events (e.g., osteoporosis) need to 
be reported as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment.   
l.
Window ±7 days. At baseline screening, all prior medications, including analgesics, are to be recorded. Thereafter, collect all medications, including analgesics, up to 
30 days post last study treatment administration. Thereafter, until the end of the active follow-up period, only collect medications used to treat any grade adverse drug 
reaction and analgesics. Analgesic use has to be recorded via the analgesic concomitant medication eCRF. The initiation of bone health agent (BHA) such as 
bisphosphonates or denosumab should be considered by investigators taking into consideration applicable guidelines
m.
Record any cancer-related and prior multiple myeloma treatments. The option of starting bone health agent (BHA) including bisphosphonates or denosumab should be 
considered, taking into consideration applicable guidelines. 
n.
Window ±1 day. The measurement of vital signs will include: blood pressure, heart rate, respiratory rate, and temperature.
o.
Required at screening, otherwise as clinically indicated. Hypokalemia should be corrected prior to ECG collection. Twelve-lead ECG should be obtained when serum 
potassium is ≥3.5 mmol/L. 
p.
Window ±1 day. Body weight should be obtained without shoes, using a calibrated electronic physician (column) scale with digital display, measurement units 0.1 kg. 
The same scale should be used for a given subject throughout the study. At all sites (US and ex-US), weight is to be taken before each Day 1 bortezomib dose AND 3 to 
5 days before each radium-223 dichloride/placebo dose (for US sites) or 72 hours before each radium-223 dichloride/placebo dose (for ex-US sites). The weight 
measurements prior to radium-223 dichloride/placebo dose must be reported to the country PRD depot to allow adequate time for PRD preparation and delivery
(approximately 2 days). All efforts should be made to measure weight at the same visit with the pre-dose laboratory assessments in order to avoid 2 pre-dose clinic 
visits. Body weight can be obtained at the local healthcare provider on a calibrated scale and the results sent by fax to the Principal Investigator with advanced notice 
and agreement from the Covance Medical Monitor for each subject.
q.
Window ±1 day. A full physical examination must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, dermatological, 
musculoskeletal, and neurological systems. The physical exam is to be performed before every radium-223 dichloride dose/placebo and before every Day 1 BOR 
injection.
r.
Window ±1 day. The ECOG-PS is to be assessed every Day 1 of BOR before injection. 
s.
The screening hematology values are recommended to be measured within 2 weeks before the first dose of radium-223 dichloride/placebo and the first radium-223 
dichloride/placebo dose should be done as soon as possible after enrollment. The same sample can be used for dosing radium-223 dichloride/placebo if taken within 
72 hours before dosing, otherwise a repeat sample within 72 hours before dosing will be required. Hematology parameters will include hematocrit, Hb, platelet counts, 
RBC counts, WBC counts, WBC differential. Subjects with platelet counts <75x109/L and/or absolute neutrophil count <1.0x109/L should undergo repeat weekly 
hematology examination until resolution.
t.
Window ±1 day. Hematology will be collected a minimum of once weekly. Sites may collect hematology assessments more often, if that is the standard of care at that 
site. In addition, hematology must also be collected 72 hours before radium-223 dichloride/placebo dosing. A complete blood count must be performed before every 
radium-223 dichloride/placebo and BOR dosing during combination therapy. Analysis and evaluation of hematology samples must be completed within 72 hours before 
radium-223 dichloride/placebo dosing. During maintenance treatment, within 3 days prior to each dose of BOR/DEX, hematology, must be assessed and the 
Investigator must confirm that the subject meets dosing criteria for bortezomib. Hematology assessments will also be performed at the EOT visit. Additional laboratory 
assessments should be performed according to the institutional guidelines.
u.
Window ±1 day. Pregnancy tests will be administered at screening and 72 hours before radium-223 dichloride/placebo dosing. After the last radium-223 
dichloride/placebo dose, pregnancy tests will be administered on Day 1 of the BOR-only cycle through the EOT. Women of child-bearing potential must have a 
negative urine pregnancy test performed within 72 hours before the first dose of radium-223 dichloride/placebo. Postmenopausal women (as defined in Section 6.1) are 
not required to undergo a pregnancy test. An estradiol assay is required within 72 hours before the first dose of radium-223 dichloride/placebo in premenopausal women 
with radiotherapy ovarian ablation or medical ovarian suppression and postmenopausal women age <55 years and 1 year or more of amenorrhea and no ovarian 
suppression. 
v.
Window ± 1 day. The screening clinical chemistry values are recommended to be measured within 2 weeks before the first dose of radium-223 dichloride/placebo and 


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the first radium-223 dichloride/placebo dose should be done as soon as possible after enrollment. The same sample can be used for dosing radium-223 
dichloride/placebo if taken within 72 hours before dosing, otherwise a repeat sample within 72 hours before dosing will be required. Clinical chemistry samples will be 
taken at screening and on Days 1 and 11 for the first 2 cycles, then Day 1 of BOR dosing from Cycle 3 onwards. Sodium, potassium, chloride, calcium, aspartate 
aminotransferase, alanine aminotransferase, lactate dehydrogenase, total alkaline phosphatase, serum creatinine, bilirubin (total), glucose, phosphate, and albumin. 
Blood urea nitrogen or urea will also be collected, according to each site’s standard of care.
w.
Required at screening, otherwise as clinically indicated.
x.
Subjects are not eligible if they have active hepatitis B or C infection requiring treatment; subjects with occult or prior HBV infection (defined as positive HBcAb and 
negative HBsAg) may be included if HBV-DNA is undetectable at screening. Subjects positive for HCV antibody must be negative for HCV-RNA by PCR assessment.
y.
Window ±7 days. Blood and urine samples for biomarkers will be collected at screening, before radium-223 dichloride/placebo doses 1 to 6 and then 30 days after the 
last dose of radium-223 dichloride/placebo, or disease progression, whichever occurs first.
z.
Window ±7 days. For ctDNA, plasma samples will be collected at screening, before radium-223 dichloride/placebo doses 1 to 6 and then 30 days after the last dose of 
radium-223 dichloride/placebo, or disease progression, whichever occurs first.
aa.
Whole blood will be collected prior to every dosing with radium-223 dichloride/placebo for dose 1 through 6 and end of radium-223 dichloride treatment.
bb. At baseline screening and repeated to confirm complete response per IMWG criteria. A bone marrow aspirate is acceptable. After the percentage of plasma cells is 
determined by the local laboratory, the remaining bone marrow sample will be sent to the central laboratory for biomarker testing.
cc.
At screening if EMD present at baseline as per IMWG criteria subject is not eligible. To repeat if suspicion of new EMD lesion.
dd. M-protein samples will be drawn , disease response assessments, and SSEs will be performed on Cycle 1 Day 1 and every 21 days (±7 days) thereafter through Cycle 8 
of BOR/DEX, and then every 28 days thereafter (±7 days) through the end of treatment. These assessments should be based on laboratory results provided by the 
central lab and according to IMWG criteria.
ee.
All bone fractures, or any relevant bone event (e.g., osteoporosis) should be reported as SSE and need to be collected as either AEs or SAEs if the criteria of SAE were 
met, regardless of the investigator’s causality assessment.
ff.
Window ±7 days. The skeletal survey should be conducted at EITHER 30 days after last dose of radium-223 dichloride/placebo OR at the end of all study treatment, 
whichever occurs first). Magnetic resonance imaging, low-dose CT, or PET-CT are allowed as alternatives to the skeletal survey at sites where this is considered the 
institutional standard; the same methodology (MRI, low-dose CT, PET-CT, or skeletal survey) should be used at baseline and all subsequent assessments.
gg. The final DLT assessment should occur prior to bortezomib dosing on Cycle 4, Day 1.


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Table 9–2: Schedule of assessments for maintenance period and follow-up periods (Phase 1b and Phase 2)
Study
Period
Treatment a,b
Follow-up Periods
Maint (BOR/DEX)
EOT c
Active Follow-up
Long-term Follow-up x
Cycle
11+
Weeks
30 days post last dose
Q8 wk for 2 years 
after last radium-223 
dichloride dose 
Every 6 months 
for up to 5 years
BOR/DEX dosing d
X
BPI-SF e
X
X
X
RUQ e
X
X
X
24-hr analgesic use e
X
X
X
Opioid use
X
X
X
AEs, SAEs f
X
X
X
X
Prior and con meds g,h
X
X
X
X
Vital signs i
X
X
X
Weight j
X
Physical examination k
X
ECOG-PS l
X
X
Hematology m,n 
X
X
Pregnancy test and estradiol assay o
X
X
Clinical chemistry p
X
X
Bone marrow biopsy q
Performed according to IMWG criteria
EMD assessments r
Performed according to IMWG criteria
M-protein measurements by SPEP, 
UPEP, Freelite assay IF (central lab) s
X
X
X
Disease response assessment s,t
X
X
X
SSEs/other relevant bone events s
X
X
X
X
Blood biomarkers u
X
X
X
Urine biomarkers u
X
X
Plasma for ctDNA analysis v
X
X
X
Whole blood for CTCs analysis w
X
X
X
Survival status
X


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Abbreviations: AE=adverse event; BOR=bortezomib; BPI-SF=Brief Pain Index-Short Form; con med=concomitant medication; CT=computed tomography;
CTCs= circulating tumor cells; ctDNA= circulating tumor DNA; DEX=dexamethasone; ECOG-PS=Eastern Cooperative Oncology Group Performance 
Status; eCRF=electronic case report form; EMD=extramedullary disease; EOT=end of treatment; Hb=hemoglobin; IC=Investigator’s choice; 
IF=Immunofixation; IMWG=International Myeloma Working Group; maint=maintenance; MRI=magnetic resonance imaging; PET=positron emission 
tomography; PFS=progression-free survival; Q=every; RBC=red blood cell; RUQ=Resource Utilization Questionnaire; SAE=serious adverse event; 
SPEP=serum protein electrophoresis; SSE=symptomatic skeletal event; UPEP=urine protein electrophoresis; US=United States; WBC=white blood cell; 
wk=week 
a.
All assessments at treatment visits should be performed before study treatment administration.
b.
Subjects treated with BOR/DEX will continue in the treatment period up to 2 years after the first dose of study treatment, until a progression-free 
survival (PFS) event occurs, the subject withdraws consent or an unacceptable toxicity develops, whichever occurs first. 
c.
The EOT visit will be conducted 30 days (+7 days) after last dose of study treatment (radium-223 dichloride/placebo, BOR/DEX, , whichever is last).
d.
Bortezomib will be administered on Days 1 and 15 of a 28-day cycle. Dexamethasone will be administered 20 mg/dose, on Days 1 and 15 of a 28-day 
cycle along with bortezomib.
e.
Window ±7 days. Analgesic use (24-hr), RUQ, and BPI-SF will be dispensed to the subject every 28 days through the end of the Maintenance Period, 
at the EOT visit, and at active follow-up clinic visits. Pain medication will also be assessed at each visit by study site; subjects should be requested to 
bring all pain medication to each visit. Analgesic use will be recorded in the appropriate eCRF page. 
f.
Window ±1 day for AEs. Adverse events will be collected through 30 days post-last study treatment administration. Investigator should check for 
occurrences of any new malignancy: new primary malignancy (including AML) or hematological conditions (e.g. MDS, aplastic anemia, myelofibrosis) 
must be reported as SAEs at any time and regardless of the investigator’s causality assessment. All AEs and SAEs considered related to any agent of 
study treatment (radium-223 dichloride/placebo, bortezomib, dexamethasone) occurring up to 30 days after the last study treatment administration will
be collected. During the follow-up (either active or long-term follow up). All bone fractures, or any relevant bone event (e.g., osteoporosis) should be 
reported as SSE and need to be collected as either AE(s) or SAEs if the criteria of SAE were met, regardless of the investigator’s causality 
assessment. Any occurrence of febrile neutropenia and hemorrhage considered related to radium-223 dichloride will also be reported until end of 
follow-up period.
g.
Window ±7 days. Collect all medications, including analgesics, up to 30 days post last study treatment administration. Thereafter, until the end of the 
follow-up period, only collect medications used to treat any grade adverse drug reaction and analgesics. Analgesic use has to be recorded via the 
analgesic concomitant medication eCRF. 
h.
Record any cancer-related treatments and bone health agent (BHA) therapy. The option of starting BHA including bisphosphonates or denosumab 
should be considered, taking into consideration applicable guidelines.
i.
Window ±1 day. The measurement of vital signs will include: blood pressure, heart rate, respiratory rate, and temperature.
j.
Window ±1 day. Body weight should be obtained without shoes, using a calibrated electronic physician (column) scale with digital display, 
measurement units 0.1 kg. The same scale should be used for a given subject throughout the study. At all sites (US and ex-US), weight is to be taken 
every 28 days, at minimum, or according to the Investigator’s standard of care, whichever is more frequent. Body weight can be obtained at the local 
healthcare provider on a calibrated scale and the results sent by fax to the Principal Investigator with advanced notice and agreement from the 
Covance Medical Monitor for each subject.
k.
Window ±1 day. A full physical examination must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, 
dermatological, musculoskeletal, and neurological systems. The physical exam is to be performed every 28 days (at minimum), or according to the 
Investigator’s clinical judgment.
l.
Window ±1 day. The ECOG-PS is to be assessed every 28 days (at minimum), or according to the Investigator’s clinical judgment. 


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m.
Hematology parameters will include hematocrit, Hb, platelet counts, RBC counts, WBC counts, WBC differential. Subjects with platelet counts 
<75x109/L and/or absolute neutrophil count <1.0x109/L should undergo repeat weekly hematology examination until resolution.
n.
Within 3 days prior to Day 1 of each cycle, safety laboratory assessments, including hematology and clinical chemistry, must be assessed and the 
Investigator must confirm that the subject meets dosing criteria for bortezomib, as applicable. Additional laboratory assessments should be performed 
according to the institutional guidelines.
o.
If the End of radium-223 dichloride/placebo visit occurs at the same time as the EOT visit, the pregnancy test only needs to be performed once. 
Postmenopausal women (as defined in Section 6.1) are not required to undergo a pregnancy test. 
p.
Window ± 1 day. Clinical chemistry samples will be taken every 28 days, beginning at the start of the Maintenance Period. Sodium, potassium, 
chloride, calcium, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total alkaline phosphatase, serum creatinine, bilirubin 
(total), glucose, phosphate, and albumin. Blood urea nitrogen or urea will also be collected, according to each site’s standard of care. 
q.
To confirm complete response per IMWG criteria. Bone marrow aspirate is acceptable. After the percentage of plasma cells is determined by the local 
laboratory, the remaining bone marrow sample will be sent to the central laboratory for biomarker testing.
r.
To perform if suspicion of new EMD lesion
s.
Window ±7 days. Beginning at the start of the Maintenance Period, collection will occur every 28 days through the end of treatment. During active 
follow-up, M protein will be evaluated according to the site procedures but not less frequently than every 8 weeks. During the follow-up (either active or 
long-term follow up) all bone fractures, or any relevant bone event (e.g., osteoporosis) should be reported as SSE and need to be collected as either 
AEs) or SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment.
t.
Window ±7 days. Response/disease progression assessments will be performed on Cycle 1 Day 1, and every 28 days thereafter through the end of 
the Maintenance Period. During active follow-up, disease response will be assessed according to the site procedures but not less frequently than every 
8 weeks. These assessments should be based on laboratory results provided by the central lab and according to IMWG criteria.
u.
Window ±7 days. Blood and urine samples for biomarkers will be collected before radium-223 dichloride/placebo doses 1 to 6 and then 30 days after 
the last dose of radium-223 dichloride/placebo, or disease progression, whichever occurs first. During the maintenance period, samples will be 
collected every 4 cycles (every 16 weeks). During active follow up visits, samples will be drawn every other visit (every 16 weeks).
v.
Window ±7 days. Plasma samples for circulating tumor DNA will be collected before radium-223 dichloride/placebo doses 1 to 6 and then 30 days after 
the last dose of radium-223 dichloride/placebo, or disease progression, whichever occurs first.
w.
Whole blood for CTC analysis will be collected prior to every dosing with radium 223 dichloride/placebo then 30 days after the last dose of radium-223 
dichloride/placebo, or disease progression, whichever occurs first. During maintenance period, samples will be collected every 4 cycles (every 16 
weeks).
x.
Subjects who have completed the 2 year active follow-up, will be followed with a telephone call every 6 months (±28 days) up to 5 years. A separate 
long-term follow-up study has been set up to follow subjects who received radium-223 dichloride or placebo in the course of Bayer-sponsored clinical 
trials. All subjects will be asked to transition into this separate study to complete their long-term follow-up. The long-term follow-up may start in the 
current trial and subjects will then be asked to transition into the separate roll-over study.


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Figure 9–1: Schedule of drug administration for radium-223 dichloride/placebo, bortezomib, and dexamethasone 
A maximum delay of 28 days is allowed for starting the next cycle of bortezomib + dexamethasone (See Sections 6.3.1.1 and 7.4.4 for further details).
A maximum delay of 28 days due to toxicity (maximum time between two consecutive doses is 10 weeks) is allowed for administering the next dose of radium-
223 dichloride/placebo (See Sections 6.3.1.1 and 7.4.4 for further details). Subjects with radium-223 dichloride/placebo administration delayed from the date 
of the intended dose may receive the subsequent cycles of radium 223 dichloride/placebo at another day other than Day 1 of bortezomib/dexamethasone 
planned schedule.
In case bortezomib is permanently discontinued, radium-223 dichloride/placebo will also be discontinued. (See Section 7.4.4.2 for further details).


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9.2
Visit description
Computed tomography, magnetic resonance, or other imaging conducted at any time 
during the study should be collected and stored.
9.2.1
Screening period
Pre-treatment evaluations will only be performed after the subject has agreed to participate 
and has signed and dated the ICF. No treatment- or trial-related procedures will be initiated 
before the signed consent has been obtained. Skeletal survey, bone marrow specimens 
(bone marrow aspirate or biopsy) and blood and urine protein-M tests (as well as any other 
specific multiple myeloma tumor assessment blood and urine tests) may be done before 
obtaining informed consent if done as part of local standard of care routine and only when 
performed up to 14 days prior to ICF signature. After the percentage of plasma cells is
determined by the local laboratory, the remaining bone marrow sample will be sent to the 
biorepository for retrospective biomarkers testing. Details of the sample handling will be 
summarized in the biosample management report.
The same skeletal survey imaging method (magnetic resonance imaging [MRI], low-dose 
computed tomography [CT], or positron emission tomography CT [PET-CT] are 
acceptable if it is the institutional standard) should be used for the baseline measurement 
and throughout the study. Subjects will not be required to undergo skeletal survey or bone 
biopsy/aspirate if suitable images/samples taken up to 14 days prior to ICF signature are 
available. 
If logistical reasons require, only for eligibility confirmation, local lab results of blood and 
urine specific multiple myeloma tumor assessment tests can be used. If indeed any local 
lab samples are used for eligibility confirmation, blood and urine samples for central lab 
analysis will still be collected and used as the final baseline value for data analysis.  
Pre-treatment evaluations will be performed according to the eligibility criteria. If the 
subject is eligible for the study, the parameters at the screening visit showing subject 
health status, including blood values, will be recorded in the eCRF.
After eligibility has been confirmed and documented, an additional period of up to a total 
of 21 days will take place before the administration of the first study drug, to account for 
all logistical needs related to radium-223 dichloride dose preparation and transportation.
All efforts will be made to shorten this period as much as possible.
9.2.1.1
Study Procedures 
Screening Procedures
The following procedures and evaluations will be performed within 21 days after the time 
of ICF signature.

Sign informed consent

Subject registration and subject number assignment via IxRS

Review of inclusion and exclusion criteria and confirm eligibility

Demographics


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
Record disease history

Record medical history

Record prior SRE

Administer the BPI-SF questionnaire 

Administer the Resource Utilization Questionnaire (RUQ)

Record analgesics on the eCRF. Subjects will be asked to record 24-hour analgesic 
use. Pain medication will also be assessed at each visit by study site; subjects should 
be requested to bring all pain medication to each visit.

Record opioid use

Record AEs and SAEs
Note: all bone fractures and bone associated events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment

Record concomitant medications/therapy including bone health agent (BHA) (e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record prior multiple myeloma-related treatment

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature

12-lead ECG; hypokalemia should be corrected prior to ECG collection. ECG 
should be obtained when serum potassium is ≥3.5 mmol/L.

Record height and weight. Body weight should be obtained without shoes, using a 
calibrated electronic physician (column) scale with digital display, measurement 
units 0.1 kg. The same scale should be used for a given subject throughout the 
study. Body weight can be obtained at the local healthcare provider on a calibrated 
scale and the results sent by fax to the Principal Investigator with advanced notice 
and agreement from the Covance Medical Monitor for each subject. At all sites (US 
and ex-US), weight is to be taken 3 to 5 days before each radium-223 dichloride/
placebo dose (for US sites) or 72 hours before each radium-223 dichloride dose (for 
ex-US sites). The weight measurements prior to radium-223 dichloride/placebo dose 
must be reported to the country PRD depot to allow adequate time for PRD 
preparation and delivery (approximately 2 days).

Perform full physical examination

ECOG-PS

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, white 
blood cell (WBC) counts, and WBC differential. Hematology should be measured 
within 2 weeks before the first radium-223 dichloride/placebo dose. The same 
sample can be used for dosing radium-223 dichloride/placebo if taken within 


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72 hours before dosing, otherwise a repeat sample within 72 hours before dosing 
will be required. 

Pregnancy test and estradiol assay: women of child-bearing potential must have a 
negative urine pregnancy test performed at screening and within 72 hours before the 
first dose of radium-223 dichloride/placebo. Postmenopausal women (as defined in 
Section 6.1) are not required to undergo a pregnancy test. An estradiol assay is 
required within 72 hours before the first dose of radium-223 dichloride/placebo in 
premenopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and postmenopausal women age <55 years and 1 year or more of 
amenorrhea and no ovarian suppression.

Blood draw for clinical chemistry: sodium, potassium, chloride, calcium, ALT, 
AST, lactate dehydrogenase (LDH), total ALP, serum creatinine, blood urea 
nitrogen (BUN; or urea), bilirubin (total), glucose, phosphate, and albumin; clinical 
chemistry should be measured within 2 weeks before the first radium-223 
dichloride/placebo dose. The same sample can be used for dosing radium-223 
dichloride/placebo if taken within 72 hours before dosing, otherwise a repeat sample 
within 72 hours before dosing will be required.

A coagulation panel: PT, PTT, and INR of PT

Hepatitis B and C assessment: Subjects are not eligible if they have an active 
Hepatitis B or C infection requiring treatment. Subjects with occult or prior HBV 
infection (defined as positive HBcAb and negative HBsAg) may be included if 
HBV-DNA is undetectable at screening. Subjects positive for HCV antibody must 
be negative for HCV-RNA by PCR assessment.

Collect blood for serum and plasma as well as urine samples for exploratory 
evaluation of biomarkers

Plasma for ctDNA analysis

Bone marrow evaluation for assessment of percentage plasma cells if no suitable 
sample is available that was taken as part of local routine standard of care up to 14 
days prior to ICF signature; repeat assessment is required to confirm CR per IMWG 
criteria. Samples must be sent to the local laboratory for evaluation.

Extramedullary disease (EMD; i.e., soft-tissue plasmacytoma) assessment: the 
method of assessment will be recorded in the eCRF; if EMD is present at screening 
as per IMWG criteria subject is not eligible, if suspicion of new lesion then see 
Section 9.4.2 for additional details.

Blood draw and 24-hour urine collection for M-protein and β2-microglobulin 
assessments by SPEP, 24-hour UPEP, and Free lite assay. Serum and urine 
immunofixation (IF) is only performed at study entry and to confirm a CR 
(conducted on the first observation of a CR in the SPEP and/or UPEP sample and 
repeated every 28 days until disease progression). These measurements will be 
performed at the Central Laboratory. These samples should be collected and sent to 
Central Laboratory even in the case that local lab samples are used for the purpose 
of eligibility confirmation.


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
Disease assessments should be based on laboratory results provided by the central 
lab and according to IMWG criteria.

Record SSEs during the screening period. The Investigator will assess the subject 
for the following disease events:

Use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-
vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Skeletal survey (MRI, low-dose CT, or PET-CT are acceptable if it is the 
institutional standard): if no suitable images are available that were taken as part of 
local routine standard of care up to 14 days prior to ICF signature. Skeletal survey 
should include chest (postero-anterior [PA] or antero-posterior [AP]; lateral), skull 
(lateral), upper extremities (shoulder to elbow; AP), lower extremities (hip to knee; 
AP), pelvis (AP), and cervical/thoracic/lumbar spine (AP and lateral). The same 
skeletal survey imaging method should be used for the baseline measurement and 
throughout the study. All digitized images (both baseline and post-baseline) will be 
collected and stored for potential retrospective analysis.
Important note: If re-screening is indicated, approval from the Sponsor’s medical monitor 
is required. No more than 1 re-screening attempt will be allowed for each subject. Please 
refer to Section 6.3.1 for further guidance on cases in which re-screening is allowed and 
the time window for re-screening.
9.2.2
Randomization
Phase 2 only
Randomization in the IXRS may occur only after the completion of the screening 
evaluations and re-confirmation of subject eligibility and weight. Randomization may 
coincide with the end of a screening visit if all evaluations are complete; otherwise, 
randomization may be performed in a separate clinic visit. Once the subject is registered in 
IXRS, the initial drug shipment will be triggered.
9.2.3
Treatment period
Treatment consists of the following:
Phase 1b: up to 6 doses of radium-223 dichloride (1 dose every 6 weeks) at 2 different 
planned dose levels administered to ascending dose cohorts, in combination with 10 cycles 
(3 weeks per cycle for the first 8 cycles, then every 4 weeks) of BOR and DEX (Cohort 1 
and Cohort 2), followed by ongoing maintenance treatment with BOR and DEX (4 weeks 
per cycle) up to 2 years after the first dose of study treatment or until a PFS event occurs
(death or MM progression as per IMWG uniform criteria), unacceptable toxicity develops, 
or the subject withdraws consent, whichever occurs first.
Phase 2: up to 6 doses of radium-223 dichloride/placebo (1 dose every 6 weeks) at the
MTD/RP2D in combination with 10 cycles (3 weeks per cycle for the first 8 cycles, then 


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every 4 weeks) of BOR and DEX followed by ongoing maintenance treatment with BOR 
and DEX (4 weeks per cycle) up to 2 years after the first dose of study treatment or until a 
PFS event occurs (death or MM progression as per IMWG uniform criteria), unacceptable 
toxicity develops, or the subject withdraws consent, whichever occurs first.
All subjects must have safety evaluations for 30 days after the last dose of study treatment. 
If the subject does not return for a 30-day safety follow-up visit regardless of the reason, 
the site should at a minimum contact the subject for the 30-day safety follow-up by 
telephone, email, or letter.
The treatment period extends from the day of the first dose of radium-223 dichloride/
placebo to 30 days after last dose of study treatment (radium-223 dichloride/placebo, 
BOR, or DEX, whichever is last) or after discontinuation from study treatment. 
During the treatment period, the subject will visit the study center at regular intervals. 
Radium-223 dichloride/placebo will be injected once every 6 weeks for a total of 6 doses. 
The minimum time window between 2 doses of radium-223 dichloride/placebo must be 
6 weeks (Section 7.1). 
Bortezomib will be administered subcutaneous (SC) at 1.3 mg/m2/dose, on Days 1, 4, 8, 
and 11 in a 21-day cycle, for 8 cycles. 
For extended therapy beyond 8 cycles (Cohort 1 and Cohort 2), BOR will be administered 
on Days 1 and 15 of a 28-day cycle for up to 2 years after the first dose of study treatment. 
Dexamethasone will be administered orally at 40 mg, on Days 1, 4, 8, and 11 in a 21-day 
cycle, for 8 cycles. DEX administration may be split over 2 days (on the day of BOR
administration and the day after BOR administration) at the discretion of the Investigator.
For extended therapy beyond 8 cycles (Cohort 1 and Cohort 2), DEX will be administered 
orally at 20 mg/dose, on Days 1 and 15 of a 28-day cycle along with BOR for up to 2 years 
after the first dose of study treatment, or until a progression-free survival (PFS) event 
occurs, the subject withdraws consent or unacceptable toxicity develops, whichever occurs 
first.
Omit BOR if delay is >3 days. Maintenance BOR and DEX is administered on Days 1 and 
15 of a 28-day cycle beginning at the start of the Maintenance Period for up to 2 years 
after the first dose of study treatment, or until a progression-free survival (PFS) event 
occurs, the subject withdraws consent or unacceptable toxicity develops, whichever occurs 
first (Section 7.1).
Note: Subjects who experience improvement of disease symptoms from the study 
treatment may continue radium-223 dichloride/placebo plus BOR-DEX at the investigator 
discretion and with sponsor agreement.
On Cycle 1 Day 1 only, radium-223 dichloride/placebo must be administered before BOR
or DEX and the sample collection for M-protein must be completed before administration 
of radium-223 dichloride/placebo. 
Weight is to be assessed 3 to 5 days before each radium-223 dichloride/placebo dose (for 
US sites) or 72 hours before each radium-223 dichloride/placebo dose (for ex-US sites). 
The weight measurements prior to radium-223 dichloride/placebo dose must be reported to 
the country PRD depot to allow adequate time for PRD preparation and delivery 


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(approximately 2 days). It is the responsibility of the unblinded site staff to calculate the 
required volume of radioactivity for the subject’s radium-223 dichloride dose based on the 
subject’s body weight before the dosing day, and the reference date of the received study 
medication (Section 7.4).
Before administration of radium-223 dichloride/placebo, the subject must be well 
hydrated; thus, the subject should be instructed to drink ad libitum. 
The blood samples for clinical chemistry and hematology should be taken within 72 hours 
before each radium-223 dichloride/placebo dose, and the hematology parameters, 
including a complete blood count (CBC), must be evaluated before each radium-223 
dichloride/placebo dose. 
Pregnancy test and estradiol assay: women of child-bearing potential must have a negative 
urine pregnancy test performed within 72 hours before each radium-223 dichloride/placebo
dose. Postmenopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test. An estradiol assay is required within 72 hours before the first radium-223 
dichloride dose in premenopausal women with radiotherapy ovarian ablation or medical 
ovarian suppression and postmenopausal women age <55 years and 1 year or more of 
amenorrhea and no ovarian suppression.
Laboratory parameters will be checked before dosing of study treatment per Section 7.4.4.
If there is more than a 28 day delay in the next dose (i.e., more than 10 weeks between 
doses), radium-223 dichloride/placebo doses should be permanently discontinued. Subjects 
who discontinue radium-223 dichloride/placebo treatment prior to experiencing an SSE or 
a PFS event can continue to receive BOR/DEX if considered by the Investigator to be in 
the subject’s best interest and be followed up for SSEs and response/disease progression. 
Subjects with radium-223 dichloride/placebo administration delayed from the date of the 
intended dose may receive the subsequent cycles of radium 223 dichloride/placebo at 
another day other than Day 1 of BOR/DEX.
9.2.3.1
Day of administration of radium-223 dichloride/placebo (total of 6 
doses to be given once every 6 weeks) 
Assessments to be performed BEFORE radium-223 dichloride/placebo
administration:

Ensure radium-223 dichloride/placebo dosing criteria have been met
Please note: For Cycle 10, Day 15 (dose # 6) not all assessments below are required 
(see Table 9–1).

Review and ensure subjects complete: 

The BPI-SF questionnaire

The RUQ

24-hour analgesic use; subjects should bring all pain medications to each visit. 
Record analgesic use on the eCRF.

Record opioid use


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
Record AEs, SAEs and DLTs 
Note: All bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.

Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature

Record weight. Body weight should be obtained without shoes, using a calibrated 
electronic physician (column) scale with digital display, measurement units 0.1 kg. 
The same scale should be used for a given subject throughout the study. Body 
weight can be obtained at the local healthcare provider on a calibrated scale and the 
results sent by fax to the Principal Investigator with advanced notice and agreement 
from the Covance Medical Monitor for each subject. At all sites (US and ex-US), 
weight is to be taken 3 to 5 days before each radium-223 dichloride dose (for US 
sites) or 72 hours before each radium-223 dichloride/placebo dose (for ex-US sites). 
The weight measurements prior to radium-223 dichloride/placebo dose must be 
reported to the country PRD depot to allow adequate time for PRD preparation and 
delivery (approximately 2 days).

Perform full physical examination

ECOG-PS

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential. The blood sample for hematology must be taken, 
analyzed, and evaluated within 72 hours before each radium-223 dichloride/placebo
dose.

Pregnancy test: women of child-bearing potential must have a negative urine
pregnancy test performed within 72 hours before each radium-223 
dichloride/placebo dose. Post-menopausal women (as defined in Section 6.1) are not 
required to undergo a pregnancy test. 

Blood draw for clinical chemistry: sodium, potassium, chloride, calcium, ALT, 
AST, lactate dehydrogenase (LDH), total ALP, serum creatinine, blood urea 
nitrogen (BUN; or urea), bilirubin (total), glucose, phosphate, and albumin; clinical 
chemistry should be measured within 72 hours before each radium-223 
dichloride/placebo dose.


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
Collect blood for serum and plasma as well as urine samples for exploratory 
evaluation of biomarkers 

Plasma for ctDNA analysis

Whole blood for CTCs analysis

Blood draw and 24-hour urine collection for M-protein assessments by SPEP, 
24-hour UPEP, and Freelite assay. Serum and urine IF is only performed to confirm 
a CR (conducted on the first observation of a CR in the SPEP and/or UPEP sample 
and repeated every 21 days (±7 days) through Cycle 8 and then every 28 days (±7 
days) thereafter until disease progression). These measurements will be performed 
at the Central Laboratory.

Record disease assessment according to IMWG criteria based on central laboratory 
results

Record SSEs (in accordance with the schedule of procedures (see Table 9–1). The 
Investigator will assess the subject for the following disease events:

Use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Administer radium-223 dichloride/placebo. One of 2 different doses of radium-223
dichloride (33 or 55 kBq/kg) will be administered in the phase 1b, then the 
MTD/RP2D in the phase 2. 
Assessments to be performed AFTER each dose of radium-223 dichloride/placebo:

The IxRS must be accessed for drug re-supply in preparation for the next study visit. 
This should be done on the day of the current treatment visit (where possible) to 
provide the maximum time in advance of the next scheduled subject visit date and in 
accordance with country-specific order lead-times.
9.2.3.2
Day 1 of bortezomib/dexamethasone Cycles 1 through 8 (±7 days) 

Review and ensure subjects complete: 

24-hour analgesic use; subjects should bring all pain medications to each visit. 
Record analgesic use on the eCRF

Record opioid use

Record AEs, SAEs and DLTs
Note: All bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.


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
Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature

Record body weight 

Perform full physical examination

ECOG-PS

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential. Hematology samples must be drawn a minimum of 
once weekly, or according to the site’s standard of care, whichever is more frequent. 
A CBC must be performed before each BOR injection. 

Pregnancy test: women of child-bearing potential must have a negative urine 
pregnancy test performed within 72 hours before each radium-223 dichloride dose. 
Post-menopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test.

Blood draw for clinical chemistry on Day 1 of each cycle: sodium, potassium, 
chloride, calcium, ALT, AST, LDH, total ALP, serum creatinine, BUN (or urea) 
bilirubin (total), glucose, phosphate, and albumin.

Blood draw and 24-hour urine collection for M-protein assessments by SPEP, 
24-hour UPEP, and Freelite assay. Serum and urine IF is only performed to confirm 
a CR (conducted on the first observation of a CR in the SPEP and/or UPEP sample 
and repeated every 21 days (±7 days) through Cycle 8 and then every 28 days (±7 
days) thereafter until disease progression). These measurements will be performed 
at the Central Laboratory.

Bone marrow evaluation for assessment of percentage of plasma cells: only to 
confirm CR after CR was observed at 2 consecutive visits based on M-protein 
results

Record response/disease progression according to IMWG criteria based on central 
laboratory results

Record SSEs in accordance with the schedule of procedures (see Table 9–1). The 
Investigator will assess the subject for the following disease events:

Use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Administer BOR plus DEX


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9.2.3.3
Days 4, 8, and 11 of bortezomib/dexamethasone Cycles 1 through 8
(±3 days) 

Record opioid use

Record AEs, SAEs and DLTs
Note: All bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.

Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate,  and temperature

Record body weight

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential. Hematology samples must be drawn a minimum of 
once weekly, or according to the site’s standard of care, whichever is more frequent. 
A CBC must be performed before each BOR injection.

Blood draw for clinical chemistry on Day 11 of Cycles 1 and 2: sodium, potassium, 
chloride, calcium, ALT, AST, LDH, total ALP, serum creatinine, BUN (or urea) 
bilirubin (total), glucose, phosphate, and albumin. 

Administer BOR plus DEX
9.2.3.4
End of radium-223 dichloride/placebo visit
The End of radium-223 dichloride/placebo visit will be conducted 30 days (+7 days) after 
the last dose of radium-223 dichloride/placebo. 

24-hour analgesic use; subjects should bring all pain medications to each visit.
Record analgesic use on the eCRF

Record opioid use

Record AEs and SAEs
Note: All bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.

Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature


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
Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential.

Pregnancy test. Post-menopausal women (as defined in Section 6.1) are not required 
to undergo a pregnancy test. 

Collect blood for serum and plasma as well as urine samples for exploratory 
evaluation of biomarkers

Plasma for ctDNA analysis

Whole blood for CTCs analysis

A skeletal survey (MRI, low-dose CT, or PET-CT are acceptable if it is the 
institutional standard) will be completed and should include the chest (PA or AP; 
lateral), skull (lateral), upper extremities (shoulder to elbow; AP), lower extremities 
(hip to knee; AP), pelvis (AP), and cervical/thoracic/lumbar spine (AP and lateral).
9.2.3.5
Maintenance treatment with bortezomib/dexamethasone
For extended therapy beyond 8 cycles, BOR and DEX will be administered on Days 1 and 
15 of a 28-day cycle as maintenance therapy for up to 2 years after the first dose of study 
treatment, or until a progression-free survival (PFS) event occurs, the subject withdraws 
consent or unacceptable toxicity develops, whichever occurs first.
Note: For cycles 9 and 10, radium-223 dichloride/placebo may be administered (see Table 
9–1).

Review and ensure subjects complete (every 28 days): 

The BPI-SF questionnaire

The RUQ

24-hour analgesic use; subjects should bring all pain medications to each visit. 
Record analgesic use via the analgesic concomitant medication eCRF.

Record opioid use

Record AEs and SAEs
Note: all bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AE(s) or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.

Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature

Perform full physical examination every 28 days (at minimum), or according to the 
Investigator’s clinical judgment


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
Record weight at least every 28 days, or per the Investigator’s standard of care, 
whichever is more frequent

ECOG-PS every 28 days (at minimum), or according to the Investigator’s clinical 
judgment

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential to be done within 3 days prior to each dose of BOR
and the Investigator must confirm that the subject meets dosing criteria for BOR. 
Additional laboratory assessments should be performed according to the 
institutional guidelines. 

Pregnancy test will be administered 72 hours before radium-223 dichloride/placebo
dosing. After the last radium-223 dichloride/placebo dose, pregnancy tests will be 
administered on Day 1 of the BOR-only cycle through the EOT.

Blood draw for clinical chemistry every 28 days: sodium, potassium, chloride, 
calcium, ALT, AST, LDH, total ALP, serum creatinine BUN (or urea), bilirubin
(total), glucose, phosphate, and albumin. 

Blood draw and 24-hour urine collection every 28 days for M-protein assessments 
by SPEP, 24-hour UPEP, and Freelite assay. Serum and urine IF is only performed 
to confirm a CR (conducted on the first observation of a CR in the SPEP and/or 
UPEP sample and repeated every 28 days until disease progression). These 
measurements will be performed at the Central Laboratory.

Record disease assessment

Record SSEs every 28 days. The Investigator will assess the subject for the 
following disease events:

Use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Collect blood for serum and plasma as well as urine for exploratory evaluation of 
biomarkers every 4 cycles during maintenance

Plasma for ctDNA analysis every 4 cycles during maintenance

Whole blood for CTCs analysis every 4 cycles during maintenance

Administer BOR plus DEX
9.2.3.6
End of treatment visit (30 days[+7 days] post-last study treatment 
administration)
All subjects must have safety evaluations for 30 days after the last dose of study treatment. 
If the subject refuses to return for a 30-day safety follow-up visit, the site should at a 
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This visit will occur 30 days (+7 days) after the last dose of study treatment administration 
(radium-223 dichloride/placebo, BOR, DEX; whichever is last) or after discontinuation 
from study treatment. Subjects whose last dose of radium-223 dichloride/placebo coincides 
with the last dose of BOR and DEX should complete all procedures noted for both the End 
of radium-223 dichloride/placebo visit and the EOT visit; however, overlapping 
procedures from the 2 visits only need to be completed once.

Review and ensure subjects complete: 

The BPI-SF questionnaire on the day of the visit

The RUQ

24-hour analgesic use; subjects should bring all pain medications to each visit. 
Record analgesic use via the analgesic concomitant medication eCRF.

Record opioid use

Record AEs and SAEs
Note: all bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.

Record concomitant medications/therapy including bone health agent (BHA, e.g.,
bisphosphonates, denosumab) and any anti-cancer treatments
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature

ECOG PS

Blood draw for hematology: hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC differential.

Pregnancy test. Post-menopausal women (as defined in Section 6.1) are not required 
to undergo a pregnancy test.  

Blood draw for clinical chemistry: sodium, potassium, chloride, calcium, ALT, 
AST, LDH, total ALP, serum creatinine, BUN (or urea), bilirubin (total), glucose, 
phosphate, and albumin. 

Blood draw and 24-hour urine collection for M-protein assessments by SPEP, 
24-hour UPEP, and Freelite assay. Serum and urine IF is only performed to confirm 
a CR (conducted on the first observation of a CR in the SPEP and/or UPEP sample 
and repeated every cycle until disease progression). These measurements will be 
performed at the Central Laboratory.

Record disease assessment

Record SSEs. The Investigator will assess the subject for the following disease 
events:

Use of EBRT to relieve skeletal symptoms


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
New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Collect blood for serum and plasma as well as urine samples for exploratory 
evaluation of biomarkers

Plasma for ctDNA analysis

Whole blood for CTCs analysis
9.2.4
Active follow-up period
Subjects who have discontinued study treatment for any reason including progressive 
disease (PD) will be followed with a clinic visit every 8 weeks (±7 days) up to 2 years 
after the last dose of radium-223 dichloride/placebo treatment, death or consent 
withdrawal, whichever occurs first.
The maximum duration of the active follow-up period is 2 years from last dose of 
radium 223 dichloride/placebo treatment.

Review and ensure subjects complete: 

The BPI-SF questionnaire on the day of the visit

The RUQ

24-hour analgesic use; subjects should bring all pain medications to each visit. 
Record analgesic use on the eCRF

Record opioid use

Record treatment-related AEs/SAEs 
Note: all bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.
Note: Record all occurrences of leukemia, MDS, aplastic anemia, myelofibrosis, or 
any other new primary malignancy. All occurrences of leukemia, MDS, aplastic 
anemia, myelofibrosis, or any other new primary malignancy must be reported as 
SAEs regardless of the Investigator’s causality assessment. If a subject is unable to 
provide required details, this information may need to be obtained from the primary 
provider.
Note: Record any occurrence of febrile neutropenia and hemorrhage related to 
radium-223 dichloride

Record any anti-cancer treatments and bone health agent (BHA) such as 
bisphosphonates or denosumab
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record vital signs: blood pressure, heart rate, respiratory rate, and temperature


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
Blood draw and 24-hour urine collection for M-protein assessments by SPEP, 
24-hour UPEP, and Freelite assay for subjects who ended study treatment for 
reasons other than disease progression. Serum and urine IF is only performed to 
confirm a CR (conducted on the first observation of a CR in the SPEP and/or UPEP 
sample and repeated every cycle until disease progression). These measurements 
will be performed at the Central Laboratory.

Record SSEs. The Investigator will assess the subject for the following disease 
events:

Use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression

Record response/disease progression
Note: Only for subjects who ended study treatment for reasons other than disease 
progression.

Collect serum, plasma and urine samples samples for exploratory evaluation of 
biomarkers every 2 visits (every 16 weeks)

Plasma for ctDNA analysis

Whole blood for CTCs analysis
9.2.5
Long-term follow-up (telephone call every 6 months [±28 days])  
Subjects who have completed the 2 year active follow-up will be followed with a 
telephone call every 6 months (±28 days) for up to 5 years. 
A separate long-term follow-up study has been set up to follow subjects who received 
radium-223 dichloride or placebo in the course of Bayer-sponsored clinical trials. All 
subjects will be asked to transition into this separate study to complete their long-term 
follow-up. The long-term follow-up may start in the current trial and subjects will then be 
asked to transition into the separate roll-over study.

Record treatment-related AEs/SAEs  
Note: all bone fractures and bone related events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, regardless of the 
investigator’s causality assessment.
Note: Record all occurrences of leukemia, MDS, aplastic anemia, myelofibrosis, or 
any other new primary malignancy. All occurrences of leukemia, MDS, aplastic 
anemia, myelofibrosis, or any other new primary malignancy must be reported as 
SAEs regardless of the Investigator’s causality assessment. If a subject is unable to 
provide required details, this information may need to be obtained from the primary 
provider.


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Note: Record any occurrence of febrile neutropenia or hemorrhage related to 
radium-223 dichloride

Record any anti-cancer treatments and bone health agent (BHA) such as 
bisphosphonates or denosumab
Note: The initiation of BHA such as bisphosphonates or denosumab should be 
considered by investigators taking into consideration applicable guidelines.

Record survival status
Note: As this information will be collected from the subject over the telephone, it is 
the clinical site’s responsibility to obtain and make available the source 
documentation for the information collected and document it in the eCRF.
9.3
Population characteristics
9.3.1
Demographic
The following demographic characteristics will be collected:

Date of birth (where allowed by local regulation)

Age at enrollment 

Race and ethnicity (where it is allowed by local regulation)

Sex
9.3.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) meeting all 
criteria listed below will be collected as available to the Investigator:

Not pertaining to the study indication (e.g., bone related events such as 
osteoporosis)

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1.
9.3.3
Other baseline characteristics
The following other baseline characteristics will be collected:

Date of multiple myeloma diagnosis

International Staging System for multiple myeloma (ISS) at diagnosis

ISS for multiple myeloma at baseline

Treatment of multiple myeloma before enrollment (e.g., chemotherapy, stem cell 
transplantation, radiotherapy) 

Date of latest multiple myeloma relapse


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
Weight and height

Vital signs: blood pressure, heart rate, respiratory rate, and temperature

ECOG-PS

Cancer pain assessment

Laboratory assessments:

Hematology: hematocrit, Hb, platelet counts, RBC count, WBC count, WBC 
differential

Clinical chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH, 
total ALP, serum creatinine, BUN (or urea), bilirubin (total), glucose, 
phosphate, and albumin

LVEF

LVEF values will not be collected, however the investigator must verify that 
subjects meet all inclusion/exclusion criteria at study entry
9.4
Anti-multiple myeloma activity (phase 2)
9.4.1
Anti-multiple myeloma activity endpoints (phase 2)
Primary endpoint

Combined CR+VGPR rate as determined by IMWG uniform response criteria, 
defined as the proportion of subjects in the analysis population who have complete 
response (CR), and very good partial response [VGPR]) during the course of the 
study
Secondary endpoints:

Objective response rate (ORR), as determined by IMWG uniform response criteria, 
defined as the proportion of subjects in the analysis population who have complete 
response (CR), partial response (PR) and very good partial response [VGPR]) 
during the course of the study

Progression-free survival, as defined as the time (in months) from the date of 
randomization to the date of disease progression or death, whichever occurs first.

Duration of response (DOR), as determined by IMWG response criteria, is defined 
as the time (in months) from the date of first response to treatment (CR, VGPR or
PR) to the date of disease progression or death. Duration of response is only applied 
to subjects with a disease response of at least PR.

Overall survival as defined as the time (in months) the date of randomization to the 
date death.


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Exploratory endpoints:

Time to first on-study SSE, defined as the time (months) from the date of the first 
dose of radium-223 dichloride to the date of the first on-study SSE.

An on-study SSE is defined as:
Use of EBRT to relieve skeletal symptoms
Occurrence of new symptomatic pathological bone fractures (vertebral 
or non-vertebral)
Occurrence of spinal cord compression
Tumor-related orthopedic surgical intervention

Time to pain progression, defined in subjects evaluable for pain progression at 
baseline (i.e., subjects with a worst pain score of ≤8 at the baseline assessment). 
Pain intensity is measured using the Brief Pain Index-Short Form (BPI-SF) (Section 
16.7).
Pain progression is defined as the occurrence of either a pain increase or an 
increase in pain management with respect to baseline, whichever occurs first.
A pain increase is defined as an increase of 2 or more points in the “worst pain in 
24 hours” score from baseline observed at 2 consecutive evaluations ≥28 days
apart.
An increase in pain management is defined as follows:

For subjects not on opioids at baseline, initiation of short- or long-acting 
opioid use for pain will constitute an increase in pain management

For subjects being treated with ≤600 oral morphine equivalents (OMEs) 
of opioids per day at baseline, an increase by 1 point in the daily 
Analgesic Quantification Algorithm (AQA) score and an increase ≥50% 
in daily OMEs will constitute an increase in pain management

For subjects being treated at the highest AQA level (>600 OMEs/day) at 
baseline, an increase ≥50% in daily OMEs from baseline will constitute 
an increase in pain management

The time to pain progression is defined for applicable subjects as the time (in 
days) from date of the first dose of radium-223 dichloride/placebo until 
occurrence of the first post-baseline pain progression event. Subjects without 
pain progression as of the last post-baseline pain assessment, whether or not 
surviving, will be censored at the last post-baseline pain assessment. Subjects 
with insufficient baseline assessment(s) or without adequate post-baseline 
assessment(s) will be censored at the baseline date.

Change in MM disease markers:

Change in M-protein 


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
Evaluate potentially predictive biomarker candidates (ctDNA, CTCs, MM 
related cytokines)

Time to opioid use for cancer pain in subjects without opioid use at baseline, 
defined as the interval from date of the first dose of radium-223 dichloride to the 
first date of opioid use.

Bone biomarkers, including UNTx, SCTx, total ALP and B-ALP, PINP, and ICTP.

Change in the number of active bone lesions (for PET-CT, X-ray, MRI, or low-dose 
CT) and/or the intensity of PET uptake (for PET-CT) from baseline to the follow-up 
evaluation. The number of active bone lesions and the intensity of PET uptake at 
baseline will be evaluated in comparison to the follow-up PET-CT. For 
conventional skeletal surveys based on x-ray, MRI, or low-dose CT, the number of 
bone lesions at baseline and at the end of radium-223 dichloride treatment, as 
specified, will be evaluated. 
9.4.2
Anti-multiple myeloma activity evaluation
Disease Assessment
Response and disease progression will be assessed by Investigators based on central 
laboratory results and according to the IMWG uniform response criteria every 21 days
during the first 8 cycles of BOR for all cohorts and afterwards every 28 days (±7 days) 
from the first dose of radium-223 dichloride/placebo and BOR/DEX to the EOT, and at 
each visit during the active follow-up period. The assessments will include SPEP, 24-hour 
urine collection for UPEP, and Freelite assay at all visits for all subjects. Bone marrow 
specimen (bone marrow aspirate or biopsy) and EMD evaluation will be performed at 
baseline and thereafter as clinically indicated according to IMWG criteria. 
For subjects obtaining a CR, this will also include IF, a bone marrow biopsy (or aspirate)
at the time of second consecutive CR. After the percentage of plasma cells is determined 
by the local laboratory, the remaining bone marrow sample will be sent to the central 
laboratory for biomarker testing.
The anti-multiple myeloma activity endpoint of combined CR+VGPR rate and ORR 
(proportion of subjects with PR or better) will be assessed by Study Investigators. The 
responses of sCR, CR, VGPR, and PR require 2 consecutive assessments (according to 
IMWG criteria) at any time before progression or initiation of any new therapy.
Disease progression requires any 1 of the following criteria: 

Increase in serum M-protein by ≥25% above the lowest response level and an 
absolute increase of ≥ 5 g/L

Increase in urine M-protein by ≥25% above the lowest remission value and an 
absolute increase in excretion by ≥200 mg/24 hours

Appearance of soft-tissue plasmacytoma (extramedullary disease, EMD)

Appearance of new bone lesion or increase in size of existing bone lesions by ≥50%

Unexplained hypercalcemia (>2.875 mM or >11.5 g/dL)


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Progression must be confirmed according to IMWG criteria.
9.5
Pharmacokinetics / pharmacodynamics
No PK measurements will be performed in this study. No PK interaction is expected 
between radium-223 dichloride and the co-administered BOR and DEX therapy or with 
BOR and DEX. Radium-223 dichloride is an isotope and is, therefore, not metabolized. 
There are no hints that radium is involved in any transporter process. The main portion of 
radioactivity is excreted with the feces. The liver seems not to be involved in the excretion 
of radium-223 dichloride or its decay products. They are directly excreted into the small 
intestine. The co-administered products are typical small molecules that are metabolized in 
the liver. Thus, no direct impact of radium-223 dichloride on the PK of the co-
administered products is expected.
9.6
Safety
The primary objective of the phase 1b part of the study is to determine the maximum 
tolerated dose (MTD) or recommended phase 2 dose (RP2D) and the safety of radium-223 
dichloride in combination with bortezomib (BOR) and dexamethasone (DEX).
One of the secondary objectives of phase 2 is to evaluate the safety of radium-223 
dichloride in combination with BOR and DEX compared to the safety of placebo in 
combination with BOR and DEX.
The Investigator(s) and the Sponsor’s representative will review the safety data throughout 
the course of the study. Additional safety reviews will be conducted by the Steering 
Committee, IDMC and Sponsor as appropriate. 
In phase 1 b, radium-223 dichloride at 2 dose levels in combination with BOR/DEX will 
be evaluated in subjects with relapsed multiple myeloma. Subjects will be treated 
sequentially at two dose levels (33 kBq/kg body weight and 55 kBq/kg body weight). The 
starting dose is 33 kBq/kg body weight every 6 weeks, which is a dose lower than the dose 
of radium-223 dichloride monotherapy approved for CRPC (55 kBq/kg body weight) and 
will be evaluated in combination with BOR/DEX. The dose of 55 kBq/kg body weight is 
evaluated in the second cohort. 
The decision to move from one cohort to the next higher dose cohort will be made 
following a 3 + 3 design as described in Section 5.1.2. 
All subjects enrolled in this Phase 1b study must be evaluated for the occurrence of DLTs 
during the DLT observation window, which is defined as the time from the first dose of 
study treatment through 21 days after administration of the second dose of radium-223 
dichloride. 
A safety data summary review (including, but not limited to, AEs, dose modifications, and 
laboratory changes) will be conducted by the Steering Committee and Sponsor to 
determine whether dosing into the next higher cohort may proceed.
For the phase 2 part of the study, an Independent Data Monitoring Committee (IDMC) will 
conduct safety reviews in accordance with the appropriate Charter. The IDMC will review 
the safety data once 20 and 50 subjects have completed 2 doses of radium-223 dichloride 
or placebo in combination with bortezomib/dexamethasone (plus a follow-up of at least 


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3 weeks after the second radium-223 dichloride/placebo dose) treatment, and every 
6 months thereafter. The first evaluation will be performed in order to evaluate the safety 
and to confirm the MTD/RP2D. 
The following safety variables will be evaluated in this study:

Adverse events: AEs will be collected and recorded on an ongoing basis throughout 
the study as described in Section 9.6.1.

Safety variables: Safety variables will include the analysis of acute and long-term 
effects and the appearance of new primary malignancies and hematopoietic reserve 
for tolerability of subsequent chemotherapy. The complete list of variables to be 
analyzed for this study will be provided in the SAP.

Laboratory assessments: The following laboratory assessments with reference 
ranges, including Investigator determinations, will be recorded in the source 
documentation and the eCRF:

Hematology: hematocrit, Hb, platelet counts, RBC count, WBC count, WBC 
differential

Clinical chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH,
total ALP, serum creatinine, BUN (or urea), bilirubin (total), glucose, 
phosphate, and albumin

A coagulation panel: PT, PTT, and INR
All AEs will be reported according to MedDRA coding and graded for severity according 
to CTCAE v4.03. Laboratory evaluations, vital signs, and changes in physical examination 
findings will also be assessed.
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event 
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a 
subject or clinical investigation subject after providing written informed consent for 
participation in the study. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician 
treating the subject should not be recorded as an AE (however, the condition for which the 
surgery is required may be an AE).


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In the following differentiation between medical history and AEs, the term “condition” 
may include abnormal physical examination findings, symptoms, diseases, laboratory
findings, or scans.

Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded as 
medical history (e.g., seasonal allergy without acute complaints)

Conditions that started before signing of informed consent and for which symptoms 
or treatment are present after signing of informed consent, at unchanged intensity, 
are recorded as medical history (e.g., allergic pollinosis)

Symptoms that were present prior to signing of informed consent but for which the 
diagnosis was confirmed after signing of informed consent should be documented as 
medical history

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs  
Definition of serious adverse event 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of 
the following criteria:

Results in death

Is life-threatening

The term ‘life-threatening’ in the definition refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were 
more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE 
if at least 1 of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours

The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study)

The admission is not associated with an AE 
(e.g., social hospitalization for purposes of respite care)
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an 
SAE dependent on clinical judgment. In addition, where local regulatory 
authorities specifically require a more stringent definition, the local regulation 
takes precedence.

Results in persistent or significant disability/incapacity


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
Disability means a substantial disruption of a person’s ability to conduct 
normal life’s functions.

Is a congenital anomaly/birth defect

Is another serious or important medical event as judged by the Investigator
If disease progression leads to signs and symptoms that meet the criteria for seriousness 
(e.g., hospitalization), the associated signs and symptoms should be reported as SAEs, not
the underlying cause (i.e., “progressive disease” should not be recorded as an SAE). In this 
case, disease progression should be mentioned on the SAE form as an “alternative 
explanation”.
An isolated laboratory abnormality that meets the criteria for CTCAE Grade 4 
classification is not reportable as an SAE, unless the Investigator assesses that the event 
meets standard ICH criteria for an SAE. All laboratory abnormalities, including CTCAE 
Grade 4 abnormalities, will be documented on the laboratory eCRF (including values 
reported from central laboratories).
9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the Investigator according to the categories 
detailed below. 
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE should be documented using the CTCAE v4.03, JUN 2010; see
Section 16.1.
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of 
treatment is a decision to be made by the Investigator, who is a qualified physician, based 
on all information available at the time of the completion of the eCRF.
Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the Investigator feels that the event cannot be firmly attributed to 1 of the study treatments 
(e.g., owing to a suspected underlying interaction), the same assessment will be 
documented for each study treatment.
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question.
Possible answers are “yes” or “no”.


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An assessment of “no” would include:
1.
The existence of a highly likely alternative explanation (e.g., mechanical bleeding 
at surgical site)
or
2.
Non-plausibility (e.g., the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; 
cancer developing a few days after the first drug administration)
An assessment of “yes” indicates that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study 
treatment include:

The temporal sequence from drug administration: The event should occur after the 
drug is given. The length of time from drug exposure to event should be evaluated 
in the clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question

Underlying, concomitant, intercurrent diseases: Each event should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have

Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might have caused the event in question

Known response pattern for this class of drug: clinical/preclinical

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event

The pharmacology and PK of the study treatment: The PK properties (absorption, 
distribution, metabolism and excretion) of the study treatment, coupled with the 
individual subject’s pharmacodynamics should be considered

The assessment is not possible
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” 
to protocol-required procedure(s). Possible answers are “yes” or “no”.


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9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. The study treatment action should be recorded separately for each study 
treatment as detailed in the eCRF.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
9.6.1.3
Assessments and documentation of adverse events
The Investigator has to record on the respective eCRF pages all AEs occurring in the 
period from the signing of the ICF until 30 days after the last dose of study treatment 
administration; during follow-up, all bone fractures and bone associated events (e.g.,
osteoporosis) need to be reported as either AE(s)s or SAEs if the criteria of SAE were met, 
regardless of the investigator’s causality assessment. Radium-223 dichloride-related 
occurrences of febrile neutropenia or hemorrhage will also be collected during follow-up.
After the end of the follow-up period there is no requirement to actively collect AEs 
including deaths. The type of information that should be assessed and recorded by the 
Investigator for each AE is listed in Section 9.6.1.2. 
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome 
of underlying AE(s).
For all SAEs the Sponsor has to carry out a separate assessment for expectedness, 
seriousness and causal relationship to study treatment.


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9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
If disease progression leads to signs and symptoms that meet the criteria for seriousness 
(e.g., hospitalization), the associated signs and symptoms should be reported as SAEs, not 
the underlying cause (i.e., “progressive disease” should not be recorded as an SAE). In this 
case, disease progression should be mentioned on the SAE form as “alternative 
explanation”.
Reporting of additional malignancies / hematological conditions
During study treatment and follow-up periods, all occurrences of any additional 
malignancies including AML, or hematological conditions such as MDS, aplastic anemia, 
and myelofibrosis must be reported as SAEs, regardless of the Investigator’s causality 
assessment.
Investigator’s notification of the Sponsor
All Investigators will be thoroughly instructed and trained on all relevant aspects of the 
Investigator’s reporting obligations for SAEs. This information, including all relevant 
contact details, is summarized in the Investigator Site File. This information will be 
updated as needed.
The Investigator must report immediately (within 24 hours of the Investigator’s awareness) 
all SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an 
AE page in the eCRF must be completed for each SAE. 
Serious AEs occurring after the protocol-defined observation period will be processed by 
the Sponsor according to all applicable regulations.
Additionally, all occurrences of MDS, aplastic anemia, myelofibrosis, or any other new 
primary malignancy such as AML, must be reported as SAEs at any time, and regardless 
of the Investigator’s causality assessment (Section 9.6.1.1). Grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as SAEs, 
specifically when they are allowed or not excluded by the protocol inclusion/exclusion 
criteria. If Investigators are in doubt about the applicable reporting obligations, they should 
consult with the medical monitor.
For subjects who die >28 days after the administration of the last study treatment, 
submission of the AE page of the eCRF is not required. However, the SAE 
Complementary Form should be submitted to the applicable Bayer AG Pharmacovigilance 
Department if the death is considered related to study treatment. 
Notification of the IECs/IRBs
Notification of the Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) about all relevant events (e.g., SAEs, SUSARs) will be performed by the Sponsor 
and/or by the Investigator according to all applicable regulations.


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Notification of the authorities
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the Sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The Sponsor will inform all investigational sites about reported relevant events 
(e.g., SUSARs) according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 
Investigator’s Brochure/Summary of Product Characteristics for radium-223 dichloride 
and the current local product labels for BOR and DEX.
9.6.2
Pregnancies
The Investigator must report to the Sponsor any pregnancy occurring in a female study 
subject during her participation in this study. The outcome of the pregnancy should be 
followed up carefully, and any outcome of the mother and the child at delivery should be 
reported.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The Investigator should submit them 
within the same timelines as an SAE. 
9.6.3
Further safety
9.6.3.1
Laboratory safety assessments
The blood samples for clinical chemistry and hematology should be taken at Screening, 
within 72 hours before each radium-223 dichloride dose, and during active follow-up.  The 
hematology parameters, including a complete blood count (CBC), must be evaluated 
before each radium-223 dichloride dose. 
Clinical chemistry:
Sodium, potassium, chloride, calcium (and albumin-adjusted calcium), ALT, AST, lactate 
dehydrogenase (LDH), total ALP, serum creatinine, blood urea nitrogen (BUN; or urea), 
bilirubin (total), alkaline phosphatase, glucose, phosphate, and albumin.  
Coagulation panel:
PT, PTT, and INR of PT
Hematology:
Hematocrit, Hb, platelet counts, RBC counts, white blood cell (WBC) counts, and WBC 
differential. 
9.6.3.2
Vital signs
Blood pressure, heart rate, respiratory rate, and temperature should be recorded.


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9.6.3.3
Body weight 
Body weight should be obtained without shoes, using a calibrated electronic physician 
(column) scale with digital display, measurement units 0.1 kg.
9.6.3.4
Physical examination
Abnormal physical examination findings are recorded either as medical history or as 
adverse events.
9.7
Other procedures and variables
9.7.1
Resource utilization
Information on healthcare resource use that is associated with the management of AEs as 
well as subject monitoring will be collected by questionnaire (Section 16.6). 
9.7.2
Biomarkers
Radium-223 dichloride may work in subjects with multiple myeloma and tumor 
biomarkers circulating in plasma or, if available, in biopsies either collected prior to study 
entry or at disease progression. The biomarker assessment will be performed as 
exploratory objective to investigate whether prognostic and /or predictive biomarkers of 
MM response can be identified.
Biomarker status will be correlated with clinical outcome to evaluate whether any 
biological targets appear to define subject populations that are particularly sensitive or 
resistant to radium-223 dichloride. Details of the biomarker analyses will be described in a 
separate statistical analysis plan (SAP) and the results of these analyses will be provided as 
a separate biomarker report.
Tumor biomarkers may be categorized as “nonor bioma” (involving protein) or “genetic”
(involving ribonucleic acid [RNA] or deoxyribonucleic acid [DNA]). In the current study, 
analyses of both ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]) will be 
performed. Tumor biomarker studies will be performed to investigate the mechanisms by 
which the drug combinations may exert their therapeutic activity.
In the current study genetic markers by tumor DNA sequencing and/or gene expression 
studies with tissue samples taken from the primary tumor and metastases may support 
identification of biomarkers contributing to clinical benefit to therapy. Utmost care will be 
taken to protect subject identity during biomarker analyses. 
9.7.2.1
Circulating Bone Biomarkers
Bone biomarkers, including UNTx, SCTx, total ALP and B-ALP, PINP, and ICTP will be 
analyzed from plasma serum and urine.
9.7.2.2
Circulating DNA
Circulating tumor DNA will be analyzed from plasma collected at baseline and each cycle 
of radium-223 dichloride treatment prior to dosing with radium-223 dichloride.
9.7.2.3
Circulating Tumor Cells
Circulating Tumor Cells (CTCs) may serve as source of tumor metastases circulating in 
blood and may reflect the tumor phenotype or genotype. Enumeration of CTCs may serve 


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as description of tumor burden. Circulating tumor cells will be analyzed in detail from 
whole blood samples collected at various time points to assess the effect of radium-223
dichloride in decreasing numbers of CTCs as well as to characterize the phenotype and 
genotype of CTCs. 
9.7.2.4
Tumor biomarkers
Archival or freshly collected tumor tissue will be used to determine the presence of 
somatic mutations in order to identify biomarker which may have potential to confer to 
sensitivity or resistance to drug treatment. This analysis may contain the identification of 
DNA Damage Repair deficiency by analyzing mutations in genes involved in the DNA 
repair.
9.8
Appropriateness of procedures/measurements
The procedures chosen for the evaluation of safety in this study population are consistent 
with the appropriate and ethical standards used in trials of oncology drugs.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using SAS®; the version used will be specified in the 
SAP.
All  analyses will be performed for phase 1b and phase 2, separately. All data will be 
listed, and descriptive summary tables will be provided by dose level cohort for phase 1b, 
and by treatment arm for phase 2.
10.2
Analysis sets
10.2.1
Phase 2
Phase 2 Safety Set (SAF): All subjects who received at least one dose of study treatment. 
Subjects will be included in the analyses according to the treatment they actually received.
Phase 2 Intent-to-treat (ITT): All randomized subjects in phase 2. The phase 2 ITT 
population will be the primary analysis set for all efficacy endpoints. Subjects will be 
included in the analyses according to the treatment to which they are randomized. The 
definition of the ITT population is identical to that of the FAS (Full Analysis Set) 
population.
10.3
Variables and planned statistical analyses
10.3.1
Phase 1b
The following populations are defined:
Phase 1b Safety Set (SAF): All subjects who received at least one dose of study 
treatment. Subjects will be included in the analyses according to the treatment they 
actually received.


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Phase 1b Dose Evaluable Set (DES): Subjects in dose escalation cohorts who meet the 
minimum drug exposure criterion (at least 2 doses of radium-223 dichloride plus a 
follow-up of 21 days after the second radium-223 dichloride dose) or experience a DLT 
(during the DLT observation window). Subjects not evaluable for assessment of DLT due 
to early discontinuation for reasons other than DLT or subjects who have not completed 
2 doses of radium-223 dichloride and 2 cycles of BOR will be replaced and will not be 
included in the DES.
10.3.2
Variables
The primary, secondary, and exploratory endpoints are defined in Sections 9.4, 9.5 and 
9.6.
10.3.3
Statistical and analytical plans 
The details of all statistical analyses will be provided in the SAP.
10.3.3.1
Demographics and other baseline characteristics
Demographics and baseline characteristics will be summarized by dose level cohorts for 
Phase 1b and by treatment arm for Phase 2 part. Continuous data will be summarized by 
arithmetic mean, standard deviation, median, minimum, and maximum. Frequency tables
(number of data available and missing, and percent of available data) for categorical data will 
be provided.
Medical history findings will be summarized using MedDRA terms.
10.3.3.2
Safety analysis
Safety variables will be analyzed using frequency tables and descriptive statistics by dose 
level cohort for Phase 1b part and by treatment arm for Phase 2 part. The primary safety 
assessment period is from the first dose of study treatment until 30 days after the last dose
of radium-223 dichloride. After study treatment has completed, subjects will be followed 
for related AEs. All bone fractures and bone associated events (e.g., osteoporosis) as well 
as new primary malignancies/hematological conditions will be reported regardless of the 
investigator’s causality assessment. Radium-223 dichloride-related occurrences of febrile 
neutropenia or hemorrhage will also be collected during follow-up. Adverse events will be
coded using MedDRA.
The incidence of treatment-emergent AEs, drug related AEs and Serious AEs will be 
summarized using coding by MedDRA and grading of severity by NCI-CTCAE version 
4.03 terms by dose level cohort for Phase 1b part and by treatment arm for Phase 2 part.
The bone fractures and bone-associated events (e.g., osteoporosis) will be summarized 
using descriptive statistics.
Laboratory values and changes from baseline will be summarized by visit and by dose 
level cohort for phase 1 part and by treatment arm for phase 2 part using descriptive
statistics. The incidence of laboratory toxicities will be summarized by worst CTCAE 
grade and by dose level cohort for phase 1 part and by treatment arm for phase 2 part. 
Frequency tables will also be provided for the changes of worst CTCAE grade after start of 
treatment versus baseline.


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Vital signs will be summarized by visit and by dose level cohort for phase 1 part and by 
treatment arm for phase 2 part for observed values and changes from baseline using 
descriptive statistics.
10.3.3.3
Maximum tolerated dose (MTD)/Recommended phase 2 dose 
(RP2D)
MTD/RP2D will be evaluated by the sponsor in consultation with the investigators during 
the conduct of the dose escalation part of the study. MTD/RP2D will be determined using 
the incidence of DLTs during the DLT observation window, which is defined as the time 
from the first dose of study treatment through 21 days after administration of the second 
dose of radium-223 dichloride. The decision about MTD/RP2D will be made after all 
subjects in last dose escalation cohort are treated with at least 2 doses for radium-223 
dichloride and observed for 21 days after second dose. If no DLT is observed in Phase 1b 
part, a RP2D will be selected based on safety and efficacy data obtained during the phase 
1b part.
Individual listings of DLTs will be presented by dose level cohort for phase 1 part with
treatment cycle of onset, serious or nonserious, CTCAE v4.03 grade and term, and 
MedDRA terms provided for each DLT. Dose Evaluable Set (DES) will be used for the 
analyses.
10.3.3.4
Anti-multiple myeloma activity analysis
Phase 1b
Anti-multiple myeloma response assessment (CR, VGPR, PR, etc.) will be summarized 
using descriptive statistics (i.e., number and percentage of subjects) by dose level cohort.
Phase 2
Fisher’s exact test will be used for evaluating response rate difference between treatment 
groups. Response rate difference and its exact 95% CI will be provided. The descriptive 
statistics will also be used to summarize response rates (combined CR+VGPR, ORR 
[CR+VGRP+PR]), and anti-multiple myeloma response assessment The number of 
responders, percentage of responders and 95% confidence interval (CIs) will be presented 
by treatment arm. 
Time to event endpoints (e.g., DOR, PFS, OS, time to SSE, time to pain progression, and 
time to opioid use) will be summarized by treatment arm using Kaplan-Meier estimates. 
Kaplan-Meier curves will be generated, and median survival time together with the 25th
and 75th percentiles and associated Brookmeyer-Crowley 95% CIs will be presented. 
Details on these analyses will be provided in the SAP.
Descriptive statistics will also be provided for DOR only for subjects with an objective 
response (OR) (PR or higher). 
10.3.3.5
Biomarker analysis
Interest in this study is taken in identifying predictive biomarkers for radium-223
dichloride anti-multiple myeloma activity in subjects with relapsed multiple myeloma. 
Subjects’ key biomarker status at baseline will be correlated with response (OR [PR or 


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better]) to explore which biomarkers may be important in defining the appropriate 
therapeutic population for the agent. 
Biomarker analyses will be performed on urine, plasma or serum samples collected at 
various time points as well as from bone biopsies collected at study entry.
Biomarkers from plasma or serum will include the determination of changes in circulating 
cytokines or proteins as well as circulating microRNAs, ctDNA and CTCs.
Additional exploratory analyses such as examination of the relationship between 
post-treatment change in biomarker levels and various clinical endpoints may be 
considered.
Additionally for subjects who signed the optional genetic consent form, genetic 
biomarkers may be determined from bone marrow specimens (bone marrow aspirate or 
biopsy) such as gene amplifications or somatic mutations in oncogenes using Next 
Generation Sequencing. 
Data from the biomarker studies will be reported in a separate biomarker report.
10.3.4
Missing data / drop outs 
Every effort should be made to retain subjects who discontinue the treatment period for 
any reason. These subjects are to be encouraged to remain on the study for follow-up of 
primary, secondary and exploratory endpoints (i.e., continue in the active follow-up and 
long-term follow up periods).
Missing data will generally not be imputed in this study. Any further details will be 
described in the SAP if there is any imputation performed. 
10.4
Determination of sample size
Phase 1b
To evaluate the MTD/RP2D for radium-223 dichloride in combination with BOR/DEX in 
subjects with relapsed multiple myeloma, two cohorts with up to 12 subjects are planned 
for dose escalation part. The sample size was based on feasibility, not formal statistical 
calculation. Subjects not evaluable for assessment of DLT for dose escalation part due to 
early discontinuation for reasons other than DLT will be replaced until the MTD/RP2D has 
been determined. These subject numbers are considered to be sufficient for a 3 + 3 dose 
escalation design to determine whether to start the next dose level, using DLT definitions 
and the 3 + 3 dose escalation rules (see Section 5.1.2).
Phase 2
The primary endpoint is combined CR+VGPR rate in phase 2 part of the study. 
Approximately 100 subjects will be randomized at a 1:1 ratio to two treatment arms: 
radium-223 dichloride + BOR/DEX (study arm), and placebo + BOR/DEX (control arm).
The placebo + BOR/DEX arm is anticipated to have combined CR+VGPR rate of 35%. 
The radium-223 dichloride + BOR/DEX arm will be considered promising if true 
combined CR+VGPR rate will be 55% or higher. Assuming one-sided alpha of 0.2 and 50 
randomized subjects in each arm, there will be 87% of power to detect the treatment difference 
of 0.2 in combined CR+VGPR rate between two arms. 


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10.5
Planned interim analyses
No formal interim analysis will be performed. 
In the event that enrollment is halted by the Steering Committee after the review of safety 
data, an interim analysis may be performed on all evaluable subjects during the phase 1. 
See Section 13.1.2.1 for further details.
In the event that enrollment is halted by the IDMC after the review of safety data, an
interim analysis may be performed on all randomized subjects during the phase 2. See 
Section 13.1.2.2 for further details.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated EDC system called RAVE. 
Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (SAS®). 
Data required according to this protocol will be recorded by investigational site personnel 
via data entry into the internet based EDC software system RAVE, which Bayer has 
licensed from Medidata Solutions Worldwide. RAVE has been validated by Medidata 
Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively 
applies the logic to ensure data are complete and reflect the clinical data requirements of 
the study. Data queries resulting from the application of the software logic are resolved by 
the site personnel. The data are stored at a secure host facility maintained by Medidata 
Solutions Worldwide and transferred on a periodic basis to Bayer's internal computer 
system via a secure Virtual Private Network.
All access to the RAVE system is through a password-protected security system that is 
part of the RAVE software. All internal Bayer and external investigative site personnel 
seeking access must go through a thorough RAVE training process before they are granted 
access to RAVE for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed 
with trained personnel to answer questions and ensure access is maintained such that data 
entry can proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made 
to a data field, including who made the change, why the change was made, and the date 
and time it was made. This information is available both at the Investigator’s site and at 
Bayer. Data entries made in the RAVE EDC screens are supported by source documents 
maintained for all subjects enrolled in this study.
Source documentation
It is the expectation of the Sponsor that key data entered into the eCRF has source 
documentation available at the site. 


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Study-specific data not needed for the subject’s routine medical care (e.g., scores or 
questionnaires) may be entered directly into the eCRF, without availability of 
corresponding source documentation.
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with 
the site to complete this.
Data recorded from screening failures
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable. At minimum, the following data should 
be recorded in the eCRF:

Demographic information (subject number; year of birth/age; sex; if applicable 
race/ethnicity)

Date of informed consent

Reason for premature discontinuation

Date of last visit. 
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the eCRF in 
addition to the data specified above:

All information related to the SAE such as: 

Concomitant medication

Medical history

Other information needed for SAE complementary page.
11.2
Monitoring
In accordance with applicable regulations, GCP, and Sponsor’s/CRO’s procedures, 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
Sponsor’s requirements. When reviewing data collection procedures, the discussion will 
also include identification and documentation of source data items.
The Sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete. 
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol).


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
Any other study agreements, GCP, and all applicable regulatory requirements are 
met.
The Investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable Sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on eCRF as well as for data from other 
sources (e.g., IxRS, laboratory, ECG, adjudication committees).
For data coding (e.g., AEs, medication), internationally recognized and accepted 
dictionaries will be used.
11.4
Missing data 
Every effort should be made to retain subjects who discontinue the treatment period for 
any reason. These subjects are to be encouraged to remain on the study for follow-up of 
primary, secondary, and exploratory endpoints (i.e., continue in the active follow-up 
period with or without clinic visits).
The method used for imputation of missing data will be described in the SAP.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the Sponsor’s 
(or a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess 
the performance of the study at the study site and of the study documents originating there. 
The Investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) 
are possible. The Investigator should notify the Sponsor immediately of any such 
inspection.
The Investigator/institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues. Audits and inspections may occur at 
any time during or after completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that 
they are readily available upon authorities’ request.
Subject (hospital) files will be archived according to local regulations and in accordance 
with the maximum period of time permitted by the hospital, institution or private practice. 
Where the archiving procedures do not meet the minimum timelines required by the 
Sponsor, alternative arrangements must be made to ensure the availability of the source 
documents for the required period.


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The Investigator/institution notifies the Sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership).
The Investigator Site File is not to be destroyed without the Sponsor’s approval.
The contract with the Investigator/institution will contain all regulations relevant for the 
study center.
12.
Premature termination of the study
The Sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due, but not limited, 
to the following reasons: 

If 2 or more subjects experience a DLT during the 33 kBq/kg dose cohort (Cohort 1) 
, the study will be terminated. (see Section 5.1.2)

Criteria for stopping the study will be provided to the IDMC (see Section 5.1.2). In 
the Phase 2 portion of the study, the IDMC will meet to review the safety data once 
20 and 50 subjects in the phase 2 portion of the study have completed 2 doses of 
radium-223 dichloride or placebo + bortezomib/dexamethasone therapy (plus a 
follow-up of at least 3 weeks after the second radium-223 dichloride dose), and 
every 6 months thereafter. The IDMC may recommend stopping the study based on 
the stopping criteria. 

If risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g., SAEs)

Results of any interim analysis

Results of parallel clinical studies

Results of parallel animal studies 
(e.g., toxicity, teratogenicity, carcinogenicity, or reproduction toxicity).

If the study conduct (e.g., recruitment rate, dropout rate, data quality, protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame
The Investigator has the right to close her/his center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final 
decision on the closure must be in writing.

All affected institutions (e.g., IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law

All study materials (except documentation that has to remain stored at site) must be 
returned to the Sponsor. The Investigator will retain all other documents until 
notification is given by the Sponsor for destruction.


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
In the event of a partial study closure, ongoing subjects, including those in 
post-study follow-up, must be taken care of in an ethical manner
Details for individual subject's withdrawal can be found in Section 6.3.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All other study personnel not included in this section are identified in a separate personnel 
list (not part of this clinical study protocol) as appropriate. This list will be updated as 
needed; an abbreviated version with personnel relevant for the centers will be available in 
each center’s Investigator Site File.
Whenever the term ‘Investigator’ is noted in the protocol text, it may refer to either the 
Principal Investigator at the site, or an appropriately qualified, trained, and delegated 
individual of the investigational site.
The Principal Investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, ethics committee, Sponsor) 
before subject recruitment may start at the respective center. Likewise, all amendments to 
the protocol must be signed by the Principal Investigator and must have received all 
required external approvals before coming into effect at the respective center.
A complete list of all participating centers and their Investigators, as well as all required 
signature documents, will be maintained in the Sponsor’s study file.
The global Sponsor of this study is identified on the title page of this protocol. If required 
by local law, local co-Sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
13.1.1
Sponsor’s medical expert
Name:
Danila Serpico, MD 
Address:
Bayer HealthCare Pharmaceuticals Inc.
Viale Certosa 210
20156 Milano, Italy
Phone: 
+39 02 3978 2949
Mobile:
+39 349 767946
13.1.2
External data evaluation bodies
13.1.2.1
Steering Committee
The Steering Committee, participating Investigators, and Sponsor will review available 
safety data (including, but not limited to, AEs, dose modifications, and laboratory 
changes), and using defined DLT criteria will determine dose escalation, dose de-
escalation, cohort expansion, and will determine an appropriate radium-223 dichloride 
dose level for use in phase 2. 


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The Steering Committee may include external experts in the treatment of multiple 
myeloma and hemato-oncologists familiar with the existing treatment paradigm in multiple 
myeloma and are involved in current development research in this disease area as well as 
study investigators.
After 3 subjects in each sequentially enrolled cohort have received the first 2 doses of 
radium-223 dichloride in combination with BOR and DEX (plus a follow-up of at least 
21 days), the Steering Committee and Sponsor will review all available safety data to
determine, based on defined DLTs, whether enrollment in phase 2 may proceed, and will 
determine the MTD/RP2D (see Section 5.1.2).
13.1.2.2
Independent Data Monitoring Committee 
For the phase 2 part of the study, an IDMC will be established to review accumulating 
safety data at regular intervals throughout the study and monitor overall study conduct. 
The IDMC will include experts in oncology, biostatistics, and safety who are not 
participating in this trial and do not have affiliation with the investigators or the Sponsor or 
other significant conflicts of interest. Their main objective will be to protect the interests of 
the subjects in the study and of those still to be entered. They will do this by monitoring 
the study periodically for safety, study progress, and protocol compliance, as well as 
assessing the risk/benefit of the trial. The IDMC meetings will be held as per the IDMC 
Charter. Ad hoc meetings will take place if needed. 
Specific areas of concern for the IDMC are: 

Subject safety (unblinded safety data will be reviewed at each meeting and any 
cases of unexpected AEs will be considered)

Accrual factors that may potentially impact on randomization balance

Subject eligibility and adequacy of follow-up

Protocol compliance (deviations from outcome assessment schedules which may 
lead to biases will be evaluated) 
The specific duties of the IDMC, as well as statistical monitoring guidelines and 
procedures, are described in the IDMC Charter. The IDMC will review the safety data 
once 20 and 50 subjects in the phase 2 portion of the study have completed 2 doses of 
radium-223 dichloride or placebo + bortezomib/dexamethasone treatment (plus a 
follow up of at least 3 weeks after the second radium-223 dichloride dose), and every 
6 months thereafter. 
After the first IDMC meeting the following events will initiate ad-hoc IDMC meetings:

≥ 33% of subjects have discontinued study treatment due to treatment-related 
adverse events or

≥ 33% of subjects experience Grade 4 treatment-related hematologic toxicities. 
The IDMC members will provide recommendations about the continuation of study with 
or without any modifications based on safety data and if any of the following criteria has 
been observed with an absolute increase of ≥33 percentage points in the active arm over 
the placebo controlled arm of the study (using CTCAE version 4.03 for the severity grade).
Stopping criteria are defined as follows in alignment with the Phase 1b portion of the trial 


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if they occurred within the time from the first dose of study treatment through 2 doses of 
radium-223 administration + 3 weeks after 2nd radium-223 administration:
1.
Grade 4 neutropenia for > 7 days, or febrile neutropenia with or without 
supportive care
2.
Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with ≥ Grade 2 
bleeding, or Grade 3 thrombocytopenia lasting > 2 weeks with or without 
supportive care  
3.
Grade 3 to 4 anemia lasting > 2 weeks with or without supportive care
4.
Grade 3 non-hematological toxicity, except:
a.
diarrhea, vomiting, and fatigue that resolve within 72 hours with or 
without supportive care
b. neuropathy
5.
Any grade 4 non-hematological toxicity (lab abnormalities of any grade will 
not be considered toxicity unless deemed clinically significant by the 
investigator)
13.2
Funding and financial disclosure
Funding
This study will be funded by its Sponsor.
Financial disclosure 
Each Investigator (including Principal and/or any Sub-Investigators) who is directly 
involved in the treatment or evaluation of research subjects has to provide a financial 
disclosure according to all applicable legal requirements. All relevant documentation will 
be filed in the trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide 
by GCP guidelines and the guiding principles detailed in the Declaration of Helsinki. The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the Sponsor. The responsible unit 
(e.g., IEC/IRB, head of the study center/medical institution) must supply to the Sponsor, 
upon request, a list of the IEC/IRB members involved in the vote and a statement to 
confirm that the IEC/IRB is organized and operates according to GCP and applicable laws 
and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the Investigator may not modify or alter the procedures described in this 
protocol. 


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Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator or the Sponsor 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior IEC/IRB/Sponsor approval/favorable opinion. 
As soon as possible, the implemented deviation or change, the reasons for it and, if 
appropriate, the proposed protocol amendment should be submitted to the IEC/IRB/head 
of medical institution/Sponsor. Any deviations from the protocol must be explained and 
documented by the Investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject 
information sheet and ICF provided by the Sponsor or the study center. A sample subject 
information and ICF is provided as a document separate to this protocol.
Based on this subject information sheet, the Investigator or designee will explain all 
relevant aspects of the study to each subject/legal representative or proxy consenter (if the 
subject is under legal protection), prior to her/his entry into the study (i.e., before any 
examinations and procedures associated with the selection for the study are performed or 
any study-specific data are recorded on study-specific forms).
The Investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject/legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 

The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2.3.6 to be conducted after withdrawal of consent. 

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g., image reading, analysis of biological specimen 
such as blood, urine, or tissues); these data would also be retained and statistically 
analyzed in accordance with the SAP. The subject has the right to object to the 
generation and processing of this post-withdrawal data. For this, she/he needs to 
sign a corresponding declaration of objection; alternatively, the subject’s oral 
objection may be documented in the subject’s source data.
Each subject/legal representative or proxy consenter will have ample time and opportunity 
to ask questions.
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
ICF and has done so, may she/he enter the study. Additionally, the Investigator will 
personally sign and date the form. The subject/legal representative or proxy consenter will 
receive a copy of the signed and dated form.


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The signed informed consent statement is to remain in the Investigator Site File or, if 
locally required, in the subject’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures 
are performed, the study record or subject´s clinical record must clearly show that 
informed consent was obtained prior to these procedures.
If the subject is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of the Sponsor and the 
Investigator). This is to be documented by a signature from the informing physician as 
well as by a signature from the witness.
For adults under legal protection, consent shall be given by the legal guardian(s). The 
consent of an adult under legal protection shall also be requested where such a person is 
able to express her/his own will. Her/his refusal or the withdrawal of her/his consent may 
not be disregarded.
The ICF and any other written information provided to subjects/legal representatives or 
proxy consenters will be revised whenever important new information becomes available 
that may be relevant to the subject’s consent, or there is an amendment to the protocol that 
necessitates a change to the content of the subject information and/or the written ICF. The 
Investigator will inform the subject/legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm her/his participation in the study by 
signing the revised ICF. Any revised written ICF and written information must receive the 
IEC/IRB’s approval/favorable opinion in advance of use.
13.5
Publication policy and use of data
The Sponsor has made the information regarding the study protocol publicly available on 
the internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from 
the study will be the property of the Sponsor who may utilize them in various ways, such 
as for submission to government regulatory authorities or disclosure to other Investigators.
Regarding public disclosure of study results, the Sponsor will fulfill its obligations 
according to all applicable laws and regulations. The Sponsor is interested in the 
publication of the results of every study it performs. 
The Sponsor recognizes the right of the Investigator to publish the results upon completion 
of the study. However, the Investigator, whilst free to utilize study data derived from 
her/his center for scientific purposes, must obtain written consent of the Sponsor on the 
intended publication manuscript before its submission. To this end, the Investigator must 
send a draft of the publication manuscript to the Sponsor within a time period specified in 
the contract. The Sponsor will review the manuscript promptly and will discuss its content 
with the Investigator to reach a mutually agreeable final manuscript. 
13.6
Compensation for health damage of subjects/insurance
The Sponsor maintains clinical trial insurance coverage for this study in accordance with 
the laws and regulations of the country in which the study is performed.


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13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the Sponsor. Only the subject number will be 
recorded in the eCRF, and if the subject name appears on any other document (e.g.,
pathologist report), it must be obliterated before a copy of the document is supplied to the 
Sponsor. Study findings stored on a computer will be stored in accordance with local data 
protection laws. As part of the informed consent process, the subjects will be informed in 
writing that representatives of the Sponsor, IEC/IRB, or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance 
with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The Investigator will maintain a list to enable subjects to be identified.


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14.
Reference list
1. Rajkumar SV, Harousseau J-L, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-
4695.
2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. 
SEER stat fact sheets: myeloma. (2015). Available from 
http://seer.cancer.gov/statfacts/html/ mulmy.html. 
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 
66:7-30.
4. Smith D, Yong K. Multiple myeloma. BMJ. 2013;346:f3863. 
5. Eda H, Santo L, David Roodman G, Raje N. Bone Disease in Multiple Myeloma. 
Cancer Treat Res. 2016;169:251-270.
6. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. 
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J 
Med. 2005;352(24):2487-2498.
7. Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, et al. High 
response rate to bortezomib with or without dexamethasone in patients with relapsed or 
refractory multiple myeloma: results of a global phase 3b expanded access program. Br 
J Haematol. 2009;144(2):169-175.
8. Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, et al. 
Bortezomib in combination with dexamethasone for the treatment of patients with 
relapsed and/or refractory multiple myeloma with less than optimal response to 
bortezomib alone. Haematologica. 2006;91(7):929-934.
9. Boudreault J-S, Touzeau C Moreau P. Triplet combinations in relapsed/refractory 
myeloma: update on recent phase 3 trials, Exp Rev Hematol. 2017;10:3:207-215.  
10. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M et al. 
Daratumumab, Bortezomib and Dexamethasone for Multiple Myeloma. N Engl J Med. 
2016; 375:754-66.
11. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. 
Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J 
Med. 2016;375(14):1319-1331.
12. Bayer, Report R-9657. Effects of combination treatment with radium-223 dichloride 
and bortezomib in a syngeneic 5TGM1 multiple myeloma mouse model in treatment 
setting. 2015.
13. Suominen MI, Fagerlund KM, Rissanen JP, Konkol YM, Morko JP, Peng Z, et al. 
Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells 
and bone microenvironment in mouse models. Clin Cancer Res. 2017;23(15):4335-
4346.


Integrated Clinical Study Protocol
BAY 88-8223 / 18987
18 MAY 2018
Version 3.0
Page: 126 of 149
14. Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor 
effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an 
experimental skeletal metastases model. Cancer Res. 2002;62(11):3120-3125.
15. Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted 
radium-223 in symptomatic, hormone-refractory prostate cancer: a randomized, 
multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587-594.
16. Suominen MI, Rissanen JP, Käkönen R, Fagerlund KM, Alhoniemi E, Mumberg D, et 
al. Survival Benefit With Radium-223 Dichloride in a Mouse Model of Breast Cancer 
Bone Metastasis. J Natl Cancer Inst. 2013;105(12): 908-16
17. Parker C, Nilsson S, Heinrich D, O’Sullivan JM, Fossa SD, Chodacki A, et al. Updated 
analysis of the phase III, double-blind, randomized, multinational study of radium-223 
chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases 
(ALSYMPCA). J Clin Oncol. 2012;30(suppl):Abstract LBA4512.
18. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha 
Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med. 
2013;369(3):213-223.
19. FDA Medical Review for Xofigo (radium Ra 223 dichloride) Injection Application No 
203971. Accessed on December 11, 2014. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203971Orig1s000MedR.pdf. 
20. VELCADE Prescribing Information. Accessed on April 2018. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021602s015lbl.pdf
21. Dexamethasone Prescribing Information. Accessed on August 25, 2015. Available 
from: http:  //dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=537b424a-3e07-
4c81-978c-1ad99014032a. 
22. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, 
et al. Bortezomib induction and maintenance treatment in patients with newly 
diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ 
GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-55. Erratum in J Clin Oncol. 
2012;30(29):3654.
23. Ludwig H, Durie BG, McCarthy P, Palumbo A, San Miguel J, Barlogie B, et al. 
IMWG consensus on maintenance therapy in multiple myeloma. Blood. 
2012;119(13):3003-15.
24. Sonneveld P, Schmidt-Wolf I, van der Holt B, el Jarari L, Bertxch U, Salwender H, et 
al. Bortezomib induction and maintenance treatment in patients with newly diagnosed 
multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. 
J Clin Onc. 2012;30(24):2946-2955.
25. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T,  Extended 
follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of 
the APEX trial. Blood 2007;110:3557-60.
26. Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, et al. 
Bortezomib in combination with dexamethasone for the treatment of patients with 


Integrated Clinical Study Protocol
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18 MAY 2018
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Page: 127 of 149
relapsed and/or refractory multiple myeloma with less than optimal response to 
bortezomib alone. Haematologica. 2006;91(7):929-934.
27. Dimopoulos MA, Orlowski RZ, Facon T, Sonneveld P, Anderson KC, Beksac M, et al. 
Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus 
bortezomib monotherapy in relapsed multiple myeloma. Haematologica. 
2015;100(1):100-106.
28. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued 
improvement in survival in multiple myeloma: changes in early mortality and 
outcomes in older patients Leukemia (2014) 28, 1122–1128.
29. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M.
Subcutaneous versus intravenous administration of bortezomib in patients with 
relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 
2011;12:431–40.
30. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al.
Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America 
N Engl J Med 2007;357:2133-42.
31. Dimopoulos M, Spencer A, Attal M, Prince HM., Harousseau J-L, Dmoszynska A, et 
al. Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma  
N Engl J Med 2007;357:2123-32.
32. Kyle RA, Rajkumar SV. Treatment of Multiple Myeloma: A Comprehensive Review. 
Clin Lymphoma Myeloma. 2009;9(4):278-288.
33. Pantani L, Brioli A, Tacchetti P, Zannetti BA, Mancuso K, Rocchi S, et al. Current 
and emerging triplet combination therapies for relapsed and refractory multiple 
myeloma Exp Rev Hematol, 2016;9(3):315–323
34. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and 
dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.
35. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and 
dexamethasone for multiple myeloma. N Engl J Med. 2016;374 (17):1621–1634.
36. San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et 
al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib 
and dexamethasone in patients with relapsed or relapsed and refractory multiple 
myeloma: a multicentre, randomised, double-blind phase 3 trial.  Lancet Oncol. 
2014;15(11):1195-206
37. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or 
refractory multiple myeloma. N Engl J Med. 2015;373 (7):621–631.
38. Bird JM, Owen RG, D’Sa S, Snowden JA, Pratt G, Ashcroft J,et al. Guidelines for the 
diagnosis and management of multiple myeloma 2011. Br J Haematol. 
2011;154(1):32-75.
39. Sonmez M, Akagun T, Topbas M, Cobanoglu U, Sonmez B, Yilmaz M, et al. Effect of 
pathologic fractures on survival in multiple myeloma patients: a case control study. J 
Exp Clin Cancer Res. 2008;27(1):11.


Integrated Clinical Study Protocol
BAY 88-8223 / 18987
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Version 3.0
Page: 128 of 149
40. Saad F, Lipton A, Cook R, Chen YM, Smith R, Coleman R. Pathologic fractures 
correlate with reduced survival in patients with malignant bone disease. Cancer 
2007;110(8):1860-1867.
41. Jordan K, Proskorovsky I, Lewis P, Ishak J, Paine K, Lordan N, et al. Effect of general 
symptom level, specific adverse events, treatment patterns, and patients characteristics 
on health-related quality of life in patients with Multiple Myeloma: results of a 
European, multicenter cohort study. Support Care Cancer 2014;22(2):417-426.
42. Schulman KL, Kohles J. Economic burden of metastatic bone disease in US. Cancer 
2007;109(11):2334-2342.
43. Terpos E, Morgan G, Dimopoulos MA, Drake MT, Lentzsch S, Raje N et al. 
International Myeloma Working Group recommendation for the treatment of multiple 
myeloma-related bone disease. J Clin Oncol. 2013;31(18):2347-2357
44. Harousseau J-L. Ten Years of Improvement in the Management of Multiple Myeloma: 
2000-2010. Clin Lymphoma Myeloma Leuk. 2010;10(6):424-442.
45. Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet. 2015;385(9983):2197-
2208.
46. Terpos E, Sezer O, croucher P, Dimopoulos MA et al. Myeloma bone disease and 
proteosome inhibition therapies. Blood 2007;110(4):1098-1104
47. Zangari M, Suva LJ. The effects of proteosome inhibitors on bone remodeling in 
multiple myeloma. Bone 2016;86:131-138.
48. Rubens RD, Coleman RE. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE. 
Clinical oncology. New York: Churchill Livingstone, 1995:643-665.
49. Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the 
NIST standard for 223Ra: new measurements and review of 2008 data. J Res Natl Inst 
Stand Technol. 2015;120:37-57.
50. Snowden JA, Ahmedzai SH, Ashcroft J, D’Sa S, Littlewood T, Low E, et al. 
Guidelines for supportive care in multiple myeloma 2011. Br J Haematol. 
2011;154(1):76-103.
51. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos M-V, et al. 
International Myeloma Working Group updated criteria for the diagnosis of multiple 
myeloma. Lancet Oncol 2014;15(12):e538–48.
52. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.


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15.
Protocol amendments
15.1
Amendment 1 - 08 AUG 2017
15.1.1
Overview of changes to the study
Section 3.1 Background
The current Multiple Myeloma treatment landscape is evolving fast and several new 
treatment agents have recently been brought to the market. The background treatment 
offered in the currently approved protocol was no longer considered among the therapies 
of choice for MM patients previously treated with 1 to 3 prior therapies. 
Feedback from investigators confirmed that enrolling patients in the phase II part of the 
trial would be challenging because patients in the placebo arm would only receive 
bortezombib + dexamethasone. Therefore, the study background treatment was updated 
with the recently approved triplet therapy of daratumumab + bortezomib + dexamethasone
In order to address this decision, significant changes to the study design have been 
introduced throughout the protocol.
Section 3.2 Study treatment  
Information regarding daratumumab based on the specific product labeling has been 
introduced. In addition, clarifications of radium 223 dichloride and bortetzomib/ 
dexamethasone administration have been updated.
Section3.3 Study rationale 
Recent results from animal models of radium 223 dichloride in combination with 
bortezomib have been updated and clinical data of daratumumab/ bortezomib/ 
dexamethasone have been added.
Section 3.3.1 Benefit-risk assessment
Benefit-risk assessment has been updated with corresponding information for 
daratumumab/ bortezomib/ dexamethasone.
Section 4. Study objectives 
The objectives of the study have been revised according to the new study design.


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Section 5 Study design 
The design overview has been revised as follows:
-
The dose level of 88kBq/kg body weight has been removed 
-
The randomized phase 2 part of the study has been removed
-
Two new cohorts of radium 223 dichloride at 33kBq/kg body weight and 55kBq/kg 
body weight in combination with daratumumab/ bortezomib/ dexamethasone have 
been introduced 
-
An expansion cohort of up to 15 subjects treated with radium 223 dichloride at 
MTD in combination with daratumumab/ bortezomib/ dexamethasone have been 
added to confirm the MTD and to detect the early signal of anti-MM activity.
Section 5.1.1 Study design schematic
The schematic of study design has been modified in order to reflect the modifications of 
the study design.
Section 5.1.2 Study periods and duration
Study periods have been updated with clarifications of radium-223 dichloride and 
bortezomib/dexamethasone information. Information regarding the daratumumab/ 
bortezomib/ dexamethasone regimen has been introduced.
Section 5.1.3 Study endpoints 
Primary and secondary endpoints have been modified according to the new study design 
and exploratory endpoints have been updated.
Section 6 Study population
Study population has been updated as follow:
-
Clarifications of inclusion/ exclusion criteria and new criteria specific to 
daratumumab have been added 
-
Clarification of screen failures and subject rescreening 
-
Clarification of study withdrawal 
-
Clarification of subject replacement. 
Section 7.1 Treatments 
Information related to the treatments administered in the new cohorts exploring 
radium-223 in combination with daratumumab/ bortezomib/ dexamethasone and 
clarifications of the existing cohorts have been added.


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Section 7.4 Dosage and administration
Dosage and administration has been modified including: 
-
Clarifications of dose calculation of each study drug 
-
Dose modification has been updated with daratumumab/ bortezomib/ 
dexamethasone combination and clarifications related to treatment interruptions 
and permanent discontinuation of each study drug has been added  
-
Drug logistics and accountability was updated considering central and local supply.
Section 9 Procedures and variables 
Visits description and study procedures have been updated including:
-
Visit description was updated with the daratumumab/ bortezomib/ dexamethasone 
combination
-
Clarification of screening and study procedures 
-
Clarifications related to treatment periods of radium -223 in combination with 
bortezomib/ dexamethasone and with daratumumab/ bortezomib/ dexamethasone 
combinations
-
Clarifications related to the active follow up period 
-
Clarifications to anti-MM activity, exploratory and safety endpoints.
Section 16 Appendices
Appendices updated with the interaction potential of bortezomib with other medicinal 
products.
15.1.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes document.


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15.2
Amendment 2 - 18 MAY 2018
15.2.1
Overview of changes to the study
Rationale of the amendment
The current multiple myeloma treatment landscape is evolving fast with daratumumab 
emerging as a potent compound in MM.  We had amended the protocol to add 
daratumumab to the backbone, but this change was considered too complex by some 
authorities, who required a separate protocol for this new combination.
While no daratumumab cohort had been started yet, we consequently return to the original 
backbone with a randomized expansion cohort in order to obtain more robust data on the 
anti-multiple myeloma activity of radium-223 dichloride in combination with 
bortezomib/dexamethasone. This is also in agreement with feedback from advisory board 
experts. 
Therefore, the current phase 1b study has been amended in order to evaluate whether 
radium-223 dichloride may increase the activity of bortezomib/dexamethasone in an 
expansion randomized phase 2 trial as clinical proof of concept for the next steps of 
development. 
In order to address this decision, significant changes to the study design have been
introduced throughout this version of the study protocol. 
Section 1 Synopsis
Changes in the synopsis included:

Change from a phase 1b study to a phase 1b/2 study with corresponding changes to 
add the randomized phase 2 part of the study to all applicable sections of the 
synopsis including: dosing information, study design, methodology, reference 
drug/type of control (addition of matching placebo, isotonic saline), addition of an 
Independent Data Monitoring Committee, number of subject, primary variables and 
statistical analysis.

Changes to the phase 1b study objectives to remove information related to 
daratumumab administration during the study, change of the safety evaluation from 
secondary to primary objectives and removal of partial response (PR) and overall 
response rate (ORR) evaluations from the phase 1b part of the study. Addition of 
phase 2 study objectives.

Removal of daratumumab administration during the study from all applicable 
sections of the synopsis including: dosing information, descriptions of Cohort 3, 
Cohort 4 and Expansion Cohort (as defined in protocol amendment 1), background 
treatment, inclusion/exclusion criteria, study design, methodology

Clarification of inclusion and exclusion criteria (inclusion criteria 5, 7, 15 and 18; 
exclusion criteria 17 and 18 and removal of exclusion criteria specific to 
daratumumab (exclusion criteria 24, 25, 26, 27)


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Section 3.1 Background
Update of background information and removal of some study data already contained in 
the Investigator Brochure.
Section 3.2 Study treatment  
Study treatment sections were updated as follows:

Update of radium-223 dichloride and bortetzomib/dexamethasone background 
information and removal of some radium-223 dichloride study data already 
contained in the Investigator Brochure. Removal of background information related 
to daratumumab.

Update of dosing rationale for radium-223 dichloride and 
bortetzomib/dexamethasone administration, addition of phase 2 details and removal 
of daratumumab dosing information.
Section 3.3Study rationale
Update of rationale for the study and benefit-risk assessment information for 
bortezomib/dexamethasone and removal of information related to daratumumab. 
Section 4 Study objectives 
The objectives of the study have been revised according to the new study design. 

Changes to the phase 1b study objectives to remove reference to daratumumab 
administration during the study, change of the safety evaluation of radium-223 
dichloride in combination from secondary to primary objectives and removal of 
partial response (PR) and overall response rate (ORR) evaluations from the phase 
1b part of the study. 

Addition of phase 2 study objectives.
Section 5 Study design and Section 5.1.1 Study design schematic
The study design overview and study design schematic have been revised as follows:

A randomized phase 2 part of the study with 100 subjects has been added 

All information related to daratumumab administration during the study was 
removed

Safety follow-up information has been updated.


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Section 5.1.2 Study periods and duration
Study periods and duration were updated as follows:

Added the randomized phase 2 part of the study 

Removed all information related to daratumumab administration during the study

Added randomization step for the phase 2 part of the study

Added clarifications to the safety follow up for the collection of bone fracture and 
bone associated events 
Section 5.1.3 Study endpoints 
Primary and secondary endpoints have been modified and exploratory endpoints have been 
updated according to the new study design (addition of the randomized phase 2 part of the 
study). 
Section 5.2 Primary variable and Section 5.3 End of study
Sections updated to reflect new study design (addition of the randomized phase 2 part of 
the study).
Section 6 Study population
Study population has been updated as follow:

Section 6.1: Clarifications of inclusioncriteria 5, 7, 15 and 18

Section 6.2: Clarifications of exclusion criteria 17 and 18 and removal of exclusion 
criteria specific to daratumumab administration (exclusion criteria 24, 25, 26, 27) 

Section 6.3: Update of withdrawal and replacement sections to reflect new study 
design (addition of the randomized phase 2 part of the study and removal of all 
information for daratumumab administration during the study), update of safety 
follow-up information and clarification added for the use of an additional consent 
form for the objection of the collection of study data after withdrawal of consent.
Section 7 Treatments 
Information related to the treatments administered in the new phase 2 expansion cohorts
exploring radium-223 in combination with bortezomib/dexamethasone and clarifications 
of the existing cohorts have been added (removal of Cohorts 3 and 4). 
Additional changes to subsections of Treatments (Section 7) included:

Section 7.1: Adding reference drug information for matching placebo (isotonic 
saline) to be used in the phase 2 part of the study.


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
Section 7.3: Update of treatment assignment and IXRS/drug delivery information 
for the phase 2 part of the study.

Section 7.4: Update of dosage and administration sections to reflect new study 
design (addition of the randomized phase 2 part of the study and removal of all 
information related to daratumumab administration during the study) and to ensure 
the blinding and the use of reference placebo in the phase 2 part of the study. 
Additional changes to subsections of Section 7.4 included:
o
Section 7.4.1: Detailed instructions for handling, storage and administration 
of radium-223 dichloride were removed from the protocol. This information 
is provided separately to the sites in a standardized handling instruction 
document.
o
Section 7.4.1.4: Details of tolerance limits required for the actual amount of 
radioactivity per dose.

Section 7.5: Added sections describing blinding procedures and procedures for 
emergency unblinding for the phase 2 part of the study

Section 7.6: Added section to drug logistics and accountability describing the 
procedures for locally provided isotonic saline (placebo) and removed all 
information related to daratumumab administration during the study

Section 7.7: Update information for collection of treatment compliance while 
ensuring the blinding in the phase 2 part of the study.
Section 8 Non-study therapy
Changes to the non-study therapy subsections were as follows:

All information related to daratumumab administration during the study was 
removed

Clarification about recommended use of bone health agents 
Section 9 Procedures and variables 
All subsections of procedures and variables were updated to reflect new study design 
(addition of the randomized phase 2 part of the study and removal of all information 
related to daratumumab administration during the study).
Changes to visit description, schedule of evaluations and study procedures were as 
follows:

Removal of daratumumab administration during the study from all applicable 
sections 
o
Removal of Table 9-2 and Figure 9-2 and update of Maintenance Table
(Table 9-3 amendment 1 / Table 9-2 amendment 2)


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o
Removal of Cohort 3, Cohort 4 and Expansion Cohort as defined in 
protocol amendment 1

All applicable sections were updated to reflect new study design (addition of the 
randomized phase 2 part of the study and use of matching placebo in the phase 2 
part of the study) 
o
Clarifications related to the active and long-term follow up periods 
o
Clarifications related to anti-MM activity, exploratory and safety endpoints. 

Clarifications were added related to MM and bone biomarker exploratory 
endpoints. 

Clarification about recommended use of bone health agents 

Notes added details regarding the collection of all bone fractures and bone related 
events.
Section 10 Statistical methods and determination of sample size
All subsections of statistical methods were updated to reflect new study design (addition of 
the randomized phase 2 part of the study and removal of all information related to 
daratumumab administration during the study).

Removal of daratumumab administration during the study from all applicable 
sections

Added details regarding the collection of all bone fractures and bone related events.

Clarifications related to anti-MM activity, exploratory and safety variables and 
endpoints
Other changes in Section 10 Statistical methods and determination of sample size were:

Section 10.2: Changes to analysis sets (removal of mITT analysis set and addition 
of Phase 2 Safety Set [SAF] and Phase 2 Intent-to-treat)

Section 10.4: Changes to sample size calculation information (removal of 
daratumumab cohorts and addition of the phase 2 part of the study

Section 10.5: Addition of details regarding the termination of the study during 
phase 2 by the IDMC in regards to performing an interim analysis.
Section 12 Premature termination of the study
Addition of details regarding the termination of the study during phase 2 by the IDMC.


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Section 13 Ethical and legal aspects
All applicable subsections of ethical and legal aspects were updated to reflect new study 
design (addition of the randomized phase 2 part of the study and removal of all 
information related to daratumumab administration during the study).
Other changes in Sections 13 Ethical and legal aspects were:

Section 13.1.1: Change of sponsor’s medical expert

Section 13.1.2.2: Addition of details regarding the use of an IDMC in the phase 2 
part of the study.
15.2.2
Changes to the protocol text
Changes to the protocol text are provided in a separate track changes document.


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16.
Appendices
16.1
National Cancer Institute-Common Terminology Criteria, version 
4.03
This study will utilize the CTCAE v4.03 for grading of severity and SAE reporting. A 
copy of the CTCAE v4.03 can be downloaded from the Website:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
All appropriate treatment areas should have access to a copy of the CTCAE v4.03.


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16.2
International Myeloma Working Group (IMWG) uniform response 
criteria
Disease response and progression will be evaluated in this study using the recently revised 
IMWG uniform response criteria.(51) 
IMWG uniform response criteria
Response
Criteria
Complete response (CR)
Negative immunofixation of serum and urine, disappearance 
of any soft-tissue plasmacytomas, and <5% plasma cells in 
bone marrow; in patients for whom only measurable disease 
is by serum free light chain (FLC) level, normal FLC ratio of 
0.26 to 1.65 in addition to CR criteria is required; 
2 consecutive assessments are needed
Stringent complete response
(sCR)
CR as defined plus normal FLC ratio and absence of clonal 
plasma cells by immunohistochemistry or 2- to 4-color flow 
cytometry; 2 consecutive assessments of laboratory 
parameters are needed
Very good partial response 
(VGPR)
Serum and urine M-component detectable by immunofixation 
but not on electrophoresis or ≥90% reduction in serum 
M-component plus urine M-component <100 mg/24 hours 
(hrs); in patients for whom only measurable disease is by 
serum FLC level, >90% decrease in difference between 
involved and uninvolved FLC levels, in addition to VGPR 
criteria, is required; 2 consecutive assessments are needed
Partial response (PR)
≥50% reduction of serum M-protein and reduction in 24-hr 
urinary M-protein by ≥90% or to <200 mg/24 hrs
If serum and urine M-protein are not measurable, ≥50% 
decrease in difference between involved and uninvolved FLC
levels is required in place of M-protein criteria
If serum and urine M-protein and serum FLC assay are not 
measurable, ≥50% reduction in bone marrow plasma cells is
required in place of M-protein, provided baseline percentage 
was ≥30%
In addition, if present at baseline, ≥50% reduction in size of 
soft-tissue plasmacytomas is required
Two consecutive assessments are needed; no known 
evidence of progressive or new bone lesions if radiographic 
studies were performed
Minimal response (MR)
≥25% but ≤49% reduction of serum M-protein and reduction 
in 24-hr urine M-protein by 50% to 89%
In addition, if present at baseline, 25% to 49% reduction in 
size of soft-tissue plasmacytomas is also required
No increase in size or number of lytic bone lesions 
(development of compression fracture does not exclude 
response)
Stable disease (SD)
Not meeting criteria for CR, VGPR, PR, or PD; no known 
evidence of progressive or new bone lesions if radiographic
studies were performed


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IMWG uniform response criteria
Response
Criteria
Progressive disease (PD)
Increase of 25% from lowest response value in any of 
following:
Serum M-component with absolute increase ≥0.5 g/dL; serum 
M-component increases ≥1 g/dL are sufficient to define 
relapse if starting M-component is ≥5 g/dL and/or;
Urine M-component (absolute increase must be ≥200 mg/24 
hrs) and/or;
Only in patients without measurable serum and urine 
M-protein levels: difference between involved and uninvolved 
FLC levels (absolute increase must be >10 mg/dL);
Only in patients without measurable serum and urine 
M-protein levels and without measurable disease by FLC 
level, bone marrow plasma cell percentage (absolute 
percentage must be ≥10%)
Development of new or definite increase in size of existing 
bone lesions or soft-tissue plasmacytomas
Development of hypercalcemia that can be attributed solely to 
plasma cell proliferative disorder
Two consecutive assessments before new therapy are 
needed
Source: 51


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16.3
Calculation for glomerular filtration rate
Calculation of estimated glomerular filtration rate (Cockcroft-Gault formula, 52):
Glomerular filtration rate [mL/min per 1.73 m2]
= (140 – age) x weight (kg) [x 0.85 if female] / (72 x mean serum creatinine [mg/dL])


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16.4
New York Heart Association (NYHA) functional classification 
Class
NYHA Functional Classification
I
Subjects have cardiac disease but without the resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
II
Subjects have cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain.
III
Subjects have cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
IV
Subjects have cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is 
increased.


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16.5
Eastern Cooperative Oncology Group (ECOG) performance status
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without 
restriction. (Karnofsky 90-100)
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, 
office work). (Karnofsky 70-80)
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
(Karnofsky 50-60)
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. (Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. (Karnofsky 10-20)


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16.6
Resource Utilization Questionnaire


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16.7
Brief Pain Index-Short Form (BPI-SF)


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16.8
Interaction potential of bortezomib with other medicinal products
16.8.1
CYP3A clinical inhibitors for P450-mediated metabolisms (for 
concomitant use clinical DDI studies and/or drug labeling) (9/26/2016)
Strong inhibitors
Moderate inhibitors
Weak inhibitors
CYP3A
boceprevir, cobicistat(h), 
conivaptan(h), danoprevir and 
ritonavir(j), elvitegravir and 
ritonavir(j), grapefruit juice(k), 
indinavir and ritonavir(j), 
itraconazole(h), ketoconazole, 
lopinavir and ritonavir(h,j), 
paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir)(j), 
posaconazole, ritonavir(h,j), 
saquinavir and ritonavir(h,j), 
telaprevir(h), tipranavir and 
ritonavir(h,j), troleandomycin, 
voriconazole
aprepitant, cimetidine, 
ciprofloxacin, clotrimazole, 
crizotinib, cyclosporine, 
dronedarone(h), 
erythromycin, 
fluconazole(f), 
fluvoxamine(a), imatinib, 
tofisopam, verapamil(h)
chlorzoxazone, cilostazol, 
fosaprepitant, 
istradefylline, ivacaftor(h), 
lomitapide, ranitidine, 
ranolazine(h), tacrolimus, 
ticagrelor(h)
clarithromycin(h), diltiazem(h), 
idelalisib, nefazodone, 
nelfinavir(h)
16.8.2
CYP2C19 clinical inhibitors or P450-mediated metabolisms (for 
concomitant use clinical DDI studies and/or drug labeling) (9/26/2016) 
Strong inhibitors
Moderate inhibitors
Weak inhibitors
CYP2C19
fluconazole(f), fluoxetine(g), 
fluvoxamine(a), ticlopidine
-
omeprazole, voriconazole
16.8.3
CYP3A inducers for P450-mediated metabolisms (for concomitant use 
clinical DDI studies and/or drug labeling) (9/26/2016)
Strong inducers
Moderate inducers
Weak inducers
CYP3A
carbamazepine(d), 
enzalutamide(f), mitotane, 
phenytoin(b), rifampin(a), St. 
John’s wort(g)
bosentan, efavirenz, 
etravirine, modafinil
armodafinil, rufinamide
This is not a comprehensive list of medications which may inhibit CYP3A4/5. The above 
list was compiled by using information listed under “draft guidance for industry, drug 
interaction studies, CDER 2006”, Indiana University School of Medicine drug interaction 


Integrated Clinical Study Protocol
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18 MAY 2018
Version 3.0
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tables at http//medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp and “drug interaction 
database” from University of Washington.

SAP_000.pdf: 
Statistical Analysis Plan
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Reference Number: BPD-SOP-060
Supplement Version: 5
A phase 1b/2 trial to evaluate the safety of radium-223 dichloride (BAY 88-8223) in 
combination with bortezomib and dexamethasone in patients with relapsed multiple 
myeloma
BSP study drug
BAY 88-8223 / Radium-223 dichloride / Xofigo
Study purpose:
Safety and early signals of anti-multiple myeloma activity
Clinical study 
phase:
1b/2
Date:
28 September 2018
Study No.:
18987
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Table of Contents
1.
Introduction......................................................................................................................... 6
2.
Study Objectives................................................................................................................. 7
3.
Study Design....................................................................................................................... 8
3.1
Design Overview ......................................................................................................... 8
3.2
Determination of Sample Size..................................................................................... 8
4.
General Statistical Considerations...................................................................................... 9
4.1
General Principles........................................................................................................ 9
4.2
Handling of Dropouts and Screen Failures.................................................................. 9
4.3
Handling of Missing Data.......................................................................................... 10
4.3.1
Imputation rules............................................................................................ 10
4.4
Interim Analyses and Data Monitoring ..................................................................... 10
4.5
Data Rules.................................................................................................................. 10
4.6
Validity Review and Protocol Deviations ................................................................. 10
5.
Analysis Sets..................................................................................................................... 11
6.
Statistical Methodology.................................................................................................... 11
6.1
Population characteristics.......................................................................................... 11
6.1.1
Disposition ................................................................................................... 11
6.1.2
Demographics and Baseline Characteristics ................................................ 11
6.1.3
Medical history............................................................................................. 12
6.1.4
Drug Exposure and Compliance .................................................................. 13
6.1.5
Prior and Concomitant Medications............................................................. 13
6.2
Efficacy...................................................................................................................... 14
6.2.1
Primary Efficacy Analyses........................................................................... 14
6.2.2
Secondary Efficacy Analyses....................................................................... 15
6.2.3
Exploratory Efficacy Analysis ..................................................................... 18
6.3
Pharmacokinetics / pharmacodynamics..................................................................... 21
6.4
Safety......................................................................................................................... 21
6.4.1
Adverse events ............................................................................................. 21
6.4.2
Deaths........................................................................................................... 23
6.4.3
Clinical Laboratory Data.............................................................................. 23
6.4.4
Other Safety Analyses.................................................................................. 24
6.5
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D)................... 24
6.6
Analysis of Other Endpoints...................................................................................... 24
6.6.1
ECOG Performance Status........................................................................... 24
6.6.2
Brief Pain Index – Short Form (BPI-SF) ..................................................... 25
6.6.3
Resource Utilization Questionnaire ............................................................. 25
6.6.4
Long Term Safety......................................................................................... 25
6.7
Examination of Subgroups ........................................................................................ 25
7.
Document history and changes in the planned statistical analysis ................................... 25
8.
References......................................................................................................................... 26


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Abbreviations
AE
adverse event
BMI
body mass index
BOR
bortezomib
CI
confidence interval
CR
complete response
CRF
case report form
CT
computed tomography
ctDNA
circulating tumor DNA
CTCs
circulating tumor cells
CTCAE 
Common Terminology Criteria for Adverse Events
DEM 
dose escalation meeting 
DES
dose evaluable set
DEX
dexamethasone
DK
decay correction factor
DL
dose level
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EBRT
external beam radiotherapy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
United States Food and Drug Administration
Hb
hemoglobin
HR
hazard ratio
IC
investigator’s choice
ICF
informed consent form
ICH
International Conference on Harmonization
ICTP
Type I collagen telopeptide
ID
identification number


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IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee 
IF
immunofixation
IMP
investigational medicinal product
IMWG
International Myeloma Working Group
INR
international normalized ratio (reagent-independent prothrombin ratio)
IRB
Institutional Review Board
ISS
International Staging System for Multiple Myeloma
ITT
intent-to-treat
IV
intravenous
IxRS
Interactive Voice/Web Response System
kBq
kiloBecquerel; SI unit of radioactivity
kg
kilogram
LLOQ
lower limit of quantification
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mL
milliliter
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events
ORR
objective response rate
OR
overall response
OS
overall survival
PCR
polymerase chain reaction 
PD
progressive disease
PEP
protein electrophoresis
PET-CT
positron emission tomography – computed tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PR
PR interval in the ECG
PS
performance status
PSA
prostate-specific antigen
PT(-INR)
prothrombin time(-international normalized ratio)


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PTT
partial thromboplastin time
QT
QT interval in ECG
RAVE
Medidata Rave; electronic data capture tool
RBC
red blood cell
RNA
ribonucleic acid
RP2D
recommended phase 2 dose
RUQ
resource utilization questionnaire
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SD
stable disease
SRE
skeletal-related event
SSE
symptomatic skeletal event
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TTP
time to progression
ULN
upper limit of normal
US
United States
VGPR
very good partial response
WBC
white blood cell
WHO DD
World Health Organization Drug Dictionary
WPS
worst pain score
wk
week


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1.
Introduction
Protocol 18987 is a phase 1b/2 trial to evaluate the safety of radium-223 dicholoride (BAY 
88-8823) in combination with bortezomib (BOR) and dexamethasone (DEX) in patients with 
relapsed multiple myeloma. The study has two parts: Phase 1b Dose escalation and Phase 2 
double blinded randomization.
Two cohorts at 2 different dose levels are planned for phase 1b dose escalation part. After 
maximum tolerated dose/recommended phase 2 dose is identified from dose escalation 
cohorts, the blinded randomized phase 2 part of the study will start and the efficacy and safety 
of radium-223 dichloride in combination with BOR and DEX versus placebo in combination 
with BOR and DEX will be evaluated.
The following analyses are planned in this study:

The final analysis of phase 1b data will be conducted when all subjects in the phase 1b 
part have completed the end of treatment visit (including the maintenance therapy), or 
have discontinued early.

For the phase 2 part, the primary analysis will be conducted after all subjects have 
completed the end of radum-223 dichloride visit and the final analysis will be 
conducted when all subjects enrolled have completed the end of treatment visit (also 
including the maintenance therapy).
The purpose of this statistical analysis plan (SAP) is to describe the planned analysis and data 
presentations for this study. This SAP is written in accordance with the principles in the 
International Conference on Harmonisation (ICH) guidances ICH-E3 (Good Clinical 
Principles), ICH-E9 (Statistical Principles for Clinical Trials), and the Bayer standard 
operating procedure BDP-SOP-060.
The Statistical Analysis Plan (SAP) was written based on the following documentation:
Document
Date
Version
Protocol
18 May 2018
3.0
Annotated eCRF - Subject Case 
Report Forms
31 January 2017
3.0 PROD
Xofigo Biostatistical Project Plan
7 December 2016
2.0
Xofigo Biostatistical Project 
Plan_v2_07Dec2016 
final_addendum.docx
May 17, 2018


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2.
Study Objectives
Phase 1b part (open-label) 
Primary objectives:

To evaluate the safety of the combination of radium-223 dichloride plus bortezomib 
(BOR) and dexamethasone (DEX)

To determine the dose of radium-223 dichloride that will be used in the phase 2 part of 
the study (maximum tolerated dose [MTD] or recommended phase 2 dose [RP2D]) 
Secondary objectives:

To evaluate the combined complete response (CR) + very good partial response 
(VGPR), as determined by International Myeloma Working Group (IMWG) uniform 
response criteria
Phase 2 part (double-blind, randomized) 
Primary objectives:

To compare radium-223 dichloride versus placebo in addition to background treatment 
with BOR plus DEX in terms of combined CR+VGPR rate in relapsed multiple 
myeloma subjects, as determined by International Myeloma Working Group (IMWG) 
uniform response criteria.
Secondary objectives:

To evaluate safety

To evaluate the objective response rate (ORR), as determined by IMWG uniform 
response criteria

To evaluate overall survival (OS) 

To evaluate progression-free survival (PFS)

To evaluate duration of response (DOR)
Exploratory objectives:

To evaluate time to first on-study symptomatic skeletal event (SSE)

To evaluate bone biomarkers

To evaluate change in bone lesions

To evaluate change in MM disease markers

To evaluate circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs)

To evaluate time to opioid use for cancer pain in subjects without opioid use at 
baseline

To evaluate time to pain progression


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3.
Study Design
3.1
Design Overview 
This study will be conducted in 2 parts. The phase 1b part will be an international, phase 1b, 
open-label, dose-escalation assessment of radium-223 dichloride administered with BOR and 
DEX in subjects with relapsed MM. The phase 2 part will be an international, phase 2, 
double-blind, randomized, placebo-controlled assessment of radium-223 dichloride versus 
placebo administered with BOR and DEX, in subjects with relapsed MM.
For the Phase 1b open-label part of the study, 2 dose levels of radium-223 dichloride were
administered, following sequential dose escalation using  a ‘3 + 3’ design, in order to 
determine maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) for phase 2: 

Cohort 1: 33 kiloBecquerel (kBq)/kg body weight every 6 weeks for a total of 6 
radium-223 dichloride doses in combination with BOR and DEX

Cohort 2: 55 kBq/kg body weight every 6 weeks for a total of 6 radium-223 dichloride 
doses in combination with BOR and DEX
For the Phase 2 double-blind randomized part of the study, the MTD/RP2D, as determined by 
the phase 1b part of the study, will be administered once every 6 weeks for a total of 6 
radium-223 dichloride doses.
Up to approximately total 12 subjects in the 2 dose cohorts combined will be treated in the 
phase 1b part of the study and approximately 100 subjects will be enrolled in the phase 2 part 
of the study.
3.2
Determination of Sample Size
Phase 1b
To evaluate the MTD/RP2D for radium-223 dichloride in combination with BOR/DEX in 
subjects with relapsed multiple myeloma, two cohorts with up to 12 subjects are planned for 
dose escalation part. The sample size was based on feasibility, not formal statistical 
calculation. Subjects not evaluable for assessment of DLT for dose escalation part due to early 
discontinuation for reasons other than DLT will be replaced until the MTD/RP2D has been 
determined. The number of subjects is considered to be sufficient for a 3 + 3 dose escalation 
design to determine whether to start the next dose level, using DLT definitions and the 3 + 3 
dose escalation rules.
Phase 2


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The primary endpoint is combined CR+VGPR rate in phase 2 part of the study. 
Approximately 100 subjects will be randomized at a 1:1 ratio to two treatment arms: radium-
223 dichloride + BOR/DEX (study arm), and placebo + BOR/DEX (control arm). The 
placebo + BOR/DEX arm is anticipated to have combined CR+VGPR rate of 35%. The 
radium-223 dichloride + BOR/DEX arm will be considered promising if true combined 
CR+VGPR rate will be 55% or higher. Assuming one-sided alpha of 0.2 and 50 randomized 
subjects in each arm, there will be a 87% power to detect a treatment difference of 0.2 in 
combined CR+VGPR rate between two arms.
4.
General Statistical Considerations
4.1
General Principles
All data analyses will be carried out using the software package SAS® Version 9.2 or higher
(SAS Institute Inc., Cary, NC, USA). 
For continuous endpoints, the mean, the standard deviation, median, minimum, and maximum 
will be provided. For categorical data, the frequency and percent distributions will be 
provided.
In general, all analyses will be performed for phase 1b and phase 2, separately. All data will 
be listed, and descriptive summary tables, including demographics and baseline 
characteristics, will be provided by dose level cohort and overall for phase 1b, and by 
treatment arm and overall for phase 2. Any test of comparison performed for phase 2 will be 
one-sided at 20% level of significance unless otherwise specified. 
If more than one value is reported at a scheduled visit, the latest value will be used. 
4.2
Handling of Dropouts and Screen Failures
A “dropout” is defined as a subject who has received the first dose of study treatment and 
discontinues study participation prematurely for any reason. For phase 1b part, subjects not 
evaluable for assessment of DLT due to early discontinuation for reasons other than DLT or 
subjects who have not completed 2 doses of radium-223 dichloride and 2 cycles of 
bortezomib will be replaced until the MTD/RP2D has been determined. For phase 2 part, a
subject who prematurely discontinues the study will be counted toward the total enrollment 
goal and will not be replaced. 
A subject who, for any reason (e.g., failure to satisfy the selection criteria) terminates the 
study before the first dose of radium-223 dichloride for phase 1b or before randomization for 
phase 2 is regarded as a “screening failure”. 


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4.3
Handling of Missing Data
In order to achieve the goal of a well conducted clinical trial according to ICH Good Clinical 
Practice (ICH-GCP), every effort should be made to collect all data. However, despite best 
efforts, it may be inevitable that missing or incomplete data are reported. All missing or 
partial data will be presented in the subject data listing, as they are recorded on the Case 
Report Form (CRF). Except as noted, missing data will not be imputed or carried forward in 
any statistical analysis.
4.3.1
Imputation rules 
Unless otherwise specified data will not be imputed, and rules for imputation are specified in 
the dataset specification documents following rules described in Xofigo Biostatistical Project 
Plan [3].
4.4
Interim Analyses and Data Monitoring
No formal interim analysis will be performed. 
In the event that enrollment is halted by the Steering Committee after the review of safety 
data, an interim analysis may be performed on all evaluable subjects during the phase 1. 
In the event that enrollment is halted by the IDMC after the review of safety data, an interim 
analysis may be performed on all randomized subjects during the phase 2. 
4.5
Data Rules
Baseline value for demographic and baseline characteristic table, as well as that for efficacy 
and other endpoints is defined as the last available (non-missing) value on or before the date 
of randomization for phase 2 part.
Baseline value for demographic and baseline characteristic table, as well as that for efficacy 
and safety endpoints in the phase 1b part and safety endpoints in the phase 2 parts is defined 
as the last available (non-missing) value on or before the first dose date of any study drug.
If more than one value is reported at a scheduled visit, the last valid (non-missing) value will 
be used in the by visit summaries. All values will be included in the listings.
4.6
Validity Review and Protocol Deviations
The results of validity (protocol deviations) review meetings will be documented in the 
Validity Review Reports and may comprise decisions and details relevant for statistical 
evaluation. Any changes to the statistical analysis prompted by the results of the validity 
review meeting will be documented in an amendment or, if applicable, in a supplement to this 
SAP.


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5.
Analysis Sets
Phase 1b Safety Set (SAF): All subjects who received at least one dose of study treatment. 
Subjects will be included in the analyses according to the treatment they actually received.
Phase 1b Dose Evaluable Set (DES): Subjects in dose escalation cohorts who meet the 
minimum drug exposure criterion (at least 2 doses of radium-223 dichloride plus a follow-up 
of 21 days after the second radium-223 dichloride dose) or experience a DLT (during the DLT 
observation window). Subjects not evaluable for assessment of DLT due to early 
discontinuation for reasons other than DLT or subjects who have not completed 2 doses of 
radium-223 dichloride and 2 cycles of BOR will be replaced and will not be included in the 
DES.
Phase 2 Intent-to-treat (ITT): All randomized subjects in phase 2. The phase 2 ITT 
population will be the primary analysis set for all efficacy endpoints. Subjects will be 
included in the analyses according to the treatment to which they are randomized. The 
definition of the ITT population is identical to that of the FAS (Full Analysis Set) population.
Phase 2 Safety Set (SAF): All subjects who received at least one dose of study treatment. 
Subjects will be included in the analyses according to the treatment they actually received.
Safety population will be used in the analyses of all safety endpoints.
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
For the phase 1b part of the study, the number and percentage of subjects screened, and 
treated will be summarized by cohort and overall. For the phase 2 part of the study, the 
number and percentage of subjects screened, randomized, and treated will be presented by 
treatment group and overall.  In addition, the number of subjects discontinued prior to 
receiving the 6th injection will be tabulated. The reasons for subjects discontinuing from 
radium-223 treatment, from study treatment, from active follow-up, and from survival follow-
up will be tabulated by treatment group and overall. In addition, the number of subjects 
included in each analysis population will be displayed overall and by country and 
investigator.
6.1.2
Demographics and Baseline Characteristics
All demographic and baseline characteristics will be summarized by cohort and overall for the 
phase 1b SAF population and by treatment group and overall for the phase 2 ITT population, 
using descriptive statistics such as frequency and proportion (for categorical variables), mean, 
median, standard deviation, minimum and maximum (for continuous variables). 


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These will include, but may not be limited to; 
Demographics

Sex  

Age 

Age category (
65

vs. 
65

years)

Race / Ethnic group

Height (cm)

Weight (kg) 

Body Mass Index, calculated as:
Baseline disease characteristics  

Easter Cooperative Oncology Group (ECOG) performance status 

Number of prior lines MM therapy (1 vs. >1)

Prior Skeletal Related Events (SRE) (yes/no)

Revised-ISS at initial diagnosis (Stage I, II and III)

Revised-ISS at baseline (Stage I, II and III)

Prior stem cell transplantation (yes, no)

Serum albumin 

2 microglobulin

Time since initial diagnosis to study entry (days)

Time since first progression to study entry (days)

Time since most recent progression to study entry (days)

Time since first progression to most recent progression (days)

Time since last bortezomib administration

Baseline worst pain score (WPS) in the last 24 hours
Baseline disease characteristics for phase 2 only

Type of biological progression M-protein, PEP/SEP, FLC

Bone marrow aspirate

Response to prior therapy

Time since last MM therapy
6.1.3
Medical history
Medical history will be summarized by MedDRA body system organ class (SOC) and preferred 
term (PT) for the Safety population by cohort and overall for the phase 1b part, and for the ITT 
population by treatment group and overall for the phase 2 part. 


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6.1.4 Drug Exposure and Compliance
Descriptive statistical summaries by cohort and overall for phase 1b and by treatment group 
and overall for phase 2 will be provided for the following variables using SAF: 

Number of radium-223 dichloride/placebo injections received. Summary statistics will 
include both descriptive statistics of number of injections received, and number and 
percent of subjects by number of injections received

Number and percentage of radium-223 dichloride/placebo injection interruption or 
delays, reason for interruption or delays due to AEs, reasons other than AEs

Number of interruption of bortezomib, reason for interruption or delays due to AEs, 
reasons other than AEs

Dose reduction of bortezomib, reason for interruption or delays due to AEs, reasons 
other than AEs

Cumulative dose or dose intensity of bortezomib 

Duration of study treatment for radium-223, bortezomib and dexamethasone, 
respectively: the date of the last dose of study treatment – date of the first dose of 
study treatment + 1

Duration of treatment (overall): last dose date of last administered component – first 
dose date of first administer component +1.

Total radioactivity of radium-223 received (sum of activity in all doses) in kBq and 
kBq/kg

Planned dose, actual dose per day including interruptions/delays, actual dose per day 
excluding interruptions/delays, actual total amount of dose received, and percent of 
total planned dose for BOR and DEX will be summarized separately. Percent of total 
dose is calculated as actual daily dose per day including interruptions/delays, divided 
by the planned dose.
6.1.5
Prior and Concomitant Medications
All investigator-reported non-study medications taken before and/or during the study will be 
coded using the Bayer modified version of World Health Organization Drug Dictionary 
(WHO-DD) September 2017 and the Anatomical Therapeutic Chemical (ATC) classification 
system. Coding will include the drug class and generic drug name.
Non-study medications taken before, during and/or after the study will be categorized as prior 
medications, concomitant medications, and post treatment medications. They are defined 
based on when the medications are taken vs the first and last dosing dates of study treatment 
(radium-223 dichloride, BOR, or DEX). There are 8 scenarios see Table 6–1.
If a start date is missing, the medication will be assumed to start prior to first dose of study 
drug. If the end date is unknown and ‘ongoing’ was not checked in CRF, the medication will 
be assumed to end at the last visit date, death date or withdrawal from study date, whichever 
is the latest.  


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All medications will be listed, including verbatim descriptions and coded terms, and flags for 
prior/concomitant/post treatment medications. Prior, concomitant, and post treatment 
medications will be summarized using frequencies of subjects reporting each drug category 
and generic drug name. For each subject, multiple records of the same concomitant 
medication will be counted once within a drug class and generic drug name.
The same approach will be used to summarize anti-cancer therapies (systemic anti-cancer 
therapy, radiotherapy as well as diagnostic and therapeutic procedures) in the Safety 
population.
Table 6–1 Medication Classification
Prior to 
study 
drug
Study 
drug
started
Treatment 
with study 
drug
Study 
drug 
stopped
Follow 
up
Prior 
Medication?
Concomitant 
Medication?
Post-treatment 
Medication?
C1
Yes
No
No
C2
Yes
Yes
No
C3
No
Yes
Yes
C4
Yes
Yes
Yes
C5
No
No
Yes 
C6
No
Yes 
No 
C7
No
Yes 
No 
C8
No
Yes 
No 
C1= medication started before study drug administration and ended on or before study drug administration
C2= medication started before study drug administration and ended during study drug administration 
C3= medication started on or after study drug administration and ended after study drug administration
C4= medication started before study drug administration and ended after study drug administration 
C5= medication started on or after study drug administration and ended after study drug administration
C6= medication started on or after study drug administration and ended before or on the same date as end of study drug 
administration
Note: C7and C8 are covered under C6.
6.2
Efficacy
For phase 1b part, efficacy analyses will be performed for SAF. All efficacy analyses for 
phase 2 part will be performed for ITT population. Censoring for time to event endpoints 
(DOR, PFS, OS, time to SSE, time to pain progression, and time to opioid use) will be listed 
in each subsection accordingly, which follow the rules from the Xofigo project plan [3].
6.2.1
Primary Efficacy Analyses
Phase 1b
There is no planned primary efficacy analysis with phase 1b part. 
Phase 2
Fisher’s exact test will be used for evaluating response rate difference between treatment 
groups. Response rate difference and its exact 95% CI will be provided. The descriptive 


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statistics will also be used to summarize response rates (combined CR+VGPR) , as 
determined by IMWG uniform response criteria. The number of responders, percentage of 
responders and 95% confidence interval [CIs]) will be presented by treatment arm. All ITT 
subjects with baseline disease assessment will be included as denominator in the response rate 
calculation.
All subjects who do not meet the criteria for a combined CR+VGPR by the analysis cutoff 
date will be considered non-responders.
6.2.2
Secondary Efficacy Analyses
Phase 1b
Anti-multiple myeloma response assessment (CR, VGPR, PR, etc.) will be summarized using 
descriptive statistics (i.e., number and percentage of subjects) by dose level cohort and 
overall. All subjects with baseline disease assessment will be included as denominator in the 
response rate calculation.
Phase 2
Secondary efficacy analyses in phase 2 part comparing the effects of radium-223 dichloride 
dose group versus placebo in addition to background treatment with BOR plus DEX on the 
following set of endpoints will be performed: objective response rate (ORR) as determined by 
IMWG uniform response criteria, duration of response (DOR), progression-free survival 
(PFS), and overall survival (OS).
Fisher’s exact test as described in Section 6.2.1 for primary efficacy endpoint will be used for 
evaluating ORR difference between treatment groups. 
Time to event endpoints (DOR, PFS, OS) will be summarized by treatment arm using Kaplan-
Meier estimates [1]. Kaplan-Meier curves will be generated, and median survival time 
together with the 25th and 75th percentiles and associated Brookmeyer-Crowley [2] 95% CIs 
will be presented. Log-rank test will be applied to test difference between treatment groups.
The treatment effect (hazard ratio) will be estimated using the Cox proportional hazards 
regression model with treatment group as a factor. 
6.2.2.1
Objective response rate (ORR)
The objective response rate is defined as the proportion of subjects in the analysis population 
who have complete response (CR), partial response (PR) and very good partial response 
[VGPR]) during the course of the study.
6.2.2.2
Duration of Response (DOR)
The duration of response (DOR) for a given subject, as determined by IMWG response 
criteria, will be defined as the time (in months) from the date of first response to treatment


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(CR, VGPR or PR) to the date of disease progression or death. Duration of response is only 
applied to subjects with a disease response of at least PR.
The censoring rules for duration of response are summarized in Table 6-2.
Table 6-2: Duration of Response censoring rules
Situation (all situations occur 
after first response to treatment, 
i.e., CR, VGPR or PR)
End Date 
Censored
Reason for Censoring
Subject had a disease 
assessment of PD (no more than 
one missed disease assessment)
Date of first PD
No*
N/A
Subject discontinued from study 
for other than PD or death
Last disease 
assessment without PD
Yes
Subject discontinued 
from study due to a 
reason other than PD 
or death
Death during the study (no 
more than one missed disease 
assessment) without disease PD 
assessment before death
Date of death
No*
N/A
Subject discontinued from study 
due to PD, but no documented 
PD date
Date of last disease 
assessment
Yes
Subjects discontinued 
from study due to PD, 
but no documented 
date of PD
Subject still on study at the time 
of data cutoff without PD
Last disease 
assessment before data 
cutoff
Yes
Subjects is still alive 
without PD
Death or PD after more than 
one missed or incomplete 
disease assessment
Date of last disease 
assessment before 
missed or incomplete 
assessment
Yes
Missed more than one 
disease assessment
New systemic anticancer 
treatment started prior to PD or 
death 
Date of last disease 
assessment before 
starting new systemic 
anticancer treatment
Yes
New systemic 
anticancer treatment 
started
*Earliest end dates in the above table are used in calculating the DOR.
6.2.2.3
Progression-free survival (PFS)
For a given subject, PFS will be defined as the time (in months) from the date of 
randomization to the date of disease progression or death, whichever occurs first. 
The censoring rules for progression free survival is summarized in Table 6-3.


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Table 6-3: Progression Free Survival censoring rules
Situation
End Date 
Censored
Reason for 
Censoring
No baseline or post-baseline 
disease assessment
Randomization date
Yes
No  baseline or post-
baseline disease 
assessment
Subject had a disease 
assessment of PD (no more 
than one missed disease 
assessment)
Date of first PD
No*
N/A
Subject discontinued from 
study for other than PD or 
death
Last disease 
assessment without 
PD
Yes
Subject discontinued 
from study due to a 
reason other than PD 
or death
Death during the study (no 
more than one missed disease 
assessment) without disease 
PD assessment before death
Date of death
No*
N/A
Subject discontinued from 
study due to PD, but no
documented PD date
Date of last disease 
assessment
Yes
Subjects discontinued 
from study due to PD, 
but no documented 
date of PD
Subject still on study at the 
time of data cutoff without PD
Last disease 
assessment before data 
cutoff
Yes
Subjects is still alive 
without PD
Death or PD after more than 
one missed disease assessment
Date of last disease 
assessment before 
missed assessment
Yes
Missed more than one 
disease assessment
New systemic anticancer 
treatment started prior to PD or 
death
Date of last disease 
assessment before 
starting new systemic 
anticancer treatment
Yes
New systemic 
anticancer treatment 
started
Progression Free Survival (PFS) = End Date – Date of Randomization +1
*Earliest end dates in the above table are used in calculating the PFS.
6.2.2.4
Overall Survival (OS)
Overall survival for a given subject will be defined as the time (in months) the date of 
randomization to the date of the subject's death. 


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The censoring rules for overall survival are summarized in Table 6-4.
Table 6-4: Overall Survival censoring rules
Situation
End Date 
Censored
Reason for 
Censoring
Death on or prior to database 
cutoff date
Date of Death
No
N/A
Death occurred or subject 
known to be alive after database 
cutoff date
Database cut-off date
Yes
Alive as of data cut-
off date
Last known alive date is on or 
prior to data cutoff date
Last known alive date 
(LKAD)
Yes
The reasons are based 
on the study CRF: 
e.g., subjects lost to 
follow up, withdrew 
consent etc.
The date of last known alive will be estimated based on the date that subject was reported 
alive from the post-treatment visits, date of disease progression assessment in the post-
treatment visits, start/end date of post-study cancer therapy in the post-treatment visit, last 
available vital sign measurement, performance status assessment, or physical exam, CT scan, 
clinical visit for disease progression, whichever is the last. 
6.2.3
Exploratory Efficacy Analysis
There is no planned exploratory efficacy analysis with phase 1b part. Exploratory analysis for 
time to event endpoints (time to SSE, time to pain progression, and time to opioid use) for 
phase 2 part will be summarized by treatment arm using Kaplan-Meier estimates. Kaplan-
Meier curves will be generated, and median survival time together with the 25th and 75th
percentiles and associated Brookmeyer-Crowley 95% CIs will be presented. Log-rank test 
will be applied to test difference between treatment groups.
6.2.3.1
Time to first on-study SSE
The time to first on-study SSE is defined as the time (months) from the date of randomization
to the date of the earliest occurrence of one of the following:

the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms

the occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral)

the occurrence of spinal cord compression

a tumor-related orthopedic surgical intervention
The censoring rules for time to first on-study SSE is summarized in Table 6-5.


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Table 6-5:Time to first on-study SSE censoring rules
Situation
End Date 
Censored
Reason for 
Censoring
No post-baseline SSE 
assessment
Date of 
Randomization
Yes
No post-baseline SSE 
assessment 
Subject had an SSE event
Date of first SSE
No
N/A
No SSE, and at least one on-
study SSE assessment
Last SSE assessment
Yes
No SSE
6.2.3.2
Time to pain progression
Pain intensity is measured using the Brief Pain Index-Short Form (BPI-SF) at scheduled 
visits. In addition, 24-hour analgesic usage and opioid usage for each subject will be recorded 
on the eCRF. The time to pain progression is defined for evaluable subjects (i.e., subjects with 
a worst pain score of ≤8 in the BPI-SF at the baseline assessment) as the time (in days) from 
date of randomization until occurrence of the first post-baseline pain progression event. 
Pain progression is defined as the occurrence of either a pain increase or an increase in pain 
management with respect to baseline, whichever occurs first.
A pain increase is defined as an increase of 2 or more points in the BPI-SF “worst pain in 24 
hours” score from baseline observed at 2 consecutive evaluations ≥28 days apart. 
An increase in pain management is defined as follows:

For subjects not on opioids at baseline, initiation of short- or long-acting opioid use 
for pain will constitute an increase in pain management

For subjects taking weak opioid at baseline, the initiation of any strong opioid or 
adding an additional weak opioid would be considered an increase in pain 
management.

For subjects taking strong opioid at baseline, the initiation of an additional strong 
opioid (in addition to previous strong opioid) would be considered an increase in pain 
management.
The censoring rules for time to pain progression are summarized in Table 6-6.
Table 6-6:Time to pain progression censoring rules
Situation
End Date 
Censored
Reason for 
Censoring
No post-baseline assessment
Date of 
Randomization
Yes
No post-baseline
assessment
Did not experience pain 
progression by the cutoff date
Last post-baseline pain 
assessment date
Yes
Did not experience 
pain progression
Subject experienced a pain 
progression by the cutoff date
Date of first 
observation of pain 
progression
No
N/A


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6.2.3.3
Change in MM disease markers
Change in PEP/SEP M-protein will be summarized for each visit and the final visit. Change in 
FLC will be summarized for each visit and the final visit for those subjects evaluated by FLC.
Changes in plasmocytes in bone marrow aspirates will be summarized by each visit and the 
final visit. 
Descriptive statistics will be presented for the baseline and post-baseline of those markers at 
each visit. Mean change (95% CI) from baseline and mean difference between radium-223 
dichloride dose group and placebo group (95% CI) will be examined based on ANCOVA 
model with treatment group as a factor, baseline M-protein as covariate. 
6.2.3.4
Time to first opioid use for cancer pain
Time to opioid use for cancer pain is defined as the interval from the date of randomization to 
the date of opioid use.  Subjects who have no opioid use at the time of analysis will be 
censored at the last known date of no opioid use.  Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization.
The censoring rules for time to first opioid use for cancer pain are summarized in Table 6-7.
Table 6-7:Time to first opioid use for cancer pain censoring rules
Situation
End Date 
Censored
Reason for 
Censoring
No on-study assessment or no 
baseline assessment
Date of 
Randomization
Yes
No on-study 
assessment or no 
baseline assessment 
No opioid use at the time of 
datacut
Last known date of no 
opioid use 
Yes
No opioid use
Used opioid on or prior to 
datacut
The date of first 
observation of opioid 
use
No
N/A
Analgesic use will be captured via three methods:

Prior and concomitant medication case report form, where the physician records the 
analgesic medication prescribed to manage pain.  

24 hour analgesic consumption case report form, in which all analgesic medication 
taken in the last 24 hours, including dose of medication and number of pills consumed, 
will be recorded. Patients will be asked to bring all of their medication to the clinic 
visit and complete this form with the assistance of the clinician.  

Opiate use case report form, in which the information of opiate pain medication since 
last assessment was collected.
For the time to first opioid use for cancer pain, the earliest date of the first opioid use recorded 
via any of the following three methods will be used: the 24 hour analgesic consumption case 


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report form, prior and concomitant medication case report form or opiate use case report 
form.
Patients who had opioid analgesics at baseline are not eligible for the analysis of this 
endpoint.
6.3
Pharmacokinetics / pharmacodynamics
No PK measurement and analysis will be performed in this study.
6.4
Safety
All subjects enrolled in phase 1b study will be evaluated for the occurrence of DLTs during 
the DLT observation window, which is defined as the time from the first dose of study 
treatment through 21 days after administration of the second dose of radium-223 dichloride.  
The definition of DLT can be referred to protocol Section 6.3.1. The number and percentage 
of DLTs will be summarized by cohort.
Safety variables will be analyzed using frequency tables and descriptive statistics by dose 
level cohort for phase 1b part and by treatment arm for phase 2 part. For phase 2 part, primary 
safety analysis will include treatment-emergent safety events as of database cutoff when all 
subjects completed end of radium-223 visit, or discontinued early. Final safety analysis will 
be performed after the last followed patient completes active follow-up 2 years following the 
last dose of radium-223 dichloride treatment (i.e., end of treatment visit). Final safety analysis 
will be reported in the Clinical Study report. In addition, safety events emerging during long-
term follow-up will not be reported in the study Clinical Study Report, it will be reported in 
separate document(s).
All safety analyses will be performed for SAF.
6.4.1
Adverse events
All adverse events (AE) will be coded according to the latest Medical Dictionary for 
Regulatory Activities (MedDRA) Version as of database lock for the applicable analysis. The 
MedDRA version used will be documented in the CSR. The intensity of an AE will be 
documented using the NCI-CTCAE v4.03. 
Adverse Events of Interest
A summary table and a listing will be provided for subjects who experienced following  
adverse events: hematological AEs (neutropenia, thrombocytopenia, etc), bone fractures, and 
secondary malignancies.
Pre-treatment AEs
A pre-treatment adverse event is defined as any event that started before the start of study 
drug administration.


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Treatment-emergent AEs
A treatment-emergent adverse event (TEAE) is defined as any event arising or worsening 
after start of study drug administration until the end of the treatment period. The treatment 
period is defined from the day of the first dose of radium-223 dichloride/placebo to 30 days 
after last dose of study treatment (radium-223 dichloride/placebo, BOR, or DEX, whichever is 
last) 
Post-treatment AEs
A post-treatment adverse event is defined as any event arising or worsening after the end of 
the treatment period.
An overall summary of AEs will be provided to present the number and percentage of 
subjects with

any pre-treatment AEs, TEAEs, or post-treatment AEs

any study treatment related TEAEs

any serious TEAEs, 

any serious treatment related TEAEs

any CTCAE Grade ≥3 TEAEs

any TEAEs leading to drug modification 

any TEAEs leading to discontinuation

any TEAEs leading to death

any AEs leading to drug modification or discontinuation
TEAEs and post-treatment AEs will be summarized by MedDRA system organ class and 
preferred term. For each subject, multiple occurrences of the same event will be counted once 
within a system organ class and preferred term. For post- treatment AE tables, only treatment-
related AEs, serious treatment-related AEs will be reported.  
The same summaries will be repeated for related TEAES, serious TEAEs, serious related 
TEAEs, CTCAE Grade ≥3 TEAEs, TEAEs leading to drug modification or discontinuation , 
TEAEs leading to death and any AEs leading to drug modification or discontinuation.
The maximum severity of the TEAEs and post-treatment AEs will be summarized according 
to the NCI-CTCAE toxicity criteria. For each subject, multiple occurrences of the same event 
will be counted once at their maximum severity within a system organ class and preferred 
term. 
TEAE will also be summarized by NCI-CTCAE toxicity criteria and relationship to study 
medication.
Long-term follow-up (LTFU) AEs are AEs arising during the long-term follow-up period. 
LTFU AEs will not be included in safety analysis summary tables for this study, but will be 
included in listings.


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Data listings will be produced for all AE recorded in the study. Verbatim descriptions and 
coded terms will be listed for all AEs. 
Serious adverse events (SAEs), deaths, AEs leading to discontinuation and AEs of interest 
will each have a separate listing.  
6.4.2
Deaths
Deaths reported during the study period will be summarized by timing and primary reason by 
cohort and overall for phase 1b part and by treatment group and overall for phase 2 part.     
6.4.3
Clinical Laboratory Data
The following laboratory parameters will be summarized:
Hematology:
Hematocrit, Hemoglobin (Hb), platelet counts, RBC counts, white blood cell (WBC) counts, 
and WBC differential. 
Chemistry:
Sodium, potassium, chloride, calcium (and albumin-adjusted calcium), ALT, AST, lactate 
dehydrogenase (LDH), total ALP, serum creatinine, blood urea nitrogen (BUN; or urea), 
bilirubin (total), alkaline phosphatase, glucose, phosphate, and albumin.  
Coagulation panel: 
PT, PTT, and INR of PT
Toxicity grading of laboratory values will be based on NCI CTCAE version 4.03. Descriptive 
statistics (number of observations, mean, standard deviation, minimum, median and 
maximum values) will be presented for quantitative clinical laboratory tests, their changes 
from baseline (including baseline value), and their percent changes from baseline at 
applicable visits. Graphical presentations will be generated for each laboratory parameter by 
visit to investigate trends over time and outliers in the data. In addition, changes from baseline 
will be summarized in shift tables according to baseline and worst CTCAE grades. Frequency 
tables will be provided for qualitative lab data.
If more than one assessment occurred at any visit (i.e. repeat samples taken), the last valid 
(non-missing) value will be used in the summaries. Unscheduled laboratory data will be listed 
but will not be included in the summary tables. However, all visits will be used in CTCAE 
summary tables.


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6.4.4
Other Safety Analyses
Vital sign measurements (systolic and diastolic blood pressure, heart rate, body temperature, 
respiration rate) and ECG will be summarized by visit. Assessments will be summarized with 
descriptive statistics at each applicable visit and for change from baseline to post-baseline 
assessments. 
Body weight will be collected at screening and before each dosing. Body weight will be listed 
by visit. 
Abnormal physical examination findings will be recorded either as medical history or as 
adverse events. There will be no separate listing for physical examination.
Pregnancy testing will be performed at the Screening and scheduled visits. All the pregnancy 
reported during the study will be included in the SAE listing, no separate listing will be 
generated for pregnancy.
The new primary malignancies will be summarized by cancer type (n, percent), and reported 
through listings.
6.5
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D)
MTD/RP2D will be evaluated by the sponsor in consultation with the investigators during the 
conduct of the dose escalation part of the study. MTD/RP2D will be determined using the 
incidence of DLTs during the DLT observation window, which is defined as the time from the 
first dose of study treatment through 21 days after administration of the second dose of 
radium-223 dichloride. The decision about MTD/RP2D will be made after all subjects in last 
dose escalation cohort are treated with at least 2 doses for radium-223 dichloride and 
observed for 21 days after second dose. If no DLT is observed in Phase 1b part, a RP2D will 
be selected based on safety and efficacy data obtained during the phase 1b part.
Individual listings of DLTs will be presented by dose level cohort for phase 1 part with 
treatment cycle of onset, serious or nonserious, CTCAE v4.03 grade and term, and MedDRA 
terms provided for each DLT. Dose Evaluable Set (DES) will be used for the analyses.
6.6
Analysis of Other Endpoints
All the analyses listed in this section will be performed by cohort for phase 1b part for SAF
and by treatment group for phase 2 part for ITT population.
6.6.1
ECOG Performance Status
The ECOG-PS is to be assessed every Day 1 of BOR before injection. The number and 
percentage of subjects in each ECOG-PS category will be presented by visit. Changes from 


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baseline in ECOG-PS score will be summarized in shift tables according to baseline and post-
baseline assessment by visit.
6.6.2
Brief Pain Index – Short Form (BPI-SF)
BPI-SF is composed of 9 questions asking whether subject experiences pain, location and 
severity of the pain. Subject will be asked to rate the pain they experienced with 0 as no pain 
and 10 for as pain as imagine. Score for Question 3 “worst pain in the last 24 hours” will be 
used for calculating time to pain progression as described in Section 6.2.3. A data listing will 
be presented for BPI-SF assessments at each scheduled visit.
6.6.3
Resource Utilization Questionnaire
Information on healthcare resource use that is associated with the management of AEs as well 
as subject monitoring will be collected by resource utilization questionnaire. A data listing 
will be presented for RUQ at each scheduled visit.
6.6.4
Long Term Safety
Safety data arising during the long-term safety follow-up period in this study will be 
presented through listings. In the event subjects in this study transfer into a long term safety 
follow-up study for all or a portion of their long-term follow-up period, any data not collected 
in this study is outside the scope of this SAP. 
6.7
Examination of Subgroups
There will be no planned subgroup analysis for this study.
7.
Document history and changes in the planned statistical analysis
Changes in the planned statistical analysis from protocol:
1) “changes in bone lesions” were removed from the analysis due to no data will be 
collected.
2) Analysis for bone biomarkers, ctDNA, CTCs, and MM related cytokines were removed as 
they will be described in a separate SAP. 
3) Time to first on-study SSE, time to pain progression, and time to first opioid use are 
defined as the time from the date of randomization, instead of from the first dose of 
radium-223 dichloride.


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8.
References
1. Kaplan E and Meier P. Nonparametric estimation from incomplete observations. J Amer 
Statist Assn 53:457–481 (1958)
2. Brookmeyer R and Crowley J. A confidence interval for the median survival time. 
Biometrics 38:29-41 (1982)
3. Xofigo Biostatistical project Plan version 2.0 dated 12 December 2016. 
4. _Xofigo Biostatistical Project Plan_v2_07Dec2016 final_addendum.docx dated 17 May 
2018.