Clinical trial NCT03224507
Conditions: Multiple Myeloma
Keywords: multiple myeloma induction therapy autologous hematopoietic cell transplantation KRdD Daratumumab Carfilzomib Lenalidomide
Sponsor: University of Alabama at Birmingham
Start date: 2018-03-14; Completion date: 2023-06-30
Enrollment: 123 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Multiple myeloma (MM), a plasma cell disorder, is the second most common hematologic malignancy in the U.S. No standard curative therapy has yet been found. A variety of therapeutic measures including high dose melphalan, induction therapy, and continuous therapy have been used but the goal of complete response without relapse has not been achieved. More active treatment regimens and better tools for response assessment are needed.

Detailed description:
This trial will assess the safety and efficacy of an induction therapy using the combination of dexamethasone, lenalidomide (revlimid), daratumumab (Darzalex) and carfilzomib (Kyprolis) to treat patients with newly diagnosed multiple myeloma. The therapy with KRdD (Kyprolis, Revlimid, dexamethasone, Darzalex) will be followed by autologous hematopoietic cell transplantation (auto-HCT) and KRdD consolidation. Duration of therapy will be guided by eradication of minimal residual disease (MRD). The hypothesis is that the KRdD therapy particularly in combination with the auto-HCT will be safe and lead to deep remission. Patients who become MRD- will discontinue therapy (no maintenance therapy) and be actively monitored for resurgence of MRD or clinical relapse.

Arms: arm 1: Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22 (KRd-Dara). Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Days 8 and 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, auto-HCT is done (consolidation 1), then up to two 4-cycle blocks of KRd-Dara consolidation (consolidations 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance. arm 2: Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then @ 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22. Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Day 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, Following induction therapy, patients will receive up to three 4-cycle blocks of KRd-Dara consolidation (consolidations 1, 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.
Interventions: intervention 1: KRdD followed by auto-HCT intervention 2: KRdD only
Intervention descriptions: intervention 1: Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will be followed by autologous hematopoietic cell transplantation and KRdD consolidation. intervention 2: Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will not be followed by autologous hematopoietic cell transplantation but will proceed with KRdD consolidation.

Protocol documents:
Prot_SAP_001.pdf: 
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PROTOCOL INFORMATION 
Study Title:  MONOCLONAL ANTIBODY-BASED SEQUENTIAL THERAPY FOR 
DEEP REMISSION IN MULTIPLE MYELOMA – MASTER TRIAL 
 
NCT # 03224507 
UAB # 1735 
Amgen # ISS -20167173 
Janssen# 54767414MMY2018 
IND#135181 
 
Protocol team: 
 
Yelak Biru (patient advocate) 
Natalie S. Callander, MD  
Robert Frank Cornell, MD 
Luciano J. Costa, MD, PhD (Chair, sponsor-investigator) 
Saurabh Chhabra, MD 
Parameswaran Hari, MD 
Eva Medvedova, MD 
James Omel, MD (patient advocate) 
 
Sponsor: 
University of Alabama at Birmingham 
 
Support: 
Amgen (funding and investigational agent) 
Janssen (funding and investigational agent) 
 
 
 
 
 
 
 


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Statistician: 
Name: Yufeng Li 
Address: MT 644, 1717 11th Ave S, Birmingham, AL 35294-4410 
Phone No: 205.934.3679 
Fax No: 205.934.4262 
Email Address: yli@uabmc.edu 
 
 
University of Alabama at Birmingham, Clinical Trials Network and Monitoring Office – 
UAB CTNMO 
(Multicenter Operations) 
 
Name: Pam Dixon Hardwick, RN, OCN, CCRP 
Address: 1802 6th Avenue South; NP 2515, Birmingham, AL 35294 
Phone:  (205) 975-5387 
Fax No:   (205) 975 9875 
Email Address: pamdixon@uab.edu 
 
 
 
 
 
 
 
 
Protocol Version History:  
 
Original date May 19, 2017 
Amendment #1 October 30, 2017 
Amendment #2 May 21, 2018  
Amendment #3 Feb 14, 2019 
Amendment #4 Aug 19, 2019 
Amendment#5 Nov 15, 2019 
Amendment#6 Feb 12, 2022   
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE: 
MONOCLONAL ANTIBODY-BASED SEQUENTIAL 
THERAPY FOR DEEP REMISSION IN MULTIPLE 
MYELOMA – MASTER TRIAL  
 
OBJECTIVES: 
PRIMARY OBJECTIVE 
 
To determine the frequency of MRD(-) remissions (≤10-5 MM-
associated molecules)  after completion of intense treatment plan 
that consist of induction therapy, followed by consolidation 
therapy with a multi-drug regimen combined with continuous 
daratumumab therapy in patients with newly diagnosed multiple 
myeloma 
 
 
SECONDARY OBJECTIVES 
 
To determine the toxicity profile of the combination of 
carfilzomib, lenalidomide, dexamethasone and daratumumab 
(KRdD) in the treatment of patients with newly diagnosed MM. 
 
To determine the frequency of Imaging plus MRD-negative 
patients (≤10-5 MM-associated molecules in bone marrow and no 
area of PET/CT FDG uptake greater than mediastinal blood pool 
or surrounding normal tissue). 
 
 
To determine the frequency of MRD(-) status after induction 
therapy with KRdD 
 
To determine the frequency of conversion from MRD(+) to 
MRD(-) status with auto-HCT after completion of KRdD 
induction. 
 
To determine the frequency of patients achieving complete 
remission (CR) with the above mentioned treatment regimen. 
 
To determine the feasibility and effectiveness of MRD-guided 
treatment discontinuation in newly diagnosed MM patients that 
have confirmed MRD(-). 
 
To determine the risk and timing of resurgence of MRD (≥10-5) 
after discontinuation of therapy in confirmed MRD(-) patients 


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EXPLORATORY OBJECTIVES 
 
To estimate PFS in cytogenetically defined high-risk patients [ 
myeloma harboring t(4;14), t(14;16), del17p] and cytogenetically 
defined standard risk patients who discontinue therapy upon 
confirmed MRD<10-5 
 
 
 
STUDY DESIGN: 
Single arm, multi-center, open label phase 2 trial with safety lead 
in and response-adapted therapy.  
STUDY 
POPULATION: 
Adult patients with newly diagnosed multiple myeloma and 
indication for initiation of therapy 
 
INCLUSION 
CRITERIA: 
 
1. Age >18 years with no upper age limit 
2. Diagnosis of newly diagnosed multiple myeloma with 
indication for initiation of therapy. 
3. Eastern Cooperative Oncology Group (ECOG) performance 
status 0–2 
4. No prior MM-directed therapy except for dexamethasone (up 
to 160 mg) and/or bortezomib (up to 5.2 mg/m2) and/or 
cyclophosphamide up to 1000 mg/m2 administered for 
management of acute manifestations of MM (hypercalcemia, 
renal impairment, pain) for no longer than 4 weeks prior to 
enrollment (pre induction). If subject received any prior 
therapy, pretreatment parameters necessary for disease 
characterization and response assessment must be available. 
5. Measurable disease meeting at least one of the following 
criteria (at screening or prior to pre induction): 
     -Serum monoclonal (M) protein ≥1.0 g/dl 
     -≥ 200 mg of M protein/24h in the urine 
     -Serum free light chain ≥10 mg/dL and abnormal kappa to    
       lambda ratio. 
6. Available FISH report (performed locally or by third party 
cytogenetics laboratory) that informs absence or presence of 


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high risk chromosome abnormalities [del17p, t(4;14) and 
t(14;16)] 
7. Life expectancy ≥ 12 months. 
8. Adequate hepatic function, with serum ALT ≤ 3.5 times the 
upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 
µmol/L) within 21 days prior to initiation of therapy. 
9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days 
prior to start of therapy either measured or calculated using 
standard Cockcroft and Gault formula (available in 
https://www.kidney.org/professionals/KDOQI/gfr_calculatorC
oc ).Written informed consent in accordance with federal, 
local, and institutional guidelines.  
10. Females of childbearing potential (FCBP) must agree to 
ongoing pregnancy testing and to practice contraception 
during treatment and for 30 days after the last dose of 
carfilzomib. Male subjects must agree to practice 
contraception and refrain from donating sperm during 
treatment and for 90 days after the last dose of carfilzomib. 
11. All subjects must agree to comply with and be enrolled in 
Revlimid REMS™ program. 
 
EXCLUSION 
CRITERIA: 
 
1. Diagnosis of amyloidosis, POEMS, Waldenstrom’s 
macroglobulinemia.  
2. Major surgery, radiotherapy or infection requiring therapy 
within 14 days of starting treatment. 
3. Known FEV1 or cDLCO < 50% of predicted. 
4. Pregnant or lactating females. 
5. Known human immunodeficiency virus infection. 
6. Seropositive for hepatitis B (defined by a positive test for 
hepatitis B surface antigen [HBsAg]). Subjects with resolved 
infection (ie, subjects who are HBsAg negative but positive for 
antibodies to hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-HBs]) must be 
screened using real-time polymerase chain reaction (PCR) 
measurement of hepatitis B virus (HBV) DNA levels. Those 
who are PCR positive will be excluded. EXCEPTION: 
Subjects with serologic findings suggestive of HBV 
vaccination (anti-HBs positivity as the only serologic marker) 


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AND a known history of prior HBV vaccination, do not need 
to be tested for HBV DNA by PCR. 
7. Seropositive for hepatitis C (except in the setting of a 
sustained virologic response [SVR], defined as aviremia at 
least 12 weeks after completion of antiviral therapy). 
8. Unstable angina or myocardial infarction within 4 months 
prior to registration, NYHA Class II, III or IV heart failure, 
uncontrolled angina, history of severe coronary artery disease, 
severe uncontrolled ventricular arrhythmias, sick sinus 
syndrome, or electrocardiographic evidence of acute ischemia 
or Grade 3 conduction system abnormalities unless subject has 
a pacemaker. 
9. Cerebrovascular disease manifested as prior stroke at any time 
or TIA in the 12 months prior to initiation of therapy 
10. Nonhematologic malignancy within the past 3 years with the 
exception of a) adequately treated basal cell carcinoma, 
squamous cell skin cancer, or localized thyroid cancer; 
b) carcinoma in situ of the cervix or breast; c) prostate cancer 
of Gleason Grade 6 or less with stable prostate-specific 
antigen levels; or d) cancer considered cured by surgical 
resection or unlikely to impact survival during the duration of 
the study, such as localized transitional cell carcinoma of the 
bladder or benign tumors of the adrenal or pancreas. 
11. Significant neuropathy (Grades 3–4, or Grade 2 with pain) 
within 21 days prior to registration. 
12. Known history of allergy to Captisol® (a cyclodextrin 
derivative used to solubilize carfilzomib). 
13. Subjects with pleural effusions requiring thoracentesis or 
ascites requiring paracentesis within 21 days prior to 
registration.  
14. Contra indication or intolerance to required supportive care 
medications (Aspirin and Acyclovir) 
15. Any other 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. 
 
STUDY 
PROCEDURES: 
 
 
 
 
Initially 6 patients will be enrolled in a safety lead-in. If dose 
limiting toxicity is seen during the first 2 cycles in 2 or more 
subjects, the study will be reviewed by the data safety monitoring 


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board that may recommend protocol amendment. If less than 2 
subjects develop dose-limiting toxicity during the first 2 cycles of 
therapy accrual will continue at the initial dose level. 
With approval of protocol amendment 2 (PA2) and change on dose 
and schedule of carfilzomib (from 6 to 3 doses per cycle), the next 6  
patients starting therapy will be considered to be in a safety lead-in 
at the new dose and schedule and followed the same procedure 
outlined above. Once a new dose and schedule is declared safe, 
previously enrolled patients will switch from 6 doses of carfilzomib 
to 3 doses of carfilzomib per cycle. 
Subjects are expected to transition from induction therapy, to 
consolidation therapy and from consolidation therapy to 
observation/ maintenance therapy according to MRD status. 
Autologous hematopoietic cell transplantation (auto-HCT) is the 
initial step in consolidation therapy. Subjects not eligible for auto-
HCT (per investigator’s assessment) or who choose to defer auto-
HCT will receive four additional cycles of consolidation therapy as 
“replacement” for auto-HCT. Each cycle of therapy has duration of 
4 weeks, except for auto-HCT that is expected to last 16 weeks 
(including recovery)  
 
INDUCTION THERAPY  
Screening – Subjects likely to meet eligibility criteria will be 
offered participation in the study after the investigator verifies UAB 
CTNMO registration. Subjects will sign informed consent prior to 
any protocol associated procedure. Screening procedures are 
outlined in Table 7 and will ensure that subject 1) meets all the 
eligibility criteria, 2) obtain disease assessment to allow efficacy 


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measurements, 3) assess baseline toxicity, and 4) provide 
identification samples for subsequent MRD assessment. 
KRdD Induction Therapy- The total duration of induction is 4 
cycles of 28-day duration each. In all cycles patients will receive 
dexamethasone 40 mg oral on days 1,8,15 and 22 and lenalidomide 
25 mg (see adjustment for renal impairment in Table 5) daily from 
days 1-21.  During cycle 1 of induction therapy, subjects will be 
treated on a distinct schedule to avoid overlap of toxicities 
associated with first dose of daratumumab and toxicities associated 
with first dose of carfilzomib. During cycles 1 and 2 subjects will 
receive daratumumab 16 mg/kg on days 1,8,15 and 22. During 
cycles 3 and 4 subjects will receive daratumumab 16 mg/kg on day 
1 and 15 of each cycle. Carfilzomib will be administered at dose of 
20 mg/m2 on day 8 of first cycle and at dose of 56 mg/m2   on days 
15 of first cycle and days 1,8,15 of subsequent induction cycles.  
Response assessment- Response assessment based on serum and 
urine protein electrophoresis, serum and urine immunofixation and 
serum free light chains will occur at the end of cycles 2 and 4 of 
induction. Bone marrow aspiration with MRD assessment (in 
subjects found to be MRD-informative based on clone identification 
sample) will be performed at the end of cycle 4 (hereafter referred to 
as induction MRD).  
CONSOLIDATION THERAPY  
Auto-HCT – Upon completion of induction therapy patients will 
proceed with standard of care auto-HCT (consolidation 1). 
Hematopoietic progenitor cell mobilization will be performed 
utilizing growth-factors with or without the addition of plerixafor 
using standard practices. The use of chemotherapy mobilization is 
not allowed as it may add toxicity, delay transplant and post-


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transplant recovery. Chemotherapy mobilization may be employed 
after failure of initial mobilization attempt and after discussion with 
study PI. Subjects who are transplant eligible (as determined by 
investigator), but choose to defer transplant, will collect 
hematopoietic progenitor cells and them proceed to KRdD 
consolidation. Auto-HCT conditioning therapy with consist of 
Melphalan 200mg/m2 administered as single dose on day -2 or -1. 
Supportive care following auto-HCT will follow standard of care 
institutional practices. Subjects will resume consolidation therapy 
not earlier than 90 days and ideally not later than 112 days after 
auto-HCT.  
 
KRdD consolidation therapy- The total duration of KRD 
consolidation (consolidations 2 and 3) will be up to 8 cycles (up to 
12 cycles for patients who don’t undergo auto-HCT) of 28-day 
duration each. In all cycles patients will receive dexamethasone 40 
mg oral on days 1,8,15 and 22 and lenalidomide 25 mg (see 
adjustment for renal impairment in Table 5) daily from days 1-21, 
daratumumab 16 mg/kg on day 1 and 15 on the first two cycles of 
consolidation and on day 1 on remaining cycles and carfilzomib 56 
mg/m2  on days 1,8,15. 
Response assessment- Response assessment based on serum and 
urine protein electrophoresis, serum and urine immunofixation and 
serum free light chains will occur 60-80 days after auto-HCT and at 
the end of each even cycle during KRdD consolidation. Bone 
marrow aspiration with MRD assay (in subjects found to be MRD-
informative based on clone identification sample) will be performed 
60-80 days after auto-HCT (or on day 1 of cycle 3 of KRdD 
consolidation#1 for patients not undergoing auto-HCT), hereafter 


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referred to as consolidation-1 MRD , and, when applicable, on day 1 
of cycles 3  KRdD  consolidation (cycle 7 for subjects who did not 
undergo auto-HCT) hereafter referred to as consolidation-2 MRD 
and on day 1 of cycle 7 of KRdD consolidation (cycle 11 for 
subjects who did not undergo auto-HCT) hereafter referred to as 
consolidation-3 MRD . This approach of assessing MRD at the 
beginning of the third cycle of each 4-cycle “block” of KRdD 
allows patients who have become confirmed MRD(-) to effectively 
receive two full cycles of consolidation (the third and fourth cycle in 
the block) before having therapy discontinued. 
 
OBSERVATION/MAINTENANCE THERAPY 
 
Transition to observation/maintenance therapy – Subjects will 
start observation/maintenance therapy after completing the entire 
planned consolidation therapy or after obtaining a confirmed MRD(-
), defined as ≤10-5 MM-associated molecules in 2 consecutive tests, 
that is induction-MRD plus consolidation-1 MRD or consolidation-1 
MRD plus consolidation-2 MRD or consolidation -2 MRD and 
consolidation-3 MRD. 
MRD negative observation cohort– Subjects who obtain 
confirmed MRD(-) assessment in either consolidation-1 MRD or 
consolidation-2 MRD or consolidation-3 MRD will be managed in 
the MRD (-) observation cohort. In this cohort, subjects will be 
observed without MM-directed therapy and undergo monitoring, 
including MRD surveillance during an active surveillance phase (72 
weeks). Subjects who test positive for MRD at any of the 
subsequent surveillance MRD assessments while off therapy are 
encouraged to start standard of care maintenance lenalidomide as 
discussed for MRD(+) cohort. 


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MRD negative cohort disease assessment- Response assessment 
based on serum and urine protein electrophoresis, serum and urine 
immunofixation and serum free light chains will occur at a 
minimum of every 8 weeks for the first 24 weeks and every 16 
weeks thereafter. Bone marrow aspiration with MRD surveillance 
will be performed 24 and 72 weeks after start of observation.  
MRD positive maintenance cohort– Subjects who are not 
evaluable for MRD status or don’t have confirmed MRD(-) at the 
end consolidation-3 will not receive more experimental therapy 
beyond consolidaton-3 and will be observed in the MRD(+) cohort. 
In this cohort subjects will be monitored for overall and 
progression-free survival. It is highly recommended that subjects 
receive standard of care lenalidomide maintenance. Recommended 
starting regimen is lenalidomide 10 mg/day continuously until 
progression or intolerance, with dose modifications and adjustments 
being performed at treating physician discretion.  
MRD positive cohort disease assessment- Response assessment 
based on serum and urine protein electrophoresis, serum and urine 
immunofixation and serum free light chains is strongly 
recommended not less often than every 16 weeks until disease 
progression .  
 
PRIMARY 
ENDPOINT: 
 
Rate of MRD negative remissions (≤10-5 MM-associated molecules) 
at completion of consolidation therapy.  
 
SECONDARY 
ENDPOINTS: 
 
 
 
Toxicity profile of the KRdD combination. 


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EXPLORATORY 
ENDPOINT: 
Rate of Imaging plus MRD-negative patients (≤10-5 MM-associated 
molecules in bone marrow and no area of PET/CT FDG uptake 
greater than mediastinal blood pool or surrounding normal tissue) 
Rate of negative MRD at completion of induction. 
Rate of conversion from positive to negative MRD with auto-HCT. 
Rate of achievement of complete remission (CR) upon completion 
of induction and consolidation. 
Rate and kinetics of conversion from negative MRD to positive 
MRD upon treatment discontinuation. 
Progression-free survival (PFS) and overall survival (OS) for entire 
study population. 
 
PFS for patients with confirmed MRD(-) and undergoing 
observation without additional therapy. 
 
 
 
 
 
STATISTICAL 
METHODS: 
 
Due to limited data on the safety of the specific combination of 
agents being studied in the induction phase, a safety lead-in was 
performed and included 6 subjects. No dose limiting toxicity was 
seen during the first 2 cycles in 2 or more subjects (in fact, none of 
the first 6 subjects experienced dose limiting toxicity). The study 


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was reviewed by the data safety monitoring board that 
recommended accrual will continue at the initial dose level. 
Using Simon’s optimal two-stage design (optimal design), a total of 
67 evaluable patients will achieve 80% power to detect at least 15% 
more MRD negative subjects in the experimental intervention 
compared to the historical benchmark ( 60% MRD negative rate at a 
KRd + auto-HCT trial) aiming to achieve at least 75% MRD 
negative upon completion of consolidation in the current protocol.  
Twenty seven patients will be enrolled in the first stage; the trial 
will be terminated if 17 or fewer patients become MRD negative in 
the first stage. If the trial goes on to the second stage, an additional 
40 evaluable patients (total of 67 evaluable patients) will be studied. 
If the total number of subjects to become MRD negative is less than 
or equal to 46, the intervention will be considered futile. By 
accounting for 20% of either subject drop out or not informative for 
MRD, a total of 82 eligible patients will be required.  
Upon approval of protocol amendment 4, as long as protocol has not 
met criteria for early stop at first stage and does not meet criteria for 
futility upon completion of second stage, accrual will continue to a 
total of 123 patients, being 77 standard risk (SR) and 44 high risk 
(HR) patients. The expansion will enable the exploratory objective 
to describe PFS on HR and SR patients with confirmed MRD (-) 
status. 
 
 


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SCHEMA 
  
  


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS...........................................................................................................3 
SCHEMA .................................................................................................................................14 
TABLE OF CONTENTS .........................................................................................................16 
1 
INTRODUCTION .......................................................................................................22 
1.1 
Disease Specific Background ..........................................................................22 
1.2 
Minimal Residual Disease in MM ...................................................................22 
1.3 
Carfilzomib Background ..................................................................................24  
1.4 
Daratumumab Background ..............................................................................26  
1.5 
Study Rationale ................................................................................................27  
2 
OBJECTIVES ..............................................................................................................29  
2.1 
Primary Objective ............................................................................................29 
2.2 
Secondary Objectives.......................................................................................29 
2.3 
Exploratory Objective………………………………………………………..29 
3 
EXPERIMENTAL PLAN ...........................................................................................30 
3.1 
Study Design ....................................................................................................30 
3.2 
Number of Centers ...........................................................................................35 
3.3 
Number of Subjects..........................................................................................35 
3.4 
Estimated Study Duration ................................................................................35 
3.5 
Treatment Schema ...........................................................................................35 
3.6 
Minimal Residual Disease Assessments ..........................................................38 
4 
SUBJECT SELECTION ..............................................................................................40 
4.1 
Inclusion Criteria .............................................................................................40 
4.2 
Exclusion Criteria ............................................................................................41 
5 
SUBJECT ENROLLMENT.........................................................................................46 
6 
TREATMENT PROCEDURES ..................................................................................44 
6.1 
Drug Preparation and Administration ..............................................................44 
6.2 
Dose Modifications/Adjustments.....................................................................49 
6.3 
Safety Considerations ......................................................................................59 
6.4 
Concomitant Medications ................................................................................64 
7 
STUDY TESTS AND OBSERVATIONS ..................................................................67 
8 
STUDY, TREATMENT AND PARTICIPATION DISCONTINUATION ...............72 


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8.1 
Reasons for Study Discontinuation ..................................................................72 
8.2 
Reasons for Treatment Discontinuation...........................................................72 
8.3 
Reasons for Study Participation Discontinuation ............................................72 
9 
ADVERSE EVENTS ...................................................................................................73 
9.1 
Overview ..........................................................................................................73 
9.2 
Management of Safety Data.............................................................................73 
9.3 
Adverse Events Definitions .............................................................................74 
9.4 
Causality ..........................................................................................................75 
9.5 
Adverse Events of Special Interest (Daratumumab) ........................................76 
9.6 
Unlisted (Unexpected) AE/Reference Safety Information ..............................76 
9.7 
Adverse Events Reporting Procedures.............................................................76 
9.8 
Serious Adverse Events Definitions ................................................................79 
9.9 
AE Reporting and Documentation Requirements (Daratumumab) .................81 
9.10 
AE Reporting and Documentation Requirements (Carfilzomib).....................90 
10 
STATISTICAL CONSIDERATIONS.........................................................................94 
10.1 
Study Design ....................................................................................................94 
10.2 
Study Endpoints ...............................................................................................94 
10.3 
Sample Size Considerations .............................................................................94 
10.4 
Statistical Analysis ...........................................................................................99 
11 
INVESTIGATIONAL PRODUCT ............................................................................102 
11.1 
Carfilzomib Description.................................................................................102 
11.2 
Carfilzomib Formulation ...............................................................................102 
11.3 
Carfilzomib Storage .......................................................................................102 
11.4 
Carfilzomib Accountability ...........................................................................102 
11.5 
Lenalidomide Description ..............................................................................103 
11.6 
Lenalidomide Formulation.............................................................................103 
11.7 
Lenalidomide Storage ....................................................................................103 
11.8 
Lenalidomide Supplier ...................................................................................104 
11.9 
Dexamethasone Description ..........................................................................104 
11.10 Dexmaethaosne Formulation .........................................................................104 
11.11 Dexamethasone Storage .................................................................................104 
11.12 Dexamethasone Supplier ...............................................................................104 
11.13 Daratumumab Description .............................................................................105 


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11.14 Daratumumab Formulation ............................................................................105 
11.15 Daratumumab Storage ...................................................................................105 
11.16 Daratumumab Accountability ........................................................................105 
11.17 Melphalan Description ...................................................................................106 
11.18 Melphalan formulation...................................................................................106 
11.19 Melphalan Storage .........................................................................................106 
11.20 Melphalan supplier.........................................................................................106 
12 
REGULATORY OBLIGATIONS.............................................................................107 
12.1 
Informed Consent...........................................................................................107 
12.2 
Compliance with Laws and Regulations........................................................107 
12.3 
Pre-study Documentation Requirements .......................................................108 
12.4 
Subject Confidentiality ..................................................................................110 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................111 
13.2 
Study Documentation and Archive ................................................................111 
13.3 
Study Monitoring and Data Collection ..........................................................112 
14 
REFERENCES ..........................................................................................................115 
APPENDIX A:  NCI-CTCAE VERSION 4.0 .......................................................................119 
APPENDIX B:  RESPONSE CRITERIA FOR MULTIPLE MYELOMA ..........................120 
PROTOCOL SYNOPSIS...........................................................................................................3 
SCHEMA .................................................................................................................................14 
TABLE OF CONTENTS .........................................................................................................16 
1 
INTRODUCTION .......................................................................................................25 
1.1 
Disease Specific Background ..........................................................................25 
1.2 
minimal residual disease in MM ......................................................................26 
1.3 
CARFILZOMIB Background ..........................................................................27 
1.4 
daratumumab Background ...............................................................................29 
1.5 
Study Rationale ................................................................................................30 
2 
OBJECTIVES ..............................................................................................................32 
2.1 
Primary Objective ............................................................................................32 
2.2 
Secondary Objectives.......................................................................................32 
2.3 
Exploratory Objective ......................................................................................32 
3 
EXPERIMENTAL PLAN ...........................................................................................33 
3.1 
Study Design ....................................................................................................33 


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3.2 
Number of Centers ...........................................................................................38 
3.3 
Number of Subjects..........................................................................................38 
3.4 
estimated study duration ..................................................................................39 
3.5 
Treatment Schema ...........................................................................................39 
3.6 
minimal residual disease assessments ..............................................................41 
4 
SUBJECT SELECTION ..............................................................................................43 
4.1 
Inclusion Criteria .............................................................................................43 
4.2 
Exclusion Criteria ............................................................................................44 
5 
SUBJECT ENROLLMENT.........................................................................................46 
6 
TREATMENT PROCEDURES ..................................................................................47 
6.1 
Drug Preparation and Administration ..............................................................47 
6.2 
Dose MODIFICATIONS/Adjustments ...........................................................51 
6.3 
Safety Considerations ......................................................................................62 
6.4 
Concomitant Medications ................................................................................67 
7 
STUDY TESTS AND OBSERVATIONS ..................................................................70 
8 
STUDY, TREATMENT AND PARTICIPATION DISCONTINUATION ...............75 
8.1 
Reasons for study discontinuation ...................................................................75 
8.2 
Reasons for treatment discontinuation .............................................................75 
8.3 
Reasons for study participation discontinuation ..............................................75 
9 
ADVERSE EVENTS ...................................................................................................76 
9.1 
overview ...........................................................................................................76 
9.2 
Management of safety data ..............................................................................76 
This Study has been designated as an interventional study.  As such, all adverse 
events, special situations including pregnancies and product quality 
complaints for J&J Medicinal Product and for Amgen Medicinal Product 
regardless of causality and special situations excluding those from subjects not 
exposed to a J&J medicinal product and/or Amgen medicinal product, quality 
complaints with or without an adverse event as described in this protocol will 
be reported from the time a subject has signed and dated an Informed Consent 
Form (ICF) until 30 days after the last documented use of product under study 
within the study. All subsequent AEs and SAEs will be collected after this 
period if the Principal Investigator considers the AE/SAE to be causally-
related to the study drug. ..................................................................................76 
For the purposes of this study, the Janssen medicinal product is: 
DARZALEX®(daratumumab) ........................................................................76 


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For the purposes of this study, the Amgen medicinal product is: KYPROLIS® 
(carfilzomib) ....................................................................................................76 
9.3 
Adverse events definitions ...............................................................................77 
9.4 
Causality ..........................................................................................................78 
9.5 
Adverse Events of special interest (daratumumab) .........................................79 
9.6 
unlisted (unexpected adverse events/reference safety information .................79 
9.7 
Adverse Events Reporting Procedures.............................................................79 
9.8 
Serious Adverse Events Definitions ................................................................82 
9.9 
Adverse Event Reporting and Documentation Requirements (daratumumab)84 
9.10 
Adverse Event Reporting and Documentation Requirements (carfilzomib) ...93 
10 
STATISTICAL CONSIDERATION ...........................................................................98 
10.1 
Study Design ....................................................................................................98 
10.2 
Study Endpoints ...............................................................................................98 
10.3 
Sample Size Considerations .............................................................................98 
10.4 
Statistical analysis ..........................................................................................103 
11 
INVESTIGATIONAL PRODUCT ............................................................................106 
11.1 
Carfilzomib Description.................................................................................106 
11.2 
Carfilzomib Formulation ...............................................................................106 
11.3 
carfilzomib Storage ........................................................................................106 
11.4 
carfilzomib Accountability ............................................................................106 
11.5 
lenalidomide Description ...............................................................................107 
11.6 
lenalidomide Formulation ..............................................................................107 
11.7 
Lenalidomide Storage ....................................................................................107 
11.8 
lenalidomide supplier .....................................................................................108 
11.9 
dexamethasone Description ...........................................................................108 
11.10 dexamethasone Formulation ..........................................................................108 
11.11 dexamethasone Storage ..................................................................................108 
11.12 dexamethasone supplier .................................................................................108 
11.13 daratumumab Description ..............................................................................109 
11.14 Daratumumab Formulation ............................................................................109 
11.15 Daratumumab Storage ...................................................................................109 
11.16 Daratumumab Accountability ........................................................................109 
11.17 melphalan Description ...................................................................................110 


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11.18 melphalan formulation ...................................................................................110 
11.19 Melphalan Storage .........................................................................................110 
11.20 melphalan supplier .........................................................................................110 
12 
REGULATORY OBLIGATIONS.............................................................................111 
12.1 
Informed Consent...........................................................................................111 
12.2 
Compliance with Laws and Regulations........................................................111 
12.3 
Pre-study Documentation Requirements .......................................................112 
12.4 
Subject Confidentiality ..................................................................................114 
13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................115 
13.1 
Protocol Amendments and Study COMPLETION ........................................115 
13.2 
Study Documentation and Archive ................................................................115 
13.3 
Study Monitoring and Data Collection ..........................................................116 
14 
REFERENCES ..........................................................................................................119 
APPENDIX A:  NCI-CTCAE VERSION 4.0 .......................................................................123 
APPENDIX B:  RESPONSE CRITERIA FOR MULTIPLE MYELOMA ..........................124 
APPENDIX C:  FOLLOW UP FORM ..................................................................................126 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
C 
degrees Centigrade 
F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
AST 
aspartate aminotransferase 
bid 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FLC 
free light chain 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 
h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
LDH 
LTD 
lactate dehydrogenase 
last tolerated dose 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
MR 
minimal response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sCR 
stringent complete response 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SPEP 
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
Tumor lysis syndrome 
TTP 
time to tumor progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 


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VGPR 
very good partial response 
WBC 
white blood count 
 


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1 
INTRODUCTION   
1.1 
DISEASE SPECIFIC BACKGROUND 
 
Multiple Myeloma (MM) is a malignant plasma cell disorder with no standard curative 
therapy(1) . Symptomatic MM is characterized by a clonal proliferation of plasma cells 
preceding clinical findings that include bone lesions, fractures, anemia, renal failure and 
hypercalcemia.(2) MM is the second most common hematologic malignancy in the US with 
30,330 expected new cases in 2016(3).  
For decades, low doses of melphalan and prednisone was the cornerstone of MM 
treatment. However, complete responses under this regimen are rare, and the median time for 
progression is not higher than 15 months (4, 5). A first significant advance in the management of 
MM was the upfront use of high doses of melphalan with autologous hematopoietic cell 
transplantation (auto-HCT), typically after short induction therapy. Such treatment has allowed 
for improved response rates, progression free survival and prolonged survival in MM(6-9) and its 
value has been recently confirmed even in the setting of modern induction therapy(10, 11). High 
dose melphalan with AHSCT therefore remains a fundamental therapeutic modality as part of the 
initial therapy for patients with newly diagnosed MM. 
Induction therapy for patients with newly diagnosed MM (NDMM) has also evolved 
substantially. The use of the proteasome inhibitor bortezomib in the setting of 3-drug regimens 
has produced remission rates in >90% of patients, is well tolerated, and prolongs survival over 
non-bortezomib containing regimens in patients who proceed to auto-HCT as well as patients 
who remain on conventional therapy(12, 13).   
A major change in paradigm in upfront myeloma therapy has been the transition from 
fixed duration of therapy to continuous therapy, of ten in the format of single agent maintenance 
therapy after either conventional induction(14, 15) or induction followed by auto-HCT 
consolidation(14, 16, 17). This approach has impacted the duration of remission and, in a subset 
of studies, also overall survival (15, 16).  
Despite impressive rates of complete remissions with induction therapy and 
implementation of maintenance therapy, the vast majority of MM patients will experience a 
relapse and eventually succumb to the disease, typically after several additional lines of therapy. 
This observation highlights the discrepancy between obtaining complete response to therapy by 


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traditional response criteria and obtaining definitive disease eradication as well as the need to 
develop more active treatment regimens and better tools for response assessment.  
 
1.2 
MINIMAL RESIDUAL DISEASE IN MM 
 
More recently, the development and validation of minimal residual disease (MRD) 
assessment by next generation sequencing (NGS) has allowed identification of group of patients 
with very distinct prognosis according to the burden of disease despite being all in the same 
traditional category of hematologic response(18-20).  
The DFCI/IFM 2009 trial treated patients with a combination of bortezomib, 
lenalidomide and dexamethasone (VRD) as induction, followed by randomization between 
immediate and deferred auto-HCT with subsequent VRD consolidation in both arms and 
lenalidomide maintenance(11). Patients with pre maintenance MRD(-)  had much improved 
progression free survival (>80% at 2 years) than patients MRD(+), identifying a subset of 
patients who may be cured from the disease and validating a disease assessment tool that may be 
employed for response-adapted therapy(18, 21). MRD assessment by NGS is currently available 
in the US as ClonoSEQ® test. 
 Other modalities of MRD assessment in MM include flow cytometry and allele-specific 
polymerase chain reaction. These modalities are currently less attractive as a management tool 
due to lower sensitivity, limited cross-validation, limited applicability and/or higher cost. 
In a recent consensus paper the International Multiple Myeloma Working Group 
(IMWG) defined MRD negative status as < 10-5 cells by flow cytometry or NGS. In this study 
we intend to also report MRD negative rates according to IMWG definition, however for MRD-
adapted therapy we will utilize the more conservative approach of requiring confirmed (2 
consecutive tests) MRD negativity ( ≤ 10-5) to drive abbreviation and discontinuation of therapy. 
Functional imaging as FDG-PET scan can add to bone marrow-based MRD testing by 
indicating residual foci of myeloma in bone and soft tissue and has been correlated with 
prognosis(22).  
While initial series using higher threshold for MRD detection indicated that MRD and 
cytogenetic abnormalities both contribute to post-remission prognosis(23, 24), more recent series 


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using more sensitive MRD assays indicate that elimination of MRD may trump even the initial 
cytogenetic risk classification(21, 25).  
 
 
1.3 
CARFILZOMIB BACKGROUND 
 
The proteasome is a multicatalytic proteinase complex that is responsible for degradation 
of a wide variety of protein substrates within normal and transformed cells.  Intracellular proteins 
targeted for degradation by the proteasome are first ubiquitinated via the ubiquitin conjugation 
system.  Ubiquitinated proteins are cleaved within the proteasome by one or more of three 
separate threonine protease activities: a chymotrypsin-like activity, a trypsin-like activity, and a 
caspase-like activity.   
Carfilzomib (PR-171, Kyprolis®) is a tetrapeptide ketoepoxide-based inhibitor specific 
for the chymotrypsin-like active site of the 20S proteasome.  Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor bortezomib 
(Velcade®).  In addition, when measured against a broad panel of proteases including metallo, 
aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-proteasomal 
proteases when compared to bortezomib(26, 27). 
Carfilzomib was initially approved in the US after demonstrating single agent activity in 
patients with relapsed and refractory multiple myeloma(28, 29), initially at the dose of 27 mg/m2 
on days 1,2,8,9, 15 and 16 of each 28-days cycle, with the dose being reduced to 20 mg/m2 on 
the first cycle.  
Subsequently, the dose of carfilzomib has been escalated in an attempt to improve anti-
myeloma activity. In a phase 1 study, the maximal tolerated dose of single agent carfilzomib was 
found to be 56 mg/m2 utilizing the traditional schedule and longer infusion time (30 
minutes)(30). This regimen led to 55% overall response rate in an independent phase 2 trial of 
heavily pretreated patients (31). The toxicity profile of higher dose of carfilzomib was not clearly 
distinct from the initial dosing with the most common grades 3 or 4 adverse events (AEs) being 
lymphopenia, thrombocytopenia,  hypertension, pneumonia and heart failure.  


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The Endeavor trial was the first to directly compare two proteasome inhibitors, namely 
bortezomib and carfilzomib, in patients with relapsed MM and 1-3 prior lines of therapy(32). 
Bortezomib was administered by subcutaneous (79%) or intravenous (21%) routes and 
conventional schedule and doses in combination with dexamethasone (Vd). Carfilzomib was 
administered at conventional schedule but in higher doses, 20 mg/m2 on days 1 and 2 of first 
cycle and 56 mg/m2 thereafter also in combination with dexamethasone (Kd). Kd led to higher 
rate of response and median improvement in PFS by 9.3 months. Patients treated with Kd were 
more likely to develop grade 3 or higher heart failure (5% vs. 2%) but less likely to develop 
grade 3 or higher peripheral neuropathy (2% vs. 8%) than patients treated with Vd. 
Investigators have also explored the use of higher doses of carfilzomib on a less intense 
schedule, allowing for greater convenience. The Champion 1 study explored weekly carfilzomib 
(i.e. days 1,8,15 of each 28 day cycle) as single agent and found the dose of 70 mg/m2 to be the 
maximum tolerated, leading to objective responses in 77% of patients with relapsed and 
refractory MM(33). More recently, the ARROW study compared weekly carfilzomib at 70 
mg/m2 with the traditional schedule at 27 mg/m2 in patients with relapsed and refractory MM and 
found the weekly dose to have similar safety profile and more prolonged progression-free 
survival(34).  
 
1.3.1 
CARFILZOMIB COMBINATION WITH LENALIDOMIDE AND 
DEXAMETHASONE 
 
 
Prior phase 1 and 2 studies demonstrated the safety and efficacy of the combination of 
lenalidomide (revlimid®), dexamethasone and carfilzomib in treating patients with relapsed 
myeloma(35). Aspire was a large international phase 3 trial comparing this triple combination 
(KRd) vs. lenalidomide plus dexamethasone (Rd) in patients with relapsed or refractory MM and 
1-3 prior lines of therapy(36). Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of each 
28-days cycle at 20 mg/m2 on days 1 and 2 of first cycle and 27 mg/m2 thereafter, reduced to 
days 1,2,15 and 16 after cycle 12 and discontinued after cycle 18. KRd was superior to Rd in 
progression-free survival (primary endpoint), overall response rate and, importantly, also quality 
of life. Patients randomized to KRd were more likely to develop hypertension (grade 3 or higher 
4.3% vs. 1.8%) and congestive heart failure (grade 3 or higher 3.8 vs 1.8%).  


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The KRd combinations has also been tested in the treatment of patients with newly 
diagnosed MM producing 61% of stringent CR and 24-month PFS rate of 92% in one study(37). 
In another study including a subset of patients with smoldering MM, the combination of 
carfilzomib, lenalidomide and dexamethasone led to 100% of VGPR or better. Importantly, 
among the 67% of patients who achieved MRD negative status by NGS, none progressed in the 
first 12 months of therapy (19). 
 
 
1.4 
DARATUMUMAB BACKGROUND 
 
Daratumumab is a human IgG1 kappa monoclonal antibody directed at CD38, a 
transmembrane protein that is overly expressed on plasma cells and malignant myeloma cells, 
while having low expression on normal lymphoid, myeloid, as well as epithelial tissue.(38) 
Functionally, daratumumab directly targets CD38-expressing tumor cells and promotes antibody-
dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, complement-
dependent cytotoxicity and apoptosis.(39) Preclinical data has demonstrated robust antitumor 
activity in xenograft models, including those with lenalidomide and bortezomib resistant cell 
lines.(39) Daratumumab (Darzalex®) is approved for treatment of relapsed MM, or newly 
diagnosed transplant ineligible MM, in combination with bortezomib, melphalan and prednisone. 
 
DARATUMUMAB SINGLE AGENT 
 
The phase 1/2 GEN501 study of daratumumab monotherapy enrolled consecutive cohorts 
receiving daratumumab from 0.005 to 24 mg/kg/dose(40) and identified 16mg/kg as the ideal 
dose with main toxicity being infusion-related events (IREs), mostly pyrexia, cough, dizziness, 
and bronchospasm. Efficacy was reported for the doses of 8mg/kg and 16 mg/kg and patients 
receiving the 16mg/kg dose had improved ORR (36%) and PFS (5.6 months) compared with the 
8mg/kg.  
The MMY2002 “Sirius” study randomized patients with 3 or more prior lines of therapy 
including a PI and an IMiD or double refractory to PI and IMiD to be treated with single agent 


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daratumumab at either 8mg/kg or 16 mg/kg every week for 8 weeks, then every other week for 
16 weeks and every week afterwards. Overall 106 patients were accrued to the 16 mg/kg arm. 
IREs were seen in 42% of patients, mostly during first infusion. In the 16 mg/kg arm the overall 
response rate was 29.2% and median duration of response was 7.4 months(41). 
1.4.2 
DARATUMUMAB COMBINATIONS 
 
In the phase 1/2 GEN 503 study, patients with relapsed MM received daratumumab in 
combination with lenalidomide and dexamethasone. Among the 32 patients who received 
daratumumab at 16mg/kg, the ORR was 88%, with 53% reaching VGPR or better. Grade 3 or 4 
neutropenia was seen in 75% of subjects, but febrile neutropenia was uncommon. IREs occurred 
in 56% of patients with only 6% being grade 3(38).  
The synergistic effect of daratumumab and IMiDs was further demonstrated with the 
combination of daratumumab, pomalidomide and dexamethasone in 77 patients with at least 2 
prior lines of therapy including prior treatment with lenalidomide and bortezomib. IREs occurred 
at a rate (61%) similar to daratumumab single agent or in combination with lenalidomide and 
dexamethasone. Neutropenia was the most common grade 3 or higher toxicity (55%). Objective 
responses were seen in 59% of patients, including 58% of the double refractory patients (42).  
Two randomized phase 3 trial have further solidified the benefit of daratumumab 
combinations with IMIDs or with PI. In the CASTOR trial patients with relapsed and refractory 
MM were randomized to receive bortezomib and dexamethasone with or without the addition of 
daratumumab. The rate of VGPR or better was higher in the daratumumab arm (59.2% vs. 
29.1%, P<0.001) as was median progression-free survival (not reached vs. 7.2 months, HR 0.39, 
P<0.001(43). Using an IMID backbone, The POLLUX trial randomized patients with relapsed 
MM and at least one prior line of therapy to receive lenalidomide plus dexamethasone with or 
without daratumumab. The rate of VGPR or better was higher in the daratumumab arm (75.8% 
vs. 44.2%) and media progression-free survival was not reached for the daratumumab arm vs. 
18.4 months in the control group (HR 0.37, P<0.001)(44) 
1.5 
STUDY RATIONALE 
 


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The KRd combination can induce high frequency of deep and durable remissions in 
patients with MM, particularly when consolidation is provided with auto-HCT. In fact a recent 
comparison between KRd conventional treatment and KRd followed by auto-HCT indicates 
further improvement in the depth of remissions with auto-HCT (sCR at 18 months 87% vs. 
55%)(45). There is limited overlapping toxicity between daratumumab and any of the agents in 
KRd. Additionally, there is strong evidence of synergism between daratumumab and IMiDs. We 
therefore hypothesize that the combination of KRd plus daratumumab (KRdD), particularly in 
combination with auto-HCT, will be safe and lead to deep remission in a large proportion of 
patients with newly diagnosed MM. In fact, a phase 1 study has explored the use of KRdD in 
newly diagnosed MM patients and found the combination to be safe and highly active(46).    
Similar to the paradigm established in other hematologic malignancies that are 
considered curable, the achievement of MRD(-) status is necessary for long term disease control 
in MM. Patients with sustained MRD(-) status may be able to undergo more abbreviated 
treatment and safely discontinue therapy without disease recurrence, while patients who remain 
MRD(+) are more likely to benefit from continuous therapy.  
Therefore, this study assesses the safety and efficacy of induction therapy with KRdD, 
followed by auto-HCT and post-transplant KRdD consolidation, with duration of therapy 
determined by achievement of MRD(-) status, and treatment discontinuation in confirmed MRD 
(-) patients. Since continuous therapy is considered the current standard of care for patients with 
newly diagnosed MM, the study will assess the feasibility of monitoring for MRD resurgence 
(≥10-5) on confirmed MRD(-) patients off therapy providing the opportunity for those subjects to 
proceed with SOC maintenance lenalidomide if resurgence of MRD. 


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2 
 OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVE 
 
• To determine the frequency of MRD(-) remissions (≤10-5 MM-associated molecules)  
after completion of intense treatment plan that consist of induction therapy, followed by 
consolidation therapy with a multi-drug regimen combined with continuous 
daratumumab therapy in patients with newly diagnosed multiple myeloma 
2.2 
SECONDARY OBJECTIVES 
 
• To determine the toxicity profile of the combination of carfilzomib, lenalidomide, 
dexamethasone and daratumumab (KRdD) in the treatment of patients with newly 
diagnosed MM. 
 
• To determine the frequency of Imaging plus MRD-negative patients (≤10-5 MM-
associated molecules in bone marrow and no area of PET/CT FDG uptake greater than 
mediastinal blood pool or surrounding normal tissue). 
 
• To determine the frequency of MRD(-) status after induction therapy with KRdD. 
 
• To determine the frequency of conversion from MRD(+) to MRD(-) status with auto-
HCT after completion of KRdD induction. 
 
• To determine the frequency of patients achieving complete remission (CR) with the 
above mentioned treatment regimen. 
 
• To determine the feasibility and effectiveness of MRD-guided treatment discontinuation 
in newly diagnosed MM patients that have confirmed MRD(-). 
 
• To determine the risk and timing of resurgence of MRD (≥10-5) after discontinuation of 
therapy in confirmed MRD(-) patients 
 
 
2.3 
EXPLORATORY OBJECTIVE 
 
• 
To describe PFS in cytogenetically defined high-risk patients [ myeloma harboring 
t(4;14), t(14;16), del17p] and cytogenetically defined standard risk patients who 
discontinue therapy upon confirmed MRD<10-5 
 
. 


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3 
EXPERIMENTAL PLAN 
3.1 
STUDY DESIGN 
This is a Single arm, multi-center, open label phase 2 trial with safety lead in and 
response-adapted therapy  
INDUCTION THERAPY 
The maximal tolerated dose of weekly carfilzomib when administered in combination 
with dexamethasone, lenalidomide and daratumumab has not been determined. The dose of 
56mg/m2 was chosen as a one level dose reduction from the dose of carfilzomib utilized as single 
agent in the ARROW trial, therefore accounting for the possibility of added toxicity when 
carfilzomib is used in combination(34).  
Therefore, upon approval of PA2 6 subjects were enrolled in a safety lead in cohort that 
received induction therapy with the following regimen, with a target dose of carfilzomib of 56 
mg/m2: 
Cycle 1 
 
Dexamethasone 40 mg PO days 1,8,15 and 22  
 
Lenalidomide 25 mg PO daily, days 1-21 
 
Carfilzomib 20 mg/m2 day 8; Carfilzomib 56 mg/m2 day 15 
 
Daratumumab 16 mg/kg days 1, 8, 15 and 22 
Cycle 2 
 
Dexamethasone 40 mg PO days 1,8,15 and 22  
 
Lenalidomide 25 mg PO daily, days 1-21 
 
Carfilzomib 56 mg/m2 days 1, 8, and 15 
 
Daratumumab 16 mg/kg days 1, 8, 15 and 22 
Cycles 3-4 
Dexamethasone 40 mg (or LTD) PO days 1,8,15 and 22  


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Lenalidomide 25 mg (or LTD) PO daily, days 1-21  
 
Carfilzomib 56 mg/m2 (or LTD) days 1, 8, and 15  
 
Daratumumab 16 mg/kg days 1,15  
 
-If < 2  subjects experience a DLT during the first two cycles in the safety lead-in cohort, 
the regimen would be considered safe and enrollment would proceed with individuals being 
treated at the same dose level. 
-If  2 or more subjects experienced a DLT during the first two cycles in the safety lead-in 
cohort, the study would be reviewed by the data safety monitoring board that may recommend 
protocol amendment.  
No DLT was verified during the first 2 cycles of the initial 6 subjects enrolled under PA2. 
Therefore the data safety monitoring board considered the combination regimen safe and 
authorized subsequent enrollment. 
Response assessment based on serum and urine protein electrophoresis, serum and urine 
immunofixation and serum free light chains will occur at the end of cycles 2 and 4 of induction. 
Bone marrow aspiration with MRD assay (in subjects found to be MRD-informative based on 
clone identification sample) will be performed at the end of cycle 4 (hereafter referred to as 
induction MRD).  
 
3.1.1.1 
Definition of DLT 
For the safety lead-in cohort, the occurrence of any of the below toxicities during the first 
2 cycles of therapy will be considered dose-limiting toxicities when definitively, probably or 
possibly attributed to study drug: 
1) Grade 3 or 4 neutropenia (absolute neutrophil count < 1000/mm3) with fever. 
2) Grade 4 neutropenia lasting more than 7 days. 
3) Grade 4 thrombocytopenia (< 25,000/mm3) with bleeding or lasting more than 7 days. 


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4) Grade 4 toxicity, other than hematological toxicity. 
5) Grade 3 toxicity other than hematological toxicity, fever, chills, dyspnea, rash, fatigue, 
flu-like syndrome, pain, anorexia, glucose intolerance, alkaline phosphatase elevation or 
hypertension. 
6) Death from any cause. 
CONSOLIDATION 
Upon completion of 4 cycles of induction therapy, patients will proceed with standard of 
care auto-HCT, hereafter called consolidation 1. Hematopoietic progenitor cell mobilization will 
be performed utilizing growth-factors (G-CSF, Pegfilgrastim or similar) with or without the 
addition of plerixafor using standard practices at the enrolling site.  
 
The use of chemotherapy mobilization is not allowed as it may add toxicity, delay 
transplant and post-transplant recovery. Chemotherapy mobilization may be employed after 
failure of initial mobilization attempt and after discussion with study PI.  
 
Subjects who are transplant eligible, but choose to defer transplant, will collect 
hematopoietic progenitor cells and them proceed to KRdD consolidation (also labeled 
consolidation block 1). Subjects that are considered by the investigator not to be transplant 
eligible will proceed to KRdD consolidation block 1 without hematopoietic progenitor cells 
collection.  
 
Auto-HCT conditioning therapy with consist of Melphalan 200mg/m2 administered as 
single or divided dose on day -2 and/or -1. Supportive care following auto-HCT will follow 
standard of care institutional practices. Subjects will resume consolidation therapy not earlier 
than 90 days and ideally not later than 112 days after auto-HCT.  
 
Subjects undergoing KRdD as consolidation block 1 will receive 4 28-day cycles 
consisting of: 
Dexamethasone 40 mg (or LTD) PO days 1,8,15 and 22  


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Lenalidomide 25 mg (or LTD) PO daily, days 1-21  
 
Carfilzomib 56 mg/m2 (or LTD) days 1, 8, and 15  
 
Daratumumab 16 mg/kg days 1 (days 1 and 15 on the first two cycles of consolidation) 
 
Subjects not achieving confirmed MRD(-) status during consolidation block 1 (i.e. <10-5 
on induction-MRD and consolidation-1 MRD )will undergo consolidation block 2 and, if still not 
confirmed MRD(-)(i.e. <10-5 on consolidation-1 MRD and consolidation-2 MRD) they will 
undergo consolidation block 3. Consolidations block 2 and block 3 consist each of a block of 4 
28-day cycles of KRdD as outlined: 
Dexamethasone 40 mg (or LTD) PO days 1,8,15 and 22  
 
Lenalidomide 25 mg (or LTD) PO daily, days 1-21  
 
Carfilzomib 56 mg/m2 (or LTD) days 1, 8, and 15 
Daratumumab 16 mg/kg days 1 (days 1 and 15 in the first two cycles of consolidation 
block 2 for patients who underwent auto-HCT as consolidation block 1) 
 
Response assessment based on serum and urine protein electrophoresis, serum and urine 
immunofixation and serum free light chains will occur 60-80 days after auto-HCT and at the end 
of each even cycle during KRdD consolidation (for consolidations 1,2 and 3). Bone marrow 
aspiration with MRD assay (in subjects found to be MRD-informative based on clone 
identification sample) will be performed 60-80 days after auto-HCT (or on day 1 of cycle 3 of 
KRdD consolidation block 1 for patients not undergoing auto-HCT), hereafter referred to as 
consolidation-1 MRD , and, when applicable, on day 1 of cycles 3  KRdD  of consolidation 
block 2 hereafter referred to as consolidation-2 MRD and on day 1 of cycle 3 of KRdD 
consolidation block 3 hereafter referred to as consolidation-3 MRD .  
.  
 
OBSERVATION/ MAINTENANCE THERAPY 
 


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Subjects will start observation/maintenance therapy after completing the entire planned 
consolidation therapy or after obtaining confirmed MRD(-)(≤10-5 MM-associated in two 
consecutive tests) assessment on consolidation-1 MRD, consolidation-2 MRD or consolidation-3 
MRD.  
 
3.1.3.1 
MRD negative cohort 
 
Subjects who obtain confirmed MRD(-) assessments  in consolidation-1 MRD, 
consolidation-2 MRD or consolidation-3 MRD  will be observed in the confirmed MRD(-
)cohort.  
Subjects will enter an active surveillance phase when they will undergo response 
assessment based on serum and urine protein electrophoresis, serum and urine immunofixation 
and serum free light chains not less often than every 8 weeks for the first 24 weeks after 
discontinuation of therapy and not less often than every 16 weeks afterwards. Subjects will 
undergo active surveillance for resurgence of MRD (≥10-5) by undergoing bone marrow aspirate 
and MRD testing at the end of 24 and 72 weeks of observation (+/- 4 weeks).  
After completion of 72 weeks of active surveillance, subjects will enter a follow up phase 
consisting of clinic visits, response assessment based on serum and urine protein electrophoresis, 
serum and urine immunofixation and serum free light chains not less often than every 16 weeks. 
During the follow up phase the study will capture at least once a year the occurrence of disease 
progression, initiation of any anti-myeloma therapy, death from any cause and any MRD 
assessment performed as part of routine care of the patient. This information will be submitted 
utilizing a follow-up form (Appendix C) at least yearly or at any time there is progression, 
initiation of anti-myeloma therapy, death or a new MRD assessment performed as part of routine 
care of the patient is reported. 
 
 
3.1.3.2 
MRD positive cohort 
 


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Subjects who are not evaluable for MRD status, remain MRD(+)(> 10-5 MM-associated 
molecules) or have only one MRD(-) test obtained on consolidation-3 (therefore not confirmed) 
will discontinue experimental therapy and be followed in the MRD(+) cohort. 
 In this cohort, it is suggested that patients receive standard of care lenalidomide 
maintenance in the follow up phase. Suggested starting dose lenalidomide is 10 mg/day 
continuously. Dose and schedule will be subsequently managed per treating physician. It is 
suggested that individuals undergo response assessment based on serum and urine protein 
electrophoresis, serum and urine immunofixation and serum free light chains not less often than 
every 16 weeks after discontinuation of experimental therapy. During the follow up phase the 
study will capture at least once a year the occurrence of disease progression, death from any 
cause, use of any anti-myeloma therapy and any MRD assessment performed as part of routine 
care of the patient. This information will be submitted utilizing a follow-up form (Appendix C) 
at least yearly or at any time there is progression, initiation of anti-myeloma therapy, death or a 
new MRD assessment performed as part of routine care of the patient is reported. 
 
3.2 
NUMBER OF CENTERS 
 
UAB (P.I. Dr. Luciano Costa) will be the coordinating center for the study with 
participation of up to 6 additional sites. 
3.3 
NUMBER OF SUBJECTS 
 
Six subjects were enrolled in the safety lead-in cohort. Additional subjects (estimated 
between 27 and 32), necessary for 27 MRD evaluable subjects will be enrolled in the first stage 
of the study. If more than 17 MRD evaluable subject reach MRD(-) status at completion of 
consolidation, additional subjects will be enrolled in the second stage for a total of 82 (and 
estimated 68 MRD evaluable) subjects in the study. As long as this experimental therapy is not 
declared futile at end of second stage, the study will be expanded to enroll additional 41 subjects 
(total 123) to enable description of PFS in HR and SR patients reaching confirmed MRD (-) and 
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3.4 
ESTIMATED STUDY DURATION 
 
Accrual is expected to last 26 months. The duration of experimental treatment will be 8-
16 months, depending on response and achievement of MRD. Primary endpoint will be assessed 
no longer than 16 months after last subject, first treatment, therefore 42 months from start of 
accrual. Exploratory endpoint will be assessed 24 months after last subject completes therapy, 
therefore up to 40 months from last subject initiating therapy. 
 
3.5 
TREATMENT SCHEMA 
 
Screening – Subjects likely to meet eligibility criteria will be offered participation in the 
study after the investigator verifies UAB CTNMO registration. Subjects will sign informed 
consent prior to any protocol associated procedure. Screening procedures are outlined in Table 7 
and will 1) ensure that subject meets all the eligibility criteria, 2) obtain disease assessment to 
allow efficacy measurements, 3) assess baseline toxicity, and 4) ensure initial disease sample is 
obtained for assessment of the myeloma-associated clone and feasibility of MRD assessment by 
NGS. 
 
 
 
 


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3.6 
MINIMAL RESIDUAL DISEASE ASSESSMENTS 
 
MRD assessment by ClonoSEQ® requires an initial marrow sample containing myeloma 
cells for identification of myeloma-specific sequences in IGH-VDJ, IDH-DJ and/or IGK. During 
screening a fresh bone marrow sample or archive, non-stained bone marrow aspirate slide (“ID 
sample”) will be sent to Adaptive biotechnologies to be assessed for the presence of myeloma-
specific sequences. 
For all samples with MRD assessment, MRD will be reported quantitatively as 
proportion of multiple myeloma-associated sequences. For treatment assignment and clinical 
trial outcome reporting, we will consider MRD(-) if the burden of MM-associated molecules is < 
10-5. 
Subjects who achieve confirmed MRD(-) status with < 10-5 MM associated molecules 
during consolidation will undergo FDG PET/CT scan prior to starting the active surveillance 
phase in the  MRD(-) cohort. FDG PET/CT will be interpreted by the enrolling site and report 


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should be made available for central, consensus review. PET/CT will be considered “negative” if 
no area of FDG uptake greater than mediastinal blood pool or surrounding normal tissue. 
TIME POINTS OF SAMPLE COLLECTION 
 
Subjects with informative sequences found on initial “ID sample” will be considered 
“MRD informative” and will undergo MRD assessment at the following time points: 
-At the end of 4th cycle of induction (Induction MRD) 
-After recovery of auto-HCT or on the 3rd cycle of KRdD consolidation (consolidation-1 
MRD)   
-When applicable, on day 1 of cycles 3 of KRdD of consolidation block 2 (consolidation-
2 MRD) and consolidation block 3 (consolidation-3 MRD) 
-For subjects undergoing observation in the MRD(-) cohort, after 24 and 72 weeks in the 
observation phase. 
  
SAMPLE COLLECTION AND SHIPMENT 
  
At each of these time points a sample for MRD will obtained through bone marrow 
aspirate. Samples will be sent to Adaptive biotechnology for ClonoSEQ® testing. Samples will 
not be retained for future analysis. 
Please refer to the Correlative Study Manual for handling and processing details. 


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4 
SUBJECT SELECTION 
4.1 
INCLUSION CRITERIA   
Subjects must meet all of the following inclusion criteria to be eligible to enroll in this 
study.   
1. Age >18 years with no upper age limit 
2. Diagnosis of newly diagnosed multiple myeloma with indication for initiation of therapy. 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0–2 
4. No prior MM-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib 
(up to 5.2 mg/m2) and/or cyclophosphamide up to 1000 mg/m2 administered for management 
of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer than 4 
weeks prior to enrollment (pre induction). If subject received any prior therapy, pretreatment 
parameters necessary for disease characterization and response assessment must be available. 
5. Measurable disease, characterized by one of the following parameters (at screening or prior 
to pre induction): 
a. -Serum monoclonal (M) protein ≥ 1 g/dl by protein electrophoresis 
b. ->200 mg of M protein in the urine on 24 hour electrophoresis  
c. - Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal  
serum immunoglobulin kappa to lambda free light chain ratio 
6. Available FISH report (performed locally or by third party cytogenetics laboratory) that 
informs absence or presence of high risk chromosome abnormalities [del17p, t(4;14) and 
t(14;16)] 
7. Life expectancy ≥ 12 months. 
8. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum 
direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to initiation of therapy. 
9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days prior to start of therapy either 
measured or calculated using standard Cockcroft and Gault formula( available in 
https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc ). 
10. Written informed consent in accordance with federal, local, and institutional guidelines.  
11. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to 
practice contraception during treatment and for 30 days after the last dose of carfilzomib. 
Male subjects must agree to practice contraception and refrain from donating sperm during 
treatment and for 90 days after the last dose of carfilzomib. 
12. All subjects must agree to comply with and be enrolled in Revlimid REMS™ program. 
 


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4.2 
EXCLUSION CRITERIA 
Subjects must meet none of the following inclusion criteria to be eligible to enroll in this 
study.   
 
1. Diagnosis of amyloidosis, POEMS, Waldenstrom’s macroglobulinemia. 
2. Major surgery, radiotherapy or infection requiring therapy within 14 days of starting 
treatment 
3. Known FEV1 or cDLCO <50% of predicted. 
4. Pregnant or lactating females. 
5. Known human immunodeficiency virus infection. 
6. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen 
[HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but 
positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B 
surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction 
(PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive 
will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV 
vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior 
HBV vaccination, do not need to be tested for HBV DNA by PCR.. 
7. Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], 
defined as aviremia at least 12 weeks after completion of antiviral therapy). 
8. Unstable angina or myocardial infarction within 4 months prior to registration, NYHA Class 
II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, 
severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic 
evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a 
pacemaker. 
9. Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior 
to initiation of therapy 
10. Nonhematologic malignancy within the past 3 years with the exception of a) adequately 
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in 
situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-
specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to 
impact survival during the duration of the study, such as localized transitional cell carcinoma 
of the bladder or benign tumors of the adrenal or pancreas. 
11. Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 21 days prior to 
registration. 
12. Known history of allergy to Captisol ® (a cyclodextrin derivative used to solubilize 
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13. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis 
within 21 days prior to registration. 
14. Contra indication or intolerance to required supportive care medications (aspirin and 
acyclovir).  
15. Any other 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.  
  


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5 
SUBJECT ENROLLMENT 
 
Once a patient is identified as a candidate for the trial the investigator will contact the 
UAB CTNMO registration office (205-975-5387, Fax No: 205-975-9875) prior to obtaining 
informed consent (safety lead in cohort only). Registration will be completed upon submission of 
documentation of eligibility to the registration office and issuance of a registration confirmation 
email.  
 
Prior to accepting the registration, the registration office will verify the following:  
 
- IRB approval at the registering institution. 
 
- Patient eligibility. 
 
- Existence of a signed consent form.  
 
- Existence of a signed authorization for use and disclosure of protected health information. 
- Pretreatment tests and procedures must be completed within the guidelines specified in 
the test schedule, including assessment of baseline symptoms. 
- Cytogenetic risk classification if accrual is open for a specific risk group (e.g. HR) but not 
for another group (e.g. SR) 
- Study drugs availability on site (for initial site patient only; Local site is responsible for 
assessing drug available for subsequent site enrollments).  


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6 
TREATMENT PROCEDURES 
6.1 
DRUG PREPARATION AND ADMINISTRATION   
CARFILZOMIB  
 
• Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. 
The lyophilized product is reconstituted with Water for Injection to a final carfilzomib 
concentration of 2 mg/mL prior to administration.  The dose will be calculated using the 
subject’s actual BSA at baseline.  Subjects with a BSA > 2.2 m2 will receive a dose based 
upon a 2.2 m2 BSA.   
• At the discretion of the investigator, patients thought to be at particularly high risk for the 
development of TLS, based on high tumor burden, oral hydration will be encouraged, at least 
48 hours before each dose of carfilzomib (6 to 8 cups of liquid per day) continuing up to the 
time of treatment.   
• IV hydration will be given immediately prior to carfilzomib.  This will consist of 250 to 500 
mL normal saline or other appropriate IV fluid. The goal of the hydration program is to 
maintain robust urine output (eg, ≥ 2 L/day).  Subjects should be monitored periodically 
during this period for evidence of fluid overload. On the days the subject receives both 
daratumumab and carfilzomib, the infusion of daratumumab will replace the hydration to be 
given prior to carfilzomib. 
• If the subject has a dedicated line for carfilzomib administration, the line must be flushed 
with a minimum of 20 mL of normal saline prior to and after drug administration.     
• Carfilzomib will be given as an IV infusion over approximately 30 minutes (±10 minutes). 
The dose will be administered at a facility capable of managing hypersensitivity reactions.   
• Carfilzomib will be provided by Amgen. 
LENALIDOMIDE  
 


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• Lenalidomide (revlimid®) is a thalidomide analogue immunomodulatory agent . 
Lenalidomide is a off-white to pale-yellow solid powder. It is solube in organic solvent/water 
mixtures, and buffered aqueous solvents.  
• Lenalidomide is available as 5, 10, 15 and 25 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the following inactive ingredients: 
lactose anhydrous, microcrystalline cellulose, croscalmellose sodium, and magnesium 
stearate. 
• Lenalidomide is considered standard of care for initial management of multiple myeloma, 
will be acquired commercially and not provided by the sponsor (University of Alabama at 
Birmingham).  
• In order for subjects to have access to Lenalidomide, enrollment in Lenalidomide REMS is 
required. 
 
DARATUMUMAB  
 
• Infusion solution will be prepared as a 1000ml (first infusion) or 500-mL (subsequent 
infusions) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation of 
infusion bags should be done on the day of the planned infusion.  
• Daratumumab must be administered as an IV infusion given through a well-functioning IV 
catheter by using an infusion pump. The study drug must be filtered by using an inline filter 
(0.2 μM) during the infusion. 
• Daratumumab will be administering at 16mg/kg with subject weight rounded to the nearest 
kilogram. Infusion rates will follow parameters as follows (Table 1): 
 
Table 1- Infusion parameters for daratumumab 


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Dilution 
volume 
Initial 
Infusion rate  
Rate 
increment 
Maximum rate 
First infusion. 16mg/kg 
1000 ml 
50 ml/hour 
for 1 hour 
50 ml/hour, 
every hour 
200 ml/hour 
Second infusiona.  
16 mg/kg 
500 ml 
50 ml/hour 
for 1 hour 
50 ml/hour, 
every hour 
200 ml/hour 
Subsequent infusionb. 
16mg/kg 
500 ml 
100 ml/hour 
50 ml/hour, 
every hour 
200 ml/hour 
Cycle 2 and beyondc,d 
(rapid infusion protocol) 
500 ml 
200 ml/h for 
30 min (20% 
of dose) 
400 ml/h for 
remaining of 
infusion 
(80% of 
dose) 
400 ml/hour 
a-Escalate only if there were no grade 1 or greater infusion reactions during the first 3 hours of the 
first infusion. Otherwise repeat “first infusion” sequence. 
b-Escalate only if there were no grade 1 or greater infusion reactions during a final infusion rate ≥ 
100mL/hr in the prior two infusion 
c- For institutions using daratumumab rapid infusion protocol as their standard of care(47), rapid 
infusions may be considered for Cycle 2 and subsequent infusions ONLY for patients who tolerate 
Cycle 1 Day 22 without any grade (grade 1 or greater) hypersensitivity reaction, subsequent 
daratumumab infusions can be administered at an initial rate of 20% of the total dose over 30 
minutes, followed by the remaining 80% of the total dose over 60 minutes (90-minute total 
infusion time). 
d-If a patient experiences any grade hypersensitivity reaction, the patient is not eligible to 
receive additional rapid infusions until they have received standard infusion daratumumab 
without any grade hypersensitivity reaction. 
 
• Required preinfusion medication will consist of dexamethasone 20 mg IV (or lower dose if 
dexamethasone has been dose reduced due to toxicity. Dose should not be less than 8 mg), 
acetaminophen 650 to 1000 mg PO and an antihistamine given IV or PO (diphenhydramine 
25 to 50 mg or equivalent). 


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• Any period equal or greater than 60 days without daratumumab administration (e.g for stem 
cell transplantation) will require subsequent dose to be administer per first infusion 
parameters with advancement in rate of subsequent infusions as described in Table 1.  
• Daratumumab will be provided by Janssen Scientific Affairs. 
6.1.4 
DEXAMETHASONE 
 
• Dexamethasone is a synthetic adrenocortical steroid. It is available commercially in 4 mg 
tablets for oral administration. Each tablet contains dexamethasone as the active ingredient, 
and the following inactive ingredients: calcium phosphate, lactose, magnesium stearate, and 
starch.  
• During clinical trial participation individuals will take dexamethasone in the dose and 
scheduled indicated in 3.1. Dexamethasone will be taken preferentially in the morning with 
food. On the days the subject will receive daratumumab administration, and consequently 
dexamethasone preinfusion, the dexamethasone preinfusion dose should be deducted from 
the oral dose to be taking assuming 1:1 equivalence between oral and IV formulation. For 
example, if subject is to take 40 mg of dexamethasone on that day, but is receiving 20 mg IV 
as preinfusion medication, then the oral dose will be of 20 mg. If dose of dexamethasone has 
been reduced to less than 20 mg, and patient is due for a dose of dexamethasone on same day 
of daratumumab infusion, the entire dose will be administered intravenously as pre infusion 
medication (dose should not be less than 8 mg). 
• Dexamethasone is commercially available and will not be provided by the sponsor 
(University of Alabama at Birmingham). 
 
MELPHALAN 
 
• Melphalan is commercially available and supplied as a sterile, freeze-dried powder. Each vial 
contains 50 mg melphalan hydrochloride and the inactive ingredient, povidone 20 
mg.  Reconstitute per manufacturer instructions using the diluent provided.  Further dilution 


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and administration per institutional standards. The manufacturer recommends completion of 
administration of melphalan within 60 minutes of reconstitution. 
• The dose (200 mg/m2) will be calculated using the lesser of the subject’s actual (AW) or 
corrected ideal body weight (CIBW). CIBW= IBW + 0.25(AW-IBW). The ideal body weight 
(IBW) is calculated using the formula: Males: IBW = 50 kg + 2.3 kg for each inch over 5 
feet. Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
• Solution Preparation:  Vial/50 mg:  Constitute with 10 ml of the special diluent to yield a 5 
mg/ml melphalan concentration.  May be further diluted per institutional guidelines. 
• Melphalan must be infused intravenously utilizing a central vein catheter and infusion 
completed within one hour of reconstitution.   
• IV hydration will be given immediately after melphalan per institutional guidelines. 
• Intravenous melphalan is commercially available and will not be provided by the sponsor 
(University of Alabama at Birmingham).  
 
 
6.2 
DOSE MODIFICATIONS/ADJUSTMENTS  
All toxicity assessments and dose reductions will be performed utilizing common terminology 
criteria for adverse events version 4.03 (CTCAE v.4.03) available in 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
CARFILZOMIB 
 
Dose reductions for toxicities that, according to investigator are definitively, probably or 
possibly related to carfilzomib will follow Table 2. Omitted doses will not be replaced. Patients 
who interrupt therapy due to toxicity will resume therapy as outlined in Table 3 receiving any 
remaining doses on the ongoing cycle. If no remaining doses on the current cycle, then treatment 
will resume after the cycle is completed, 28 (+/- 2) days from the initiation of the prior cycle. 
 


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Table 2 – Carfilzomib dose modifications 
 
Hematologic 
toxicity 
CTCAE v4.03 
grade 
Action 
Thrombocytopenia 
Grade 3  
Hold carfilzomib and check platelet count weekly 
until resolution to grade  2, then resume at the 
same dose. If toxicity lasts more than 3 weeks, 
reduce dose. 
 
 
Grade 4 or 
bleeding 
First or second occurrences - Hold carfilzomib 
and check platelet count weekly until resolution 
to grade  2 and no bleeding. Resume therapy at 
one level dose reduction. 
Third occurrence- Discontinue drug 
Anemia 
Grade 3 
Hold carfilzomib and check hemoglobin weekly 
until resolution to grade  2, then resume at the 
same dose. If toxicity lasts more than 2 weeks, 
reduce dose. 
 
Grade 4 or 
transfusion 
requirement 
First or second occurrences - Hold carfilzomib 
and check hemoglobin weekly until resolution to 
grade  2. Resume therapy at one level dose 
reduction 
Third occurrence- Discontinue drug. 


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Neutropenia 
Grade 3 or 4 
Hold carfilzomib and check neutrophil count 
weekly until resolution to grade  2 (growth 
factor use is permitted), then resume at the same 
dose.  If toxicity lasts more than 2 weeks, reduce 
dose. 
 
Grade 4 with 
fever or 
infection 
First or second occurrences - Hold carfilzomib 
and check neutrophil count at least weekly until 
resolution to grade  2 (growth factor use is 
permitted) and no signs of infection. Resume 
therapy at one level dose reduction 
Third occurrence- Discontinue drug. 
Non-hematologic 
toxicity 
CTC 4.0 grade 
Action 
Cardiac Toxicity 
new onset or 
worsening of 
congestive heart 
failure;decreased left 
ventricular function 
or myocardial 
ischemia 
Grades 3 or 4, 
Withhold drug until resolved or returned to 
baseline. After resolution, consider if restarting 
carfilzomib at a reduced dose is appropriate. If 
tolerated, the reduced dose may be escalated to 
the previous dose at the discretion of the 
physician 
Pulmonary 
hypertension 
Grades 2-4 
Withhold drug until resolved or returned to 
baseline. After resolution, consider if restarting 
carfilzomib at a reduced dose is appropriate. If 
tolerated, the reduced dose may be escalated to 


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the previous dose at the discretion of the 
physician 
Other pulmonary 
Grades 3 or 4 
Withhold drug until resolved or returned to 
baseline. After resolution, consider if restarting 
carfilzomib at a reduced dose is appropriate. If 
tolerated, the reduced dose may be escalated to 
the previous dose at the discretion of the 
physician 
Posterior Reversible 
Encephalopathy 
Syndrome (PRES) 
Any 
If PRES is suspected, hold carfilzomib. Consider 
evaluation with MRI for onset of symptoms 
suggestive of PRES. If PRES is confirmed, 
permanently discontinue carfilzomib. If PRES is 
excluded, may resume carfilzomib at same dose if 
clinically appropriate. If PRES recurs, 
permanently discontinue carfilzomib 
Thrombotic 
microangiopathy 
Any grade 
If TMA is suspected, hold carfilzomib and 
manage per standard of care. If TMS is 
confirmed and related to carfilzomib, 
permanently discontinue carfilzomib. If TMA is 
excluded, may restart carfilzomib. 
Progressive 
multifocal 
leukoencephalopathy 
(PML) 
Any grade 
If PML is suspect, hold carfilzomib and proceed 
immediately with diagnostic work up, including 
consultation with a neurologist. Do not resume 
carfilzomib until PML is unequivocally excluded. 
If PML can not be unequivocally excluded, 
discontinue carfilzomib permanently.  


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Hepatic Impairment 
Mild to 
moderate liver 
dysfunction 
defined as 2 
consecutive 
values, at least 
28 days apart of: 
total bilirubin 
(>33% direct > 
1x ULN to < 3x 
ULN OR an 
elevation of 
AST and/or 
ALT with 
normal bilirubin 
25% dose reduction. Dose may be re-escalated if 
liver function tests return to normal and drug-
induced hepatotoxicity is excluded.  
 
Grade 3 
elevation in 
ALT and/or 
AST (>5xULN) 
Hold carfilzomib until resolution to baseline. 
Monitor any abnormality weekly. Resume 
carfilzomib with a 25% dose reduction if drug-
induced hepatoxicity is excluded. 
 
Grade 3 
elevation in total 
bilirubin 
Hold carfilzomib until resolution. Monitor total 
bilirubin and direct bilirubin weekly. Upon 
resolution of total bilirubin to normal, reduce 
carfilzomib dosing with a 25% dose reduction if 
drug induced hepatoxicity is excluded. 
 
Drug induced 
hepatoxicity 
attributable to 
carfilzomib 
Discontinue carfilzomib 


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Table 3- Dose levels for carfilzomib 
Dose level 
Dose 
0 (zero) or safety lead-in dose 
56 mg/m2 
-1 (minus 1) 
45 mg/m2 
-2 (minus 2) 
36 mg/m2 
-3 (minus 3) 
Discontinue agent 
 
As a subject advances through phases of therapy (induction, consolidation) the dose of 
carfilzomib utilized will never be higher than the last previously tolerated dose (LTD) 
 
Any other 
Grades  2 
No action is required. Investigator is allowed to 
hold study drug for up to two weeks and then 
resume at same dose. On second occurrence, the 
investigator has the option to resume therapy at 
reduced dose. 
 
Grade 3 
Hold carfilzomib until resolution to grade  2, 
then resume at the same dose. If toxicity lasts 
more than 3 weeks, reduce dose. 
 
Grade 4 
First or second occurrence - Hold carfilzomib 
until resolution to grade  2. Resume therapy at 
one level dose reduction. 
Third occurrence- Discontinue drug. 


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6.2.2 
LENALIDOMIDE 
 
Dose reductions for toxicities that, according to investigator are definitively, probably or 
possibly related to lenalidomide will follow Table 4. Omitted doses will not be replaced. Patients 
who interrupt therapy due to toxicity will resume therapy as outlined in Table 5 receiving any 
remaining doses on the ongoing cycle. If no remaining doses on the current cycle, then treatment 
will resume after the cycle is completed, 28 (+/- 2) days from the initiation of the prior cycle. 
 
Table 4 – Lenalidomide dose modifications 
Hematologic 
toxicity 
CTCAE v4.03 
grade 
Action 
Thrombocytopenia Grade 3  
Hold lenalidomide and check platelet count 
weekly until resolution to grade  2, then resume 
at the same dose. If toxicity lasts more than 2 
weeks, reduce dose by one level. 
 
 
Grade 4 or 
bleeding 
First and second occurrence - Hold lenalidomide 
and check platelet count weekly until resolution 
to grade  2 and no bleeding. Resume therapy at 
one level dose reduction. 
Second occurrence- Discontinue drug 
Anemia 
Grade 3 
Hold lenalidomide and check hemoglobin weekly 
until resolution to grade  2, then resume at the 
same dose. If toxicity lasts more than 2 weeks, 
reduce dose. 


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Grade 4 or 
transfusion 
requirement 
First or second occurrence - Hold lenalidomide 
and check platelet count weekly until resolution 
to grade  2. Resume therapy at one level dose 
reduction 
Third occurrence- Discontinue drug. 
Neutropenia 
Grade 3 or 4 
Hold lenalidomide and check neutrophil count 
weekly until resolution to grade  2 (growth 
factor use allowed), then resume at the same dose.  
If toxicity lasts more than 2 weeks, reduce dose. 
 
Grade 4 with 
fever or 
infection 
First or second occurrence - Hold lenalidomide 
and check neutrophil count at least weekly until 
resolution to grade  2 (growth factor use 
allowed) and no signs of infection. Resume 
therapy at one level dose reduction 
Third occurrence- Discontinue therapy. 
Non-hematologic 
toxicity 
CTC 4.0 grade 
Action 
Any 
Grades  2 
No action is required. Investigator is allowed to 
hold study drug for up to two weeks and then 
resume at same dose. On second occurrence, the 
investigator has the option to resume therapy at 
reduced dose. 
 
Grade 3 
Hold therapy until resolution to grade  2, then 
resume at the same dose. If toxicity lasts more 
than 2 weeks, reduce dose by one level. 


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Table 5 -Lenalidomide dose levels and adjustment according to renal function. 
Dose level 
Induction and consolidation, part 
of KRdD 
Standard of care maintenance for 
subjects in the MRD(+) cohort 
(suggested) 
 
CrCl ≥ 
60ml/min 
CrCl< 60ml/min 
CrCl ≥ 
60ml/min 
CrCl< 60ml/min 
0 
25 mg/day 
10mg/day 
10mg/day 
5 mg/day 
-1 
15 mg/day 
5 mg/day 
5 mg/day 
5 mg every other 
day 
-2 
10 mg/day 
5 mg every 
other day 
discontinue 
discontinue 
-3 
5 mg/day 
discontinue 
discontinue 
discontinue 
-4 
discontinue 
discontinue 
discontinue 
discontinue 
 
As a subject advances through phases of therapy (induction, consolidation, maintenance) 
the dose of lenalidomide utilized will never be higher than the last previously tolerated dose 
(LTD) 
 
DEXAMETHASONE 
 
 
Grade 4 
First or second occurrences - Hold lenalidomide 
until resolution to grade  2. Resume therapy at 
one level dose reduction. 
Thirds occurrence- Discontinue drug. 


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Dose reductions for toxicities that, according to investigator are definitively, probably or 
possibly related to dexamethasone will follow Table 6. Omitted doses will not be replaced. 
Patients who interrupt therapy due to toxicity will resume therapy as outlined in Table 6 
receiving any remaining doses on the ongoing cycle. If no remaining doses on the current cycle, 
then treatment will resume after the cycle is completed, 28 (+/- 2) days from the initiation of the 
prior cycle. 
 
Table 6 – Dexamethasone dose modification 
Toxicity 
CTCAE v4.03 
grade 
Action 
Gastrointestinal 
Grades 1-2 
Treat with proton pump inhibitor. Dose reduction 
to 20 mg/dose allowed. Dose increase to 40 
mg/dose allowed once symptoms resolved. 
 
 
Grades 3 or 4 
Hold dexamethasone and treat with proton pump 
inhibitor. Once symptoms resolve or improve to 
grade 1, resume at a dose not greater than 20 
mg/dose.  Consider additional dose reductions if 
recurrence of symptoms. Dose increase not 
allowed. If multiple recurrences of grade 3 or 4 
gastrointestinal toxicity despite concomitant 
medication and dose reduction, discontinue 
dexamethasone and do not resume, except for the 
minimal dose of 8 mg as pre infusion prior to 
daratumumab. 
Cardiovascular 
Edema grades 3 
or 4  
Hold dexamethasone and treat with diuretics as 
needed. Once symptoms resolve or improve to 


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grade 1, resume dexamethasone at a dose not 
greater than 20 mg/dose. Consider additional dose 
reductions if recurrence of symptoms. Dose 
increase not allowed. If multiple recurrences of 
grade 3 or 4 edema despite concomitant 
medication and dose reduction, discontinue 
dexamethasone and do not resume, except for the 
minimal dose of 8 mg as pre infusion prior to 
daratumumab. 
Neurologic or 
psychiatric 
≥ grade 2 
Hold dexamethasone until symptoms resolve. 
Consider consultation with specialist and 
pharmacologic treatment. Once symptoms 
resolved, resume dexamethasone at dose not 
higher than 20 mg/dose. Consider additional dose 
reductions if recurrence of symptoms 
Other 
Grades 3 or 4 
Hold dexamethasone. Once symptoms resolve or 
improve to grade 1, resume at a dose not greater 
than 20 mg/dose.  Consider additional dose 
reductions if recurrence of symptoms Dose 
increase not allowed. If multiple recurrences of 
grade 3 or 4 toxicity despite concomitant 
medication and dose reduction, discontinue 
dexamethasone and do not resume, except for the 
minimal dose of 8 mg as pre infusion prior to 
daratumumab. 
 


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DARATUMUMAB 
 
There will be no dose modification (increase or decrease) for daratumumab. Any dose 
hold for greater than 28 days due to toxicity will result in permanent discontinuation of 
daratumumab.  
 
Daratumumab dosing will be held if any of the following adverse events is present. 
 
Febrile neutropenia 
 
Grade 4 hematologic toxicity 
 
Any grade 3 or 4 non-hematologic toxicity that the investigator considers definitively, 
probably or possibly caused by daratumumab. Daratumumab will be resumed when toxicity 
resolved to ≤ grade 2. 
 
MELPHALAN 
 
Melphalan will be administered as standard of care, single dose, conditioning regimen in 
preparation for auto-HCT. The recommended dose is 200mg/m2. Dose adjustments according to 
age or renal function will follow each participating site’s standards.  
 
6.3 
SAFETY CONSIDERATIONS 
 
• A “first dose effect” has been seen with carfilzomib, which is notable for fever, chills, rigors, 
and/or dyspnea occurring during the evening following the first day of infusion and an 
increase in creatinine on the following day, which may be the clinical sequelae of rapid 
tumor lysis and/or cytokine release.    


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• Carfilzomib will be generally administered on the same day of daratumumab administration. 
Carfilzomib should be administered after completion of daratumumab administration. 
Therefore, subjects will have received 20 mg of dexamethasone as premedication prior to 
daratumumab. In the event of patient receiving carfilzomib but not daratumumab in a given 
day, dexamethasone at least 4 mg IV will be administered prior to carfilzomib.  
• Should a “first dose carfilzomib effect” occur, treatment with high dose glucocorticoids (e.g. 
methylprednisolone 50–100 mg) is recommended.  In addition, intravenous fluids, 
vasopressors, oxygen, bronchodilators, and acetaminophen should be available for immediate 
use and instituted, as medically indicated.  
• CrCl changes induced by carfilzomib are mostly transient, reversible, and non-cumulative. 
All subjects should be well hydrated.  Clinically significant electrolyte abnormalities should 
be corrected prior to dosing with carfilzomib. Renal function must be monitored closely 
during treatment with carfilzomib.  Serum chemistry values, including creatinine, must be 
obtained and reviewed prior to each dose of carfilzomib. Carfilzomib must be held for 
subjects with a CrCl < 15 mL/min at any time during study participation. 
• Carfilzomib is associated with increased risk of cardiac events that are, at least in part, linked 
to increase in blood pressure. Intense blood pressure monitoring is required for patients being 
treated with carfilzomib. All subjects will receive a blood pressure monitoring log where 
daily blood pressure measurements will be recorded. The log will be reviewed at each 
clinical visit and hypertension will be actively managed by the investigator 
• Subjects with active or suspected infection of any kind that required systemic treatment 
should not be dosed with carfilzomib, lenalidomide or daratumumab until the infection has 
resolved (and preferentially the course of antibiotics has been completed).  
• Carfilzomib treatment can cause nausea, vomiting, diarrhea, or constipation sometimes 
requiring the use of antiemetic or antidiarrheal medications.  Fluid and electrolyte 
replacement should be administered to prevent dehydration. 
• Lenalidomide, a thalidomide analogue, can cause limb abnormalities. If lenalidomide is used 
during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be 
excluded before start of treatment. 


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• Lenalidomide is associated with increase in risk of venous and arterial thromboembolism. 
Anti-thrombotic prophylaxis with aspirin or anticoagulation is required. 
• Lenalidomide can impair stem cell mobilization. Stem cell collection is recommended after 
no more than 4 cycles of therapy containing lenalidomide for subjects who are consider 
adequate candidates for hematopoietic progenitor cell transplantation. 
• Daratumumab is associated with risk of infusion-related reactions (mostly fever, cough, 
dizziness, bronchospasm) in approximately 40% of patients. These reactions are mostly 
grades 1 and 2 and occur during first infusion. See guidelines for management of 
daratumumab infusion-related reactions in 6.3.2. 
• The treatment with melphalan as outlined in this protocol constitutes standard of care. The 
dose of 200mg/m2 of melphalan is myeloablative, therefore subjects are expected to develop 
grade 4 thrombocytopenia requiring transfusion, grade 4 neutropenia with near 100% risk of 
neutropenic fever and anemia requiring transfusion of red blood cells.  
• Melphalan at the doses employed in this protocol will cause nausea, vomiting and mucositis 
manifested mostly as oral pain, dysphagia and diarrhea. Subjects will receive antiemetic and 
antidiarrheal medications according to institutional guidelines. 
6.3.1 
GUIDELINES FOR MONITORING, PROPHYLAXIS, AND TREATMENT OF 
TUMOR LYSIS SYNDROME (TLS) 
 
TLS, which may be associated with multiorgan failure, has been observed in some 
patients with MM who have been treated with carfilzomib, lenalidomide and dexamethasone, 
alone or in combination, during first or second cycles of therapy.  
 
The following safety measures are mandatory for all subjects.  In addition, MM subjects 
with high tumor burden (e.g., Durie-Salmon or ISS Stage II/III) or rapidly increasing M-protein 
or light chains or compromised renal function (CrCl < 50 mL/min) should be considered to be at 
particularly high risk. Please see section 6.1.1  for hydration requirements. 
6.3.1.1 
Laboratory Monitoring 
 


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Appropriate chemistries, including creatinine and complete blood counts (CBC) with 
platelet count, should be obtained and reviewed prior to carfilzomib dosing.  Results of 
laboratory studies must be reviewed and deemed acceptable prior to administering the 
carfilzomib dose.  Subjects with laboratory abnormalities consistent with lysis of tumor cells 
(e.g., serum creatinine ≥ 50% increase, LDH ≥ 2-fold increase, uric acid ≥ 50% increase, 
phosphate ≥ 50% increase, potassium ≥ 30% increase, calcium ≥ 20% decrease) prior to dosing 
should not receive the scheduled dose.  Subjects with such abnormalities should be re-evaluated 
again within the next 24 hours (or sooner, if clinically indicated) and then periodically as 
clinically indicated.    
6.3.1.2 
 Management of Tumor Lysis Syndrome 
 
If TLS occurs, cardiac rhythm, fluid, and serial laboratory monitoring should be 
instituted.  Correct electrolyte abnormalities, monitor renal function and fluid balance, and 
administer therapeutic and supportive care, including dialysis, as clinically indicated. 
All cases of TLS must be reported to Amgen as a Serious Adverse Event (SAE) through 
the normal process within 24 hours of the clinical site becoming aware of the event. 
 
 
6.3.2 
GUIDELINES FOR MONITORING, PROPHYLAXIS, AND TREATMENT OF 
DARATUMUMAB INFUSION-RELATED REACTION (IRR) 
 
Daratumumab infusion-related reactions occur in approximately 40% of patients 
receiving first dose of daratumumab. Most reactions are grade 1 or 2, but serious, including life-
threatening reactions have occurred.  
Common manifestations of IRR are pyrexia, cough, bronchospasm, dizziness, urticaria 
reduction in blood pressure.  
6.3.2.1 
Prevention 
All patients receiving daratumumab will receive preinfusion medication consisting of: 
• Dexamethasone 20 mg IV; 


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• Acetaminophen 650 to 1000 mg PO 
• Antihistamine given IV or PO (diphenhydramine 25 to 50 mg or equivalent). 
• Montelukast 10 mg PO the day before and day of infusion. 
For subjects with a higher risk of respiratory complications, the following postinfusion 
medications should be considered: 
• Antihistamine given IV or PO (diphenhydramine 25 to 50 mg or equivalent) on 
the first and second day after all the infusions 
• Short-acting beta 2 adrenergic receptor agonists such as salbutamol aerosol. 
 
 
6.3.2.2 
Management of infusion-related reactions 
 
Subjects should be carefully observed during daratumumab infusions. Trained study staff 
at the clinic should be prepared to intervene in case of any infusion reactions, and resources 
necessary for resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also 
medical equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be 
available at bedside. Attention to staffing should be considered when multiple subjects will be 
dosed at the same time. If an infusion-related reaction develops, then the infusion should be 
temporarily interrupted or slowed down. Subjects who experience adverse events during the 
infusion must be treated according to the investigator’s judgment and best clinical practice. The 
following guidelines apply: 
• Subjects should be treated with acetaminophen, antihistamine, or corticosteroids 
as needed. Intravenous saline may be indicated. For bronchospasm, urticaria, or 
dyspnea, subjects may require antihistamines, oxygen, corticosteroids, or 
bronchodilators. For hypotension, subjects may require vasopressors. 
• In the event of a life-threatening infusion-related reaction (which may include 
pulmonary or cardiac events) or anaphylactic reaction, daratumumab should be 


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discontinued and no additional daratumumab should be administered to the 
subject. Aggressive symptomatic treatment should be applied. 
• If an infusion is paused or the infusion rate is decreased, then a longer-than-
anticipated infusion time may occur. Overnight stays at the hospital because of 
slow infusion times should not be reported as serious adverse events. 
• For IRR grades 1 and 2 the then the infusion should be paused. When the 
subject’s condition is stable, the infusion may be restarted at the investigator’s 
discretion. Upon restart, the infusion rate should be half of that employed before 
the interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion. If the subject experiences a Grade 2 or higher event of 
laryngeal edema, or a Grade 2 or higher event of bronchospasm that does not 
respond to systemic therapy and does not resolve within 6 hours from onset, then 
the subject must be withdrawn from treatment.  
• For IRR grade 3 or higher the infusion must be stopped and the subject must be 
observed carefully until resolution of the adverse event. If the intensity of the 
adverse event decreases to Grade 1 or 2 within 2 hours, then the infusion may be 
restarted at the investigator’s discretion. Upon restart, the infusion rate should be 
half of that employed before the interruption. Subsequently, the infusion rate may 
be increased at the investigator’s discretion.  
 
 
6.4 
CONCOMITANT MEDICATIONS 
 
Concomitant medication is defined as any prescription or over-the-counter preparation 
including vitamins and supplements.  Concomitant medications should be recorded from 14 days 
before Day -3 through the end of the subject’s study participation.  Any change in concomitant 
medications must be recorded.   
REQUIRED CONCOMITANT MEDICATIONS 
 


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Female subjects of child-bearing potential must agree to use dual methods of 
contraception for the duration of the study.  Male subjects must agree to use a barrier method of 
contraception for the duration of the study if sexually active with a female of child-bearing 
potential. All subjects in the study are required to be enrolled in and compliant with revlimid 
REMS® 
Dexamethasone at least 4 mg PO/IV will be administered prior to all carfilzomib doses.  
All subjects will receive prophylaxis against herpes zoster. Recommended agents and 
doses are acyclovir 400 mg PO twice a day or valacyclovir 500 mg PO daily.  
All patients will receive prophylaxis for Pneumococcal disease. Recommended agents 
and doses are Penicillin 500 mg PO twice a day or doxycycline 100 mg PO twice a day 
All subjects will receive prophylaxis against thromboembolic events while on therapy 
with lenalidomide and/or carfilzomib with Aspirin 325 mg/day, low-molecular weight heparin,or 
oral anticoagulants according to risk-strata as outlined in the International Myeloma Working 
Group guideline (48).  
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, 
HBV DNA testing by PCR is mandatory for subjects at risk for HBV reactivation. see Section 
4.2. For subjects who are diagnosed with HBV reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately controlled. If the benefits outweigh the 
risks, study treatment may be resumed with concomitant antiviral prophylaxis as per local 
standard of care. Consult a liver disease specialist as clinically indicated. 
6.4.2 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
 
Allopurinol (in subjects at risk for TLS due to high tumor burden) is optional and will be 
prescribed at the Investigator’s discretion.   
Biphosphonate therapy, per institutional guidelines, is allowed and encouraged. 
Vitamins and supplements should be recorded on the concomitant medication page.  All 
transfusions and/or blood product related procedures must be recorded on the appropriate form. 
6.4.3 
EXCLUDED CONCOMITANT MEDICATIONS 
 


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Concurrent therapy with an approved or investigative anticancer therapeutic with activity 
against multiple myeloma is not allowed.  Other investigative agents (e.g., antibiotics or 
antiemetics) should not be used during the study. 


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7 
STUDY TESTS AND OBSERVATIONS 
 
Table 7 – Study enrolment, induction therapy and study evaluations. 
 
Screening 
Cycle 1 
Cycle 2 
Cycles 3 and 4 
 
21 days from 
onset of 
therapy 
Protocol day 
Protocol day 
Protocol day 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
History and Physical 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Skeletal survey 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood 
counts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Metabolic panel (Na, 
K, Cr, BUN, Cl, 
Bicarbonate, glucose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Calcium, 
Phosphorus, Uric 
acid 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Total bilirubin, AST, 
ALT, alkaline 
phosphatase, LDH,  
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
B2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus 
(HBV) core antibody, 
HBV surface antigen, 
HBV surface 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA 
X6 
 
 
 
 
 
 
 
 
X7 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum protein 
electrophoresis 
X 
 
 
 
 
 
 
 
 
X4 
 
 
 
24h urine protein 
electrophoresis 
X 
 
 
 
 
 
 
 
 
X3,4 
 
 
 
Serum free light 
chains 
X 
 
 
 
 
 
 
 
 
X4 
 
 
 
Serum and urine 
Immunofixation 
X 
 
 
 
 
 
 
 
 
X4 
 
 
 
Bone marrow 
aspiration and 
biopsy1 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Adverse Events 
Assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications  Review 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Serum pregnancy 
test, if appropriate 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Confirmation of 
enrollment in 
Revlimid REMS® 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Carfilzomib infusion 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Lenalidomide 
treatment2 
 
X2 
X2 
X2 
 
X2 
X2 
X2 
 
X2 
X2 
X2 
 
Dexamethasone 
treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daratumumab 
infusion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
1-This assessment will include morphology, flow cytometry, FISH for myeloma-associated abnormalities and sample to be 
sent to Adaptive biotechnology for identification of myeloma-specific sequences (see section 3.6). If subject has already had 
a diagnostic bone marrow aspiration and biopsy this is not necessary as long as the enrolling site can verify that there is 
adequate FISH information and enough and adequate sample in storage to be sent to Adaptive biotechnologies for 
identification of myeloma-specific sequences  
2 – Lenalidomide treatment daily from days 1-21. 
3- Necessary only when M spike in urine is main parameter for response assessment. 
4- On cycle 3 day 1 only. 
5-Continuously 
6- For subjects with serologic evidence of resolved HBV infection (i.e., positive Anti-HBs or positive Anti-HBc) at 
Screening, HBV DNA testing by PCR must be performed locally. HBV DNA not necessary for patients positive for anti-
HBs, but negative for Anti-HBc and with a history of hepatitis B vaccination. 
7- Q12W during treatment, at the End of Treatment Visit, and Q12W for up to 6 months after the last dose of study 
treatment 
 
 
 
 


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Table 8 – Consolidation therapy and study evaluations. 
 
Prior to 
consolidation 
Subjects on auto-HCT 
for consolidation 1 
Subjects on KRdD for 
consolidation 1, cycles 1-
4 
Consolidation 2,3, 
cycles 1-4 of each block 
 
 
14 days from 
onset of 
therapy or 
mobilization4 
Protocol day 
Protocol day 
Protocol day 
-2 or -1 
0 
60 to 80 
1 
8 
15 
22 
1 
8 
15 
22 
History and 
Physical 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
Vitals 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Weight 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
Complete blood 
counts 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Metabolic panel 
(Na, K, Cr, BUN, 
Cl, Bicarbonate) 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Total bilirubin, 
AST, ALT, 
alkaline 
phosphatase 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
HBV DNA 
 
 
 
X11 
X11 
 
 
 
X11 
 
 
 
Serum protein 
electrophoresis 
X 
 
 
X 
X7 
 
 
 
X7 
 
 
 
24h urine protein 
electrophoresis 
X3 
 
 
X3 
X3 
 
 
 
X3,7 
 
 
 
Serum free light 
chains 
X 
 
 
X 
X7 
 
 
 
X7 
 
 
 
Serum and urine 
Immunofixation 
X 
 
 
X 
X7 
 
 
 
X7 
 
 
 
Bone marrow 
aspiration1  
X 
 
 
X 
X5 
 
 
 
X6 
 
 
 
Adverse Events 
Assessment8 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
monitoring 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications  
Review 
 
X 
 
X 
X 
 
 
 
X 
 
 
 
Serum pregnancy 
test, if 
appropriate 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Confirmation of 
enrollment in 
Revlimid 
REMS® 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Melphalan 
infusion 
 
X 
 
 
 
 
 
 
 
 
 
 


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Hematopoietic 
progenitor cells 
infusion 
 
 
X 
 
 
 
 
 
 
 
 
 
Carfilzomib 
infusion 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
Lenalidomide 
treatment2 
 
 
 
 
X2 
X2 
X2 
 
X2 
X2 
X2 
 
Dexamethasone 
treatment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Daratumumab 
infusion 
 
 
 
 
X 
 
X9 
 
X 
 
X10 
 
1- Sample to be provided for MRD assessment (see section 3.6).  
2 – Lenalidomide treatment daily from days 1-21. 
3- Necessary only when M spike in urine is main parameter for response assessment. 
4- May overlap with cycle 4 of induction 
5- Bone marrow aspiration with MRD assay (in subjects found to be MRD-informative based on clone identification 
sample) will be performed on day 1 of cycle 3 of KRdD consolidation 1 for patients not undergoing auto-HCT. 
6- Bone marrow aspiration with MRD assay (in subjects found to be MRD-informative based on clone identification 
sample) will be performed on day 1 of cycle 3 of KRdD consolidation 2 and, when applicable, on day 1 of cycle 3 of KRdD 
consolidation 3. 
7- To be performed on day 1 of cycles 1 and 3. 
8- Continuously 
9- Only on cycles 1 and 2 of consolidation block 1. 
10- Only on cycles 1 and 2 of consolidation block 2 and only for patients who underwent auto-HCT as consolidation 1. 
11- For subjects with serologic evidence of resolved HBV infection (i.e., positive Anti-HBs or positive Anti-HBc) at 
Screening, HBV DNA testing by PCR must be performed locally Q12W during treatment, at the End of Treatment Visit, 
and Q12W for up to 6 months after the last dose of study treatment. HBV DNA not necessary for patients positive for anti-
HBs, but negative for Anti-HBc and with a history of hepatitis B vaccination. 
 
 
 


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Table 9 – Observation/Maintenance therapy and study evaluations. 
 
MRD negative cohort 
MRD positive 
cohort 
 
Active surveillance phase 
Follow up phase 
Follow up 
Anytime 
during first 
3 weeks 
Wk, 24 
from EOT4 
Wk. 72 
from EOT4 
Ever 8 weeks5 
during wks 1-24, 
every 16 wks4 
afterwards 
Every 16 wks5 
after active 
surveillance phase 
Every 16 wks4 
History and Physical 
 
 
 
X 
X 
X 
Vitals 
 
 
 
X 
X 
X 
Complete blood 
counts 
 
 
 
X 
X 
X 
Metabolic panel 
(Na, K, Cr, BUN, 
Cl, Ca, Bicarbonate) 
 
 
 
X 
X 
X 
Total bilirubin, 
AST, ALT, alkaline 
phosphatase, LDH 
 
 
 
X 
X 
X 
HBV DNA 
 
 
 
X6 
 
 
Serum protein 
electrophoresis 
 
 
 
X 
X 
X 
24h urine protein 
electrophoresis 
 
 
 
X3 
X3 
X3 
Serum free light 
chains 
 
 
 
X 
X 
X 
Serum and urine 
Immunofixation 
 
 
 
X 
X 
X 
Bone marrow 
aspiration1  
 
X 
X 
 
 
 
FDG PET/CT scan 
X 
 
 
 
 
 
Adverse Events 
Assessment 
 
 
 
X 
 
 
Concomitant 
Medications  
Review 
 
 
 
X 
 
 
Serum pregnancy 
test, if appropriate 
 
 
 
 
 
X 
Confirmation of 
enrollment in 
Revlimid REMS® 
 
 
 
 
 
X 
SOC Lenalidomide 
treatment2 
 
 
 
 
 
X2 
1- Sample to be provided for MRD assessment (see section 3.6).  
2 –Lenalidomide treatment daily from days 1-28 is suggested, but not required 
3- Necessary only when M spike in urine is main parameter for response assessment. 
4-+/- 4 weeks- suggested timeline 
5-+/- 4 weeks 
6- Q12W during treatment, at the End of Treatment Visit, and Q12W for up to 6 months after the last dose of study 
treatment. HBV DNA not necessary for patients positive at screening for anti-HBs, but negative for Anti-HBc and with a 
history of hepatitis B vaccination. 


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8 
STUDY, TREATMENT AND PARTICIPATION DISCONTINUATION 
8.1 
REASONS FOR STUDY DISCONTINUATION  
Reasons for study discontinuation may include, but are not limited to: 
- 
Safety concerns as indicated by investigator or DSMB. 
- 
Request to discontinue the trial by a regulatory or health authority or an IRB 
- 
Manufacturing difficulties/concerns  
 
8.2 
REASONS FOR TREATMENT DISCONTINUATION  
Reasons for subject discontinuation of study treatment are: 
- 
Confirmed progressive disease (appendix B) 
- 
Toxicity that in the opinion of investigator or DSMB is not adequately controlled and/or 
recurrent despite necessary dose modifications are outlined in section 6.2. 
- 
Discontinuation of subject participation in the study. 
 
8.3 
REASONS FOR STUDY PARTICIPATION DISCONTINUATION  
Reasons for subject discontinuation of study participation are: 
- 
Withdraw of consent. 
- 
Any reason that in the opinion of the investigator, DSMB or IRB makes the subject 
participation in the study unfeasible or unsafe 


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9 
ADVERSE EVENTS 
9.1 
OVERVIEW 
As an agent of the sponsor of the Study, the PRINCIPAL INVESTIGATOR shall be 
solely responsible for complying, within the required timelines, any safety reporting obligation to 
competent Health Authorities, IRB/ECs and any participating (co or sub) investigators, as 
defined in applicable laws and regulations.  For the purposes of this section, safety data includes 
adverse events, product quality complaints (PQCs), and special situations including pregnancies. 
The PRINCIPAL INVESTIGATOR will provide safety information to Janssen Scientific 
Affairs, LLC  and Amgen Global Affairs on adverse events, special situations including 
pregnancies and product quality complaints as defined within this section. 
 
9.2 
MANAGEMENT OF SAFETY DATA 
 
This Study has been designated as an interventional study.  As such, all adverse events, 
special situations including pregnancies and product quality complaints for J&J Medicinal 
Product and for Amgen Medicinal Product regardless of causality and special situations 
excluding those from subjects not exposed to a J&J medicinal product and/or Amgen medicinal 
product, quality complaints with or without an adverse event as described in this protocol will be 
reported from the time a subject has signed and dated an Informed Consent Form (ICF) until 30 
days after the last documented use of product under study within the study. All subsequent AEs 
and SAEs will be collected after this period if the Principal Investigator considers the AE/SAE to 
be causally-related to the study drug.  
 
For the purposes of this study, the Janssen medicinal product is: 
DARZALEX®(daratumumab)  
For the purposes of this study, the Amgen medicinal product is: KYPROLIS® 
(carfilzomib) 
 
 


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9.3 
ADVERSE EVENTS DEFINITIONS 
 An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse event does 
not necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including laboratory 
test abnormalities.  
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current IB or prescribing information for a marketed compound.  Also, 
reports which add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs.  For example, an event more specific or more severe 
than described in the IB would be considered “unexpected”.    
Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 should be used to describe the event and for assessing the severity of AEs (see 
Appendix A).  Any events representing a change in the CTCAE Grade need to be reported on the 
AE case report form.  This includes any change in laboratory values.   
For AEs not adequately addressed in the CTCAE, the severity Table 10 below may be 
used: 
 
 
 
 


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Table 10- Adverse Event Severity 
Severity 
Description 
GRADE 1 – Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
GRADE 2 – Moderate 
Moderate; minimal local or noninvasive 
intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). 
GRADE 3 – Severe 
Severe or medically significant but not life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limited self-care 
ADL. 
GRADE 4 – Life-threatening 
 Life-threatening consequences; urgent intervention 
indicated. 
GRADE 5 – Fatal 
Death related to AE. 
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the 
subject signing consent for study participation is considered to be pre-existing in nature and part 
of the subject’s medical history. 
9.4 
CAUSALITY 
Using the following criteria, the relationship of the AE to the study drug should be assessed as 
follows:   
Yes:  The event is suspected to be related if:  
• there is a clinically plausible time sequence between onset of the AE and administration 
of study treatment; and/or 
• there is a biologically plausible mechanism for the study treatment to cause or contribute 
to the AE; and/or  
• the event responds to withdrawal of the study medication (dechallenge) and/or recurs 
with rechallenge (when clinically feasible); and/or 
• the AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, or 
procedures 
No:  
• the AE is more likely to be explained by the subject’s clinical state, underlying disease, 
concomitant medication, study or non-study procedure; and/or 


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• the time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
• the event is unlikely to be related to the investigational product(s) 
9.5 
ADVERSE EVENTS OF SPECIAL INTEREST (DARATUMUMAB) 
 
All Adverse events of special interest are events that Janssen Scientific Affairs, LLC 
(J&J) is actively monitoring as a result of a previously identified signal (even if non-serious). 
These adverse events are: 
• Infusion reactions: ≥ grade 3 
• Infections: ≥ grade 4 
• Cytopenias: ≥ grade 4 
• HBV reactivation 
• Other malignancies 
 
Any Adverse Event of Special Interest that is to be reported to the COMPANY should be 
recorded on a Serious Adverse Event Report From and be reported to the COMPANY within 24 
hours of knowledge of the event.  
9.6 
UNLISTED (UNEXPECTED ADVERSE EVENTS/REFERENCE SAFETY 
INFORMATION 
 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For a medicinal product(s) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the applicable product information.  
 
http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf 
 
For DARZALEX™ (daratumumab), the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure. 
9.7 
ADVERSE EVENTS REPORTING PROCEDURES 
 


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All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing 
condition or laboratory finding) with an onset date after the subject signs consent for study 
participation must be promptly documented on the appropriate summary.  Details of the event 
must include severity, relationship to study drug, duration, action taken, and outcome.  Serious 
adverse events (SAEs) will be recorded on the appropriate form. 
 
All AEs that are considered related to study drug must be followed to resolution or 
stabilization if improvement is not expected.  
 
AEs should be reported from the time the subject signs consent through 30 days post-last 
dose of study drug or initiation of a new anti-cancer therapy, whichever occurs first.  In addition, 
the Investigator should report any AE that may occur after this time period that is believed to 
have a reasonable possibility of being associated with study drug.  If a subject is registered but 
discontinues the study prior to receiving any study drug, AEs must be reported through the end-
of-study visit.  AEs which completely resolve and then recur should be recorded as a new AE.  
For subjects who complete the end of study visit less than 30 days following their last dose of 
study drug, a follow up of ongoing AEs should be attempted by telephone and documented in the 
subject’s source document.  AEs continuing at 30 days post-last dose should have a comment in 
the source document by the Investigator that the event has stabilized or is not expected to 
improve. 
 
The experimental approach encompassed in this protocol governs induction therapy and 
post auto-HCT consolidation and maintenance therapy. Auto-HCT itself is standard of care 
treatment with well known toxicity profile. Therefore AEs that occur after initiation of auto-HCT 
and before initiation of post auto-HCT consolidation are not reportable unless they occur within 
30 days of last dose of carfilzomib, daratumumab or lenalidomide. 
 


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The Principal Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and determining that documentation of the event is adequate.  Adverse events will be 
assigned a severity grade using the NCI-CTCAE grading scale v4.0.   
 
All Grade 3 and 4 adverse events must be recorded as AEs on the CRF.  Grade 1 and 2 
adverse events should only be recorded if considered clinically significant by the Investigator. 
 
The Principal Investigator may delegate these duties to Sub-investigators and must ensure 
that these Sub-investigators are qualified to perform these duties under the supervision of the 
Principal Investigator and that they are listed on the FDA Form 1572.   


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9.8 
SERIOUS ADVERSE EVENTS DEFINITIONS 
 
A serious adverse event (SAE) based on ICH and EU Guidelines on Pharmacovigilance 
for Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
Any death for any reason occurring within 30 days of the subject receiving study drug, 
regardless of the subject having discontinued from the study must be reported to the 
Janssen Scientific Affairs and Amgen Global Safety as an SAE. 
 


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HOSPITALIZATION  
 
 For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
Any event requiring hospitalization or prolongation of hospitalization that occurs 
during the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event 
(e.g., social reasons such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and where the 
underlying condition for which the hospitalization was planned has not worsened will not 
be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.] 
• 
[For convenience the investigator may choose to hospitalize the subject for 
the duration of the treatment period.]  
 
LIFE-THREATENING CONDITIONS  
 
 Disease progression should not be recorded as an adverse event or serious adverse event 
term; instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition.  
 
 


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9.9 
ADVERSE EVENT REPORTING AND DOCUMENTATION REQUIREMENTS 
(DARATUMUMAB) 
 
All SAEs occurring from the time that the subject signs consent for study participation 
through 30 days after the last administered dose of study drug will be reported.  All SAEs, 
regardless of relationship to study drug, must be followed to resolution or to stabilization if 
improvement or resolution is not expected. 
If a subject is permanently withdrawn from the study because of a SAE, this information 
must be included in the initial or follow-up SAE report as well as the appropriate form for Study 
Discontinuation. 
The PRINCIPAL INVESTIGATOR is responsible for notifying the appropriate 
Regulatory Agencies, when required, and in accordance with applicable laws and regulations of 
any Expedited Safety Reports.  Generally, these are all SAEs that are judged to be unexpected 
and related to study drug(s), as specified in ICH E2B guidelines: Clinical Safety Data 
Management Data Elements for Transmission of Individual Case Safety Reports.   However, 
certain Regulatory Agencies may have additional requirements for expedited safety report 
submissions. 
This submission of IND Safety Reports (North America) or Suspected Unexpected 
Serious Adverse Reactions (SUSARS [Europe]) will be cross referenced according to local 
regulations to Janssen Investigational Compound Number (IND, CSA, etc) at the time of 
submission.  
The Investigator is also responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), in accordance with local regulations, of all SAEs.   
 
 
 
 
 
INDIVIDUAL CASE SAFETY REPORTS (ICSR)  
 


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 A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• 
an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
• 
an identifiable reporter (investigational site) 
• 
a J&J medicinal product  
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected J&J medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• 
J&J protocol ID  
 
 
 
 
PRODUCT QUALITY COMPLAINT (PQC) 
 
 A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability monitoring, 
dose preparation, storage or distribution of the product, or delivery system.  Not all PQCs 
involve a subject.  Lot and batch numbers are of high significance and need to be collected 
whenever available. 


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Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
 
 
 
 
SPECIAL REPORTING SITUATIONS (DARATUMUMAB) 
 
 Safety events of interest for a J&J medicinal product that require expediting reporting 
and/or safety evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a J&J medicinal product  
• 
Exposure to a J&J medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a J&J medicinal product 
• 
Inadvertent or accidental exposure to a J&J medicinal product  
• 
Medication error involving a J&J medicinal product (with or without patient 
exposure to the J&J medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal 
product 
• 
 Unexpected therapeutic or clinical benefit from use of a J&J medicinal product  


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• 
Any failure of expected pharmacological action (i.e., lack of effect) of a J&J 
medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from a 
Janssen Scientific Affairs, LLC perspective, they are treated in the same manner as adverse 
events. Special situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded 
on a Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs, LLC 
within 24 hours of becoming aware of the event. 
 
 
 
PREGNANCY 
 
 All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC by 
the PRINCIPAL INVESTIGATOR within 24 hours of becoming aware of the event using the 
Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 
death, stillbirth, congenital anomaly, ectopic pregnancy) are considered serious adverse events 
and must be reported using the Serious Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn from 
the study and discontinue further study treatment. 
Because the effects of daratumumab on sperm are unknown, pregnancies in partners of 
male subjects exposed to daratumumab will be reported by the PRINCIPAL INVESTIGATOR 
within 24 hours of their knowledge of the event using the Serious Adverse Event Form.  
Depending on local legislation this may require prior consent of the partner. 


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Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
All pregnancies are considered a SAE and will require expedite reporting. Investigators 
will follow the outcome of the pregnancy for (spontaneous abortion,(any congenital anomaly 
detected in an aborted fetus is to be documented), stillbirth, neonatal death, or congenital 
anomaly. 
 
 
MAINTENANCE OF SAFETY INFORMATION 
 
All safety data should be maintained in a clinical database in a retrievable format. The 
INSTITUTION and PRINCIPAL INVESTIGATOR shall provide all adverse events, both 
serious and non-serious, in report format. However, in certain circumstances more frequent 
provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as such the data 
shall be made available within a reasonable timeframe at Janssen Scientific Affairs, LLC request 
 
 
9.9.6 
PROCEDURES FOR REPORTING SAFETY DATA AND PRODUCT QUALITY 
COMPLAINTS (PQC) FOR JANSSEN MEDICINAL PRODUCTS TO 
JANSSEN SCIENTIF AFFAIRS, LLC 
 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a Janssen medicinal product are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to a Janssen 
medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed up in accordance with clinical practice. 
 


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9.9.6.1 
SAEs. Adverse Events of Special Interest and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
The INSTITUTION and the  PRINCIPAL INVESTIGATOR will transmit all SAEs and 
special situations following exposure to a J&J product under study in a form provided by Janssen 
Scientific Affairs, LLC in accordance with Section 10,Transmission Methods, in English within 
24-hours of becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an 
unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs, LLC. 
 
All follow-up information for serious adverse events that are not resolved at the end of 
the study or by the time of patient withdrawal must be reported directly by the PRINCIPAL 
INVESTIGATOR, within 24 hours becoming aware, to Janssen Scientific Affairs, LLC using 
the Janssen Scientific Affairs, LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE, adverse 
event of special interest, serious ADR or special situation is required. 
 


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• 
The INSTITUTION and/or PRINCIPAL INVESTIGATOR is responsible for 
ensuring that these cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are received. Reporting 
of follow-up information should follow the same timeline as initial reports. 
 
• 
Copies of any and all relevant extraordinary (not including routine intiaion or 
follow-up ICSR submission) correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse events, irrespective of association with the Janssen Product 
under study, are to be provided to J&J using a transmission method in Section 9.9.8 from this 
protocol within 24 hours of such report or correspondence being sent to applicable health 
authorities.  
 
 
 
9.9.6.2 
Non-Serious AEs 
 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC 
according to the timeframe outlined in the Research Funding Agreement section entitled 
Reporting of Data. 
 
 
9.9.6.3 
PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, LLC, and are mandated by 
regulatory agencies worldwide. Janssen Scientific Affairs, LLC has established procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC 
information. Lot and/or Batch #s shall be collected or any reports failure of expected 


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pharmacological action (i.e., lack of effect). The product should be quarantined immediately and 
if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
Janssen Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 hours after 
being made aware of the event. The Janssen contact will provide additional information/form 
to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must 
report the PQC to Janssen Scientific Affairs, LLC according to the serious adverse event 
reporting timelines.  A sample of the suspected product should be maintained for further 
investigation if requested by Janssen Scientific Affairs, LLC 
 
 
 
9.9.7 
REPORTING PROCEDURES FOR REPORTING SAFETY DATA AND 
PRODUCT QUAKLITY COMPLAINTS (PQCS) FOR NON-JANSEN 
MEDICIAL PRODUCTS 
 
For SAEs, special reporting situations and PQCs following exposure to a non-J&J 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the appropriate 
regulatory/competent authority or the manufacturer of that medicinal product (in the absence of 
appropriate local legislation) as soon as possible. 
 
 
 
 


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9.9.8 
TRANSMISSION METHODS 
 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
• 
Electronically via J&J SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
• 
Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC 
 
9.9.9 
SAEs LISTING 
 
At a minimum, on a semi-annual basis and at the end of the Study, Janssen Scientific 
Affairs, LLC  will provide to the INSTITUTION and/or PRINCIPAL INVESTIGATOR, a 
listing of all SAEs reported to the COMPANY. SPONSOR and/or PRINCIPAL 
INVESTIGATOR will review this listing and will resolve any discrepancies with the data 
provided by the COMPANY. 
 
9.9.10 
DISSEMINATION 
OF 
SAFETY 
INFORMATION 
FROM 
J&J 
TO 
INSTITUTION/PRINCIPAL INVESTIGATOR 
 
PRINCIPAL INVESTIGATOR will be responsible for submitting IND safety reports for 
the Study Product to INSTITUTION’s IRB in accordance with Federal regulations 21 CFR 
312.66.  The PRINCIPAL INVESTIGATOR will provide a copy of each IND safety report to 
sub-investigators where the study design is either a multi-center or cooperative study. 


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COMPANY agrees to provide to the PRINCIPAL INVESTIGATOR IND safety reports 
for the J&J Medicinal Product as they become available until all subjects in the Protocol have 
completed their last Study visit according to the Protocol (i.e. Last Subject Last Visit has 
occurred).. 
 
9.9.11 
CONTACTING JANSSEN SCIENTIFIC AFFAIRS, LLC REGARDING SAFETY 
 
The names (and corresponding contact information) of the individuals who should be 
contacted regarding safety issues will be provided separately by J&J. 
9.9.12 
FINAL STUDY REPORT 
 
The INSTITUTION/PRINCIPAL INVESTIGATOR will prepare a final report including 
a complete and full summary of all adverse events, special situations and pregnancy reports 
according to the timeframe outlined in the Research Funding Agreement  
 
9.10 
ADVERSE EVENT REPORTING AND DOCUMENTATION REQUIREMENTS 
(CARFILZOMIB) 
 
All SAEs occurring from the time that the subject signs consent for study participation 
through 30 days after the last administered dose of study drug will be reported.  All SAEs, 
regardless of relationship to study drug, must be followed to resolution or to stabilization if 
improvement or resolution is not expected. 
If a subject is permanently withdrawn from the study because of a SAE, this information 
must be included in the initial or follow-up SAE report as well as the appropriate form for Study 
Discontinuation. 
The principal investigator, as an agent of the sponsor is responsible for notifying the 
appropriate Regulatory Agencies, when required, and in accordance with applicable laws and 
regulations of any Expedited Safety Reports.  Generally, these are all SAEs that are judged to be 
unexpected and related to study drug(s), as specified in ICH E2B guidelines: Clinical Safety 


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Data Management Data Elements for Transmission of Individual Case Safety Reports.   
However, certain Regulatory Agencies may have additional requirements for expedited safety 
report submissions. 
This submission of IND Safety Reports (North America) or Suspected Unexpected 
Serious Adverse Reactions (SUSARS [Europe]) will be cross referenced according to local 
regulations to Amgen  Investigational Compound Number (IND, CSA, etc) at the time of 
submission.  
The Investigator is also responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), in accordance with local regulations, of all SAEs.   
Additionally, the Investigator is responsible for reporting adverse events to Amgen as 
described below: 
The Investigator must inform Amgen Drug Safety in writing by Fax at the contact 
information listed below of all Expedited Safety Reports submitted to the relevant Regulatory 
Agencies.  These notifications should be performed in parallel to the Regulatory Agency 
submissions [e.g., within 7 calendar days for any Fatal or Life-threatening SUSARs and within 
15 calendar days for all other SUSARs], but in no case any later than 1 business day from the 
submission date. This must be documented on a FDA 3500A MEDWATCH form.  This form 
must be completed and supplied to Amgen Drug Safety in English and accompanied by the 
global IST SAE Report Cover Page. 
The initial report must be as complete as possible, at a minimum including the serious 
adverse event term(s), patient identifier, date of awareness of the event, an assessment of the 
causal relationship between the event and the investigational product(s), and name of the reporter 
(investigator).  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-up 
FDA 3500A MEDWATCH form and submitted to Amgen Drug Safety in the same timelines as 
outlined above.  The Amgen ISS protocol number (Amgen ISS 20167173) and the institutional 
protocol number should be included on all reports to Amgen Drug Safety.   
All other serious adverse events regardless of drug causality will be reported to Amgen 
on a FDA 3500A Medwatch form no later than 30 days from the time the sponsor-investigator 
becomes aware of the SAE.  Amgen reserve the right to review the CRFs or source documents in 
response to any inquiries by regulatory agencies that the sponsor-investigator may receive. 


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Amgen Drug Safety and Pharmacovigilance Contact Information: 
Phone:     1-888-814-8653 
Drug Safety Fax:           1-805-480-9205  
 
 
 
 
 
 
PREGNANCY 
 
 If a subject or spouse or partner of a subject becomes pregnant while enrolled in this 
clinical trial or up to three months following administration of carfilzomib, Amgen Drug Safety 
must be notified within 24 hours of the Investigator, designee, or site personnel learning of the 
pregnancy (See Amgen Drug Safety and Pharmacovigilance Contact information above).  If the 
subject is pregnant, carfilzomib must be withheld.   
 
Females of childbearing potential should be advised to avoid becoming pregnant while 
being treated with carfilzomib. If pregnancy occurs during this time, patients should be apprised 
of the potential hazard to the fetus. Carfilzomib should only be used during pregnancy if the 
potential benefits to the mother outweigh the potential risks to the fetus. Carfilzomib can cause 
fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in 
pregnant rabbits at doses that were lower than in subjects receiving the recommended doses. If 
carfilzomib is used during pregnancy , or if the subject becomes pregnant while taking 
carfilzomib, she should notifu the investigstor or study staff immediately.  
 
Subjects, spouses, or partners will be followed through the outcome of the pregnancy.  
The Investigator will be required to notify Amgen of the pregnancy and discuss follow-up with 
the subject. It is not known if carfilzomib will reduce the efficacy of oral contraceptives. Due to 
an increased risk  of venous thrombosis associated with carfilzomib, subjects currently using oral 


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contraceptives , or a hormonal method of contraception associated with a risk of thrombosis 
should consider an alternative method of contraception.  
 
All pregnancies are considered a SAE and will require expedite reporting. Investigators 
will follow the outcome of the pregnancy for (spontaneous abortion,(any congenital anomaly 
detected in an aborted fetus is to be documented), stillbirth, neonatal death, or congenital 
anomaly . 
 
Males of reproductive potential sho0uld be advised to avoid fathering a child while being 
treated with carfilzomib. The potential for carfilzomib to be transferred via semen and its effect 
on sperm is unknown. Male subjects treated with carfilzomib   and/or their female partners (if of 
childbearing potential) should use effective contraceptive methods or abstain from sexual 
activity while treated with carfilzomib and for 90 days after treatment. Male subjects shou9ld 
refrain from donating sperm while on carfilzomib and for 90 days after treatment.  
If pregnancy occurs during this time, patients should be apprised of the potential hazard to the 
fetus.  
Male subjects should be advised to inform the investigator or study staff immediately in 
the event that their female partner becomes pregnant during the study. Upon receipt of this 
information, the investigator should notify Amgen of the pregnancy and discuss follow-up 
regarding the pregnancy outcome with the subject.  
 
No studies of carfilzomib have been conducted in breastfeeding women. Carfilzomib 
should not be used during breastfeeding. Breastfeeding women and women planning on 
breastfeeding may not participate in clinical trials with carfilzomib.  
 
It is not known whether carfilzomib is present in human breast milk. Due to the potential 
for adverse effects in nursing infants from carfilzomib , a decision should be made whether to 
discontinue nursing or to discontinue carfilzomib, taking into account the potential benefit of 
carfilzomib to the mother. If a woman breastfeeds during the study, she must inform the 
investigator or study staff immediately. The investigator should notify Amgen that the subject 
has breastfed the infant and discuss the follow-up with the subject. 


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10 
STATISTICAL CONSIDERATION 
10.1 
STUDY DESIGN 
The study is a Single arm, multi-center, open label phase 2 trial with safety lead in and response-
adapted therapy.  
10.2 
STUDY ENDPOINTS 
10.2.1 
PRIMARY ENDPOINTS 
• Rate of MRD negative (10-5)remissions at completion of consolidation therapy 
SECONDARY ENDPOINTS 
• Toxicity profile of the KRdD combination. 
• Rate of negative MRD at completion of induction. 
• Rate of conversion from positive to negative MRD with auto-HCT. 
• Rate of achievement of complete remission (CR) upon completion of induction and 
consolidation. 
• Rate and kinetics of conversion from negative MRD to positive MRD upon treatment 
discontinuation. 
• Progression-free survival (PFS) and overall survival (OS) for entire study population. 
EXPLORATORY ENDPOINT 
• PFS for patients with confirmed MRD(-) and undergoing observation without additional 
therapy.  
 
10.3 
SAMPLE SIZE CONSIDERATIONS 
 
Due to limited data on the safety of the specific combination of agents being studied in 
the induction phase, a safety lead-in was performed and included 6 subjects. No dose limiting 


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toxicity was seen during the first 2 cycles in 2 or more subjects (in fact none of the first 6 
subjects experienced dose limiting toxicity). The study was reviewed by the data safety 
monitoring board that recommended accrual will continue at the initial dose level. 
 
The initial sample size considerations is based on Simon’s optimal two-stage design 
(optimum design) to estimate the rate of MRD negative cases upon completion of consolidation 
and reduce the early futility of the study. A total of 67 evaluable patients will be enrolled that 
will achieve 80% power (and alpha=0.05) to test the primary hypothesis, i.e. at least 15% more 
MRD negative in the experimental intervention than in the benchmark, ~60 % MRD negative in 
the KRD- auto-HCT trial(45) and at least 75% MRD negative in the current protocol. Twenty-
seven patients will be enrolled in the first stage; the trial will be terminated if 17 or fewer 
patients become MRD negative in the first stage. Based on the null hypothesis that P<=0.60 
versus the alternative that P>=0.75, there is 69% probability of early termination if P=P0.  If the 
trial goes on to the second stage, an additional 40 evaluable patients (total of 67 evaluable 
patients) will be studied. If the total number of subjects to become MRD negative is less than or 
equal to 46, the intervention will be considered futile. By accounting for ~20% of either patients 
drop out or subjects not informative for MRD, a total of 82 eligible patients will be required. The 
size of the study (n=67 informative subjects) will provide two-sided 95% confidence intervals 
for MRD negative estimate from 62.5% in lower limit to 84.4% in upper limit using Clopper-
Pearson exact method for one proportion assuming the MRD negative rate is 75% 
STATISTICAL CONSIDERATIONS FOR STUDY EXPANSION 
 
As of August 2019 80 patients have been enrolled, 45 have reached end of induction 
therapy and 25 have reached end of consolidation 1. Seventy-seven of 80 patients (96%) are 
MRD evaluable (vs. ~80% originally estimated). Of the 23 patients who are MRD evaluable and 
are beyond consolidation 1, 18 (78%) have reached primary endpoint (vs. 75% originally 
estimated). The proportion of patients reaching primary endpoint is expected to increase as 
patients advance to consolidation 2 and 3. Therefore, with 18/23 patients already meeting 
primary endpoint, the study did not meet criteria for early termination during first stage of 
Simon’s two stage design. (17 or fewer patients reaching primary endpoint among the first 27 
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Upon approval of protocol ammendment #4, the trial will be expanded to include a total 
of 123 patients (therefore 41 patients in addition to the 82 patients anticipated in original 
protocol and amendments 1, 2 and 3) in order to enable the exploratory objective. Accrual will 
only continue if the study does not meet criteria for futility upon completion of Simon’s 
second stage (i.e. 46 or fewer patients reach primary endpoint at completion of second stage 
among the first 67 MRD evaluable patients).    
 
The exploratory objective is to describe progression-free survival (PFS)of high-risk [HR; 
i.e. myeloma cells harboring del17p or t(4;14) or t(14;16)]and standard risk (SR) patients 
reaching confirmed MRD negative status (10-5) and discontinuing therapy. High-risk patients 
account for a minority subset of patients with NDMM (currently at 27.5% in this study, 15-20% 
in most trials for NDMM) and are also less likely to achieve MRD negative status upon therapy. 
Therefore, in order to fulfill the exploratory objective of the study, some enrichment of the 
cohort for high-risk patients is necessary. In order to estimate the optimal accrual of HR and SR 
patients we assumed the rate of MRD evaluable patients to be 95% (consistent with current 
findings), the proportion of SR patients who achieve confirmed MRD negative status to be 85% 
and the proportion of HR patients who achieve confirmed MRD negative status to be 75%. 
Different scenarios utilizing these parameters are displayed in Table 11. The scenario with 65% 
patients evaluable for exploratory objective being SR and 35% being HR patients provides the 
best balance between HR enrichment and duration of enrollment. This scenario anticipates a total 
of 77 SR and 46 HR patients being accrued (Figure below) so effectively 37.4% of accrued 
patients being HR (46/123) to yield 62 SR and 33 HR patients with confirmed MRD negative 
status and evaluable for exploratory objective. 
 
 
 
Table 11- Different scenarios of trial enrichment for HR patients. 


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Figure 1 – Sample size calculation for exploratory objective. 
 
 
 
Figure 2- Expected patient disposition  
 


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Upon activation of protocol ammendment #4 the UAB CTNMO will ensure that 
enrollment does not exceed 77 standard risk patients and 46 high risk patients. Once accrual 
target is reached for one of the risk categories (e.g SR) accrual will only continue in the other 
risk category. 
 
 Based on data from patients reaching MRD negativity followed by observation described 
from the IFM 2009 trial(21), we estimate the 2-year PFS (from discontinuation of therapy) of 
patients with confirmed MRD negativity to  be ≥ 75% for both HR and SR patients. Table 12 
provides confidence interval for a few different possibilities of 2-year PFS for HR and SR 
cohorts.  
 
Table 12- Estimated 2-year PFS and 95% confidence interval for HR and SR patients. 
 
 
HR 
N=33 
SR 
N=62 
Scenarios for 2-
yr PFS (%) 
75 
85 
95 
75 
85 
95 


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2-sided 95% CI 
(%) 
60.2-89.8 
72.8-92.2 
87.6-100.0 
64.2-85.8 
76.1-93.9 
90.0-100.0 
 
 
10.4 
STATISTICAL ANALYSIS 
 
GENERAL STATISTICAL ANALYSIS 
  
Continuous endpoints will be summarized using descriptive statistics, which will include 
the number of patients with a valid measurement (n), mean, standard deviation, median, 
minimum, and maximum. All categorical endpoints will be summarized using frequencies and 
percentages. The safety endpoints will be listed and/or summarized by relevant time points, as 
appropriate. In general, the baseline value for efficacy and safety variables is the last non-
missing value before the first dose of study treatment. Data listings will be created to support 
each table and to present all data.  Statistical analysis will be done with SAS v.10.3. 
 
MISSING DATA HANDLING 
 
No imputation of values for missing data will be performed except that missing or partial 
start and end dates for AEs and concomitant medication will be imputed according to pre 
specified, conservative imputation rules. Subjects lost to follow-up (or drop out) will be included 
in statistical analyses to the point of their last evaluation. 
 
ASSESSMENT OF SAFETY 
 
 
All enrolled subjects who receive ≥ 1 dose of study drug will be included the safety 
analysis. Safety assessments will consist of monitoring and recording DLTs, AEs and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 


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laboratory variables; measurement of protocol-specified vital signs; and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
 
Safety summaries will include summaries in the form of tables and listings. The 
frequency (number and percentage) of treatment emergent AEs will be reported by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term. 
Summaries will also be presented by the severity of the AE (per Common Terminology Criteria 
For Adverse Events [CTCAE],v4.03) and by relationship to study drug. 
 
Laboratory shift tables containing counts and percentages will be prepared by treatment 
assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory 
parameter. Figures of changes in laboratory parameters over time will be generated. 
Results of vital sign assessments and physical exams will be tabulated and summarized. 
 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments. Concomitant medications will be coded 
and tabulated according to the World Health Organization Drug Dictionary (WHODRUG). 
 
 
ANALYSIS OF EFFICACY PARAMETERS 
 
 
The primary endpoint of MRD (-) rate will be estimated along with two-sided 95% CI 
using Clopper-Pearson exact method. The same method will be used to estimate rate of negative 
MRD at completion of induction; rate of conversion from positive to negative MRD with auto-
HCT, rate of attainment of CR upon completion of consolidation and rate and kinetics of 
conversion from negative MRD to positive MRD upon treatment discontinuation. 
 
Time-to-event endpoints will be analyzed using Kaplan-Meier product limit methods to 
estimate the survival distribution, median time-to-event with 95% confidence interval, patients at 


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risk, patients with an event, patients censored and survival probabilities at selected time points. 
Progression-free survival (PFS) is defined as the interval from the start of therapy to the earlier 
of the following events: documentation of objective disease progression (appendix B), initiation 
of any non-protocol anti-myeloma therapy with exception of single agent lenalidomide in dose 
up to 15 mg/day (accepted maintenance therapy) or death from any cause. For the exploratory 
objective of describing PFS for patients with confirmed MRD negative status who discontinue 
therapy, PFS will be defined as the interval from discontinuation of therapy (and initiation of 
observation) until the earliest of the following events: documentation of objective disease 
progression (appendix B), initiation of any anti-myeloma therapy or death from any cause. 
Kaplan-Meier methods will be used to estimate the event-free curves and corresponding quartiles 
(including the median). Data from surviving, non-progressing subjects will be censored at the 
earliest of the time of initiation of antitumor treatment other than the study treatment or the last 
time that lack of disease progression was objectively documented.  
 
Overall survival (OS) is defined as the time from date of enrollment until date of death 
due to any cause. Subjects who are known to be alive or whose survival status is unknown will 
be censored at the date last known to be alive. Subjects who are completely lost to follow-up for 
survival will be censored at enrollment date. The analysis methods for overall survival will be 
similar to those described for progression free survival.  
 
INTERIM AND SAFETY ANALYSIS 
 
There will be continuous monitoring for safety.  A sequential probability ratio test 
(SPRT) approach will be used (49).  If there is strong evidence that the rate of grade 4 non-
hematologic toxicities is 0.30 or above, as compared to a null rate of 0.15, the enrollment will be 
halt and a full DSMC review will be conducted.  The stopping boundary is based on the 
likelihood ratio comparing the null rate of 0.30 versus the alternative rate of 0.15 using binomial 
likelihoods.  If the ratio favoring a rate of 0.30 (vs. 0.15) ever exceeds 10, then the study will be 
stopped.  A likelihood ratio of 10 is similar to a significance level of 0.05.  


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11 
INVESTIGATIONAL PRODUCT 
11.1 
CARFILZOMIB DESCRIPTION 
Carfilzomib is a synthetic small molecule peptide bearing the chemical name (2S)-N-
((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-
2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.  The molecular 
formula is C40H57N5O7 and the molecular weight is 719.91.  It specifically functions as an 
inhibitor of the chymotrypsin-like activity of the 20S proteasome which leads to the 
accumulation of protein substrates within the cell and induction of apoptosis.   
11.2 
CARFILZOMIB FORMULATION 
Carfilzomib for Injection will be provided as a lyophilized powder which, when 
reconstituted, contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium 
citrate buffer (pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, 
Captisol®).   
11.3 
CARFILZOMIB STORAGE 
Lyophilized Carfilzomib for Injection must be stored at 2–8ºC under the conditions 
outlined in the separate Pharmacy Manual, in a securely locked area to which access is limited to 
appropriate study personnel. 
11.4 
CARFILZOMIB ACCOUNTABILITY 
Amgen, Inc. and the Investigator will maintain records of each shipment of 
investigational product.  The records will document shipment dates, method of shipment, batch 
numbers, and quantity of vials contained in the shipment.  Upon receipt of the investigational 
product, the designated recipient at the study site will inspect the shipment, verify the number 
and condition of the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection by representatives of 
UAB, Amgen and by regulatory authorities.  


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Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must be 
readily available for inspection by representatives of UAB, Amgen and by regulatory authorities.  
Only sites that cannot destroy unused drug on-site will be required to return their unused 
supply of investigational product. 
This study uses an Amgen-supported Interactive Response Technology System (IRT) for 
study drug ordering. Training will be provided to investigators and their designees at the 
different sites at or prior to study initiation visit. 
11.5 
LENALIDOMIDE DESCRIPTION 
Lenalidomide (revlimid ®), a thalidomide analogue, is an immunomodulatory agent with 
antiangiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2Hisoindol-2-
yl) piperidine-2,6-dione. The empirical formula for lenalidomide is C13H13N3O3  with molecular 
weight of 259.3 d. 
11.6 
LENALIDOMIDE FORMULATION 
Lenalidomide is off-white to pale-yellow powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. Lenalidomide will be utilized in this study as 5, 10, 15 and 25 mg capsules for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following 
inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
11.7 
LENALIDOMIDE STORAGE 
Lenalidomide will be stored by subjects according to manufacturer instruction reported 
on labels. 


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11.8 
LENALIDOMIDE SUPPLIER 
Lenalidomide is manufacted by Celgene ® and approved in the US for treatment of 
patients with multiple myeloma in combination with dexamethasone. The study will utilize 
commercial product acquired directly by the subject. Lenalidomide will not be distributed by 
study sites. Lenalidomide is only available upon patient registration in revlimid REMS®. 
Registration in and compliance with revlimid REMS® is required for subject enrolment and 
continuation on study. 
. 
11.9 
DEXAMETHASONE DESCRIPTION 
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally 
occurring chemicals produced by the adrenal glands. Corticosteroids affect the function of many 
cells within the body and suppress the immune system. Corticosteroids also block inflammation 
and are used in a wide variety of inflammatory diseases affecting many organs. The molecular 
weight for dexamethasone is 392.47. It is designated chemically as 9-fluoro-11,17,21-trihydroxy-
16Į-methylpregna-1,4-diene-3,20-dione. The empirical formula is C22H29FO5   
11.10 
DEXAMETHASONE FORMULATION 
Dexamethasone is a white, odorless, crystalline powder. It is available commercially in 4 
mg tablets. Each tablet contains dexamethasone as the active ingredient and the following 
inactive ingredients: calcium phosphate, lactose, magnesium stearate, and starch. The tablet shell 
may contain the following: D&C Yellow 10, FD&C Yellow 6, and/or FD&C Blue 1.   
11.11 
DEXAMETHASONE STORAGE 
Dexamethasone will be stored by subjects according to manufacturer instruction reported 
on labels. 
11.12 
DEXAMETHASONE SUPPLIER 
The study utilizes commercially available dexamethasone and the drug will not be 
provided by the sponsor. Subjects will be responsible for self-administration of dexamethasone.   


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11.13 
DARATUMUMAB DESCRIPTION 
Daratumumab is a human IgG1 kappa monoclonal antibody directed at CD38, a 
transmembrane protein that is overly expressed on plasma cells and malignant myeloma cells, 
while having low expression on normal lymphoid, myeloid, as well as epithelial tissue. 
Functionally, daratumumab directly targets CD38-expressing tumor cells and promotes antibody-
dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, complement-
dependent cytotoxicity and apoptosis.(33) Preclinical data has demonstrated robust antitumor 
activity in xenograft models, including those with lenalidomide and bortezomib resistant cell 
lines.  
11.14 
DARATUMUMAB FORMULATION 
Daratumumab is a colorless to pale yellow, preservative-free solution available as 
100mg/5ml (20 mg/ml) in a single-dose vial or 400 mg/20 ml (20 mg/ml) in a single-dose vial. 
Daratumumab is prepared using aseptic technique by mixing the appropriate dose in a sterile bag 
containing 0.9% sodium chloride injection, USP as indicated in table 2 . 
11.15 
DARATUMUMAB STORAGE 
Daratumumab is stored in refrigeration at 2o.C to 8o.C. It must not be frozen or shaken 
and must be protected from light. Following dilution the infusion bag may be stored for up to 
24h in a refrigerator at 2o.C to 8o.C protected from light. 
11.16 
DARATUMUMAB ACCOUNTABILITY 
Janssen, Inc. and the Investigator will maintain records of each shipment of 
investigational product.  The records will document shipment dates, method of shipment, batch 
numbers, and quantity of vials contained in the shipment.  Upon receipt of the investigational 
product, the designated recipient at the study site will inspect the shipment, verify the number 
and condition of the vials, and prepare an inventory or drug accountability record.  
Drug accountability records must be readily available for inspection by representatives of 
UAB, Janssen and by regulatory authorities.  


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Empty and partially used vials should be accounted for and destroyed at the study site in 
accordance with the internal standard operating procedures.  Drug destruction records must be 
readily available for inspection by representatives of UAB, Janssen and by regulatory authorities.  
Only sites that cannot destroy unused drug on-site will be required to return their unused 
supply of investigational product. 
 
11.17 
MELPHALAN DESCRIPTION 
Melphalan (L-phenylamine mustard, L-PAM, L-Sarcolysin) is an alkylating agent 
coupled to an amino acid. The molecular formula is C13H18C12N2O2 and the molecular weight is 
305. 
11.18 
 MELPHALAN FORMULATION 
Melphalan is commercially available and supplied as a sterile, freeze-dried powder. Each 
vial contains 50 mg melphalan hydrochloride and the inactive ingredient, povidone 20 
mg.  Reconstitute per manufacturer instructions using the diluent provided.  Further dilution and 
administration may be done per institutional standards. The manufacturer recommends 
completion of administration of melphalan within 60 minutes of reconstitution.  
 
11.19 
MELPHALAN STORAGE 
 The intact packages of melphalan for intravenous administration should be stored at 
room temperature (15 - 30°C) protected from light.  Shelf life surveillance of the intact dosage 
form is ongoing.  
 
11.20 
MELPHALAN SUPPLIER 
Intravenous melphalan is commercially available for purchase by a third party. Its use in 
the clinical setting addressed by this protocol (high dose chemotherapy and autologous 
hematopoietic stem cell transplantation) is standard of care practice.  


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12 
REGULATORY OBLIGATIONS 
12.1 
INFORMED CONSENT 
The investigator will obtain written informed consent from all participating patients or 
their authorized representatives.  Obtaining informed consent must be done according to 
International Conference on Harmonization- Good Clinical Practice Guidelines (ICH GCP). 
Copies of the signed document will be given to the patient and filed in the Investigator’s study 
file, as well as the patient’s medical record if in conformance with the institution’s Standard 
Operating Procedures. 
12.2 
COMPLIANCE WITH LAWS AND REGULATIONS 
The study will be conducted in accordance with U.S. Food and Drug Administration 
(FDA) and International Conference on Harmonization (ICH) Guidelines for Good Clinical 
Practice (GCP), the Declaration of Helsinki, Health Canada, any applicable local health 
authority, and Institutional Review Board (IRB) or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB or Ethics Committee.  
Before the investigational drug is shipped to the Investigator, the Investigator or designee will 
provide Amgen with a copy of the IRB or Ethics Committee approval letter stating that the study 
protocol and any subsequent amendments and informed consent form have been reviewed and 
approved. 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics 
Committee reapproval throughout the duration of the study.  Copies of the Investigator’s annual 
report to the IRB or Ethics Committee and copies of the IRB or Ethics Committee continuance of 
approval must be provided to Amgen and Janssen, with copy to UAB CTNMO  
Name: Pamela Dixon Hardwick 
Address: 1802 6th Avenue South; NP 2515; Birmingham, AL 35294 
Phone No: 205- 975-5387  
Fax No: 205-975-9875   
Email Address: pamdixon@uab.edu  


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The Investigator is also responsible for notifying their IRB or Ethics Committee of any 
significant adverse events that are serious and/or unexpected. 
Amgen will provide study sites with any expedited safety reports generated from any 
ongoing studies with carfilzomib, changes to the Investigator’s Brochure, and any other safety 
information which changes the risk/benefit profile of carfilzomib during the conduct of the study, 
to allow him/her to fulfill his/her obligation for timely reporting to the IRB/ECs and other 
Investigators participating in the study. 
Upon completion of the trial, the Investigator must provide the IRB or Ethics Committee, 
Janssen and Amgen with a summary of the trial’s outcome. 
 
12.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
Participating study sites cannot begin enrollment until an initiation letter has been issued 
from the UAB CTNMO. Each center is required to participate in an initiation conference call. 
Before the start of this study and the shipment of study drug to a participating study site, 
the following documents must be on file at UAB CTNMO. Participating sites will be responsible 
for forwarding the initiation documents toUAB CTNMO.  
All start-up documents can be submitted via electronic mail to pamdixon@uab.edu or via 
fax at (205) 975-9875. Please ensure that the fax cover page clearly identifies the site, study 
identifier and is addressed to ATTN: UAB CTNMO.  
 
 
These documents are required to be submitted by each participating center:   
1. U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal 
Investigator at the participating center. 


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2. The names of any sub-investigators at the participating center must appear on e 
1572.  Investigators must also complete all regulatory documentation as required 
by local regulations. This includes any required human subjects training required 
by the site’s local IRB. 
3. Current curricula vitae and documentation of professional licensure of the 
Principal Investigator and sub-investigators listed on the 1572. 
4. Resumes and human subject protections documentation (e.g. NIH, CITI) for all 
research personnel (e.g. study coordinators, data managers and other research 
personnel) and documentation of ICH-GCP training.  
5. A signed and dated investigator brochure acceptance form.  
6. Written documentation of IRB approval of protocol (identified by title, protocol 
version and date of approval) for each site. 
7. IRB approved study informed consent and HIPAA consent form. HIPAA consent 
language can be included within the study informed consent. Please note that all 
informed consent forms should be reviewed and approved by the UAB CTNMO 
prior to submission to the site’s designated IRB. 
8. A signed Confidentiality Agreement.  
9. A signed Clinical Trial Agreement for each site.  
10. Laboratory certifications (CAP, CLIAs) and laboratory reference value ranges for 
each laboratory listed on the site’s 1572. 
11. The UAB CTNMO site specific forms as specified in the investigator-initiated 
multicenter manual.  
 


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12.4 
SUBJECT CONFIDENTIALITY 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that medical 
information be given to his/her personal physician. 
The Investigator/Institution will permit direct access to source data and documents by 
Amgen, its designee, the FDA and/or other applicable regulatory authority.  The access may 
consist of trial-related monitoring, audits, IRB or Ethics Committee reviews, and FDA 
inspections. 
Release of research results should preserve the privacy of medical information and must 
be carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 


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13 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
13.1 
PROTOCOL AMENDMENTS AND STUDY COMPLETION 
13.1.1 PROTOCOL AMENDMENTS 
No modifications will be made to the protocol without the agreement of the sponsor-
investigator. Changes that significantly affect the safety of the patients, the scope of the 
investigation, or the scientific quality of the study will require Institutional Review Board 
approval prior to implementation, except where the modification is necessary to eliminate 
apparent immediate hazard to human subjects.  Any departures from the protocol must be fully 
documented in the protocol deviation case report form and the source documentation.  
13.1.2 STUDY COMPLETION 
The following data and materials are required by UAB CTNMO , Amgen and Janssen 
before a study can be considered complete or terminated: 
1. Copies of protocol amendments and IRB approval/notification, if appropriate. 
2. Copies of the IRB final report, documentation of submission to the IRB.  
3. A summary of the study prepared by the Principal Investigator (Study report, 
manuscript and/or abstract). 
4. All regulatory documents (e.g., updated curriculum vitae for each Principal 
Investigator, updated U.S. FDA Form 1572 for each site). 
13.2 
STUDY DOCUMENTATION AND ARCHIVE 
13.2.1 DATA RECORDING  
The Clinical Research Coordinator and Investigator will be responsible for the recording 
of all data on the electronic Case Report Forms (eCRFs) on OnCore system.  
The Investigator will provide access to his/her original records to permit a representative 
from the funding or auditing institution(s) to verify the proper transcription of data.  Data 
submission will be electronically via Fax or email.  


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13.2.2 RECORD RETENTION 
Federal law requires that an Investigator maintain all study records for two years after the 
investigation is discontinued. 
13.3 
STUDY MONITORING AND DATA COLLECTION 
13.3.1 MONITORING 
UAB CTNMO will be responsible for the monitoring of study patient data and records. 
Monitoring will be performed centrally. All monitoring reports will be kept by the UAB 
CTNMO to ensure that all reports are contained in a central study file. The CTNMO manager or 
UAB internal auditor will be responsible for conducting the review of monitoring packets. A 
final monitoring report will be generated and issued to the site and will be kept in the central 
study file by the UAB CTNMO. 
13.3.1.1 
Frequency of Reviews 
The each patient at each participating center will have their eligibility criteria reviewed 
prior to enrollment by the UAB CTNMO.  
During the course of the study, each site will be selected for an audit by the UAB Quality 
Assurance Committee approximately once a year. Audit will include 10% of the subjects 
enrolled at the site. In addition to the once yearly QA audit, monitoring for each patient entered 
into this trial will be 100%. Sites are to send source information on each patient to the UAB 
CTNMO office where a shadow chart will be maintained on each subject for this trial.  Source 
will be verified to data entered into the OnCore database.  
13.3.2 PROTOCOL DEVIATIONS AND SAFETY REPORTING 
A Protocol Deviation is any variance from the protocol involving a subject or subjects 
that is not approved by the IRB prior to its initiation or implementation, and occurs when a 
member of the study team departs from the IRB-approved protocol in any way without the 
investigator first obtaining IRB approval. 


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Any protocol deviation or serious adverse event will be reported by the subsite within 24 
hours of notification. Protocol Deviations will be reported by completion of the hard copy 
Protocol Deviation Report form.  Serious Adverse Events will be reported by completion of a 
MedWatch 3500A form and hard copy Serious Adverse Event form. For both Protocol 
Deviations and Serious Adverse Events, all required forms and any supporting clinical 
documentation should be submitted to the UAB CTNMO office within 10 days of notification.  
13.3.3 DATA SAFETY MONITORING BOARD 
The University of Alabama Comprehensive Cancer Center Data Safety Monitoring Board 
will have oversight of the protocol. The UAB CCC DSMB will meet at a minimum on a monthly 
basis to discuss hematology related trials.  
In addition, all protocol deviations and SAEs as defined above will be reviewed by the 
UAB CCC DSMB for review during the DSMB monthly meetings. The coordinating center will 
review protocol deviation and SAE events for form completion and provide assistance in 
communicating to the subsite if more information is warranted. The UAB CTNMO will report 
the event report to the UAB CCC DSMB so that the information can be reviewed at the next 
available DSMB meeting. During the DSMB review, the DSMB can make recommendations for 
any further study action.  
 
13.3.4 DATA COLLECTION  
Data collection will be managed by the UAB CTNMO staff via the study database which is 
housed and maintained at UAB Cancer Center.  
 
 
Time sensitive information such as patient registration, serious adverse events reporting, 
and protocol deviation reporting will be collected via completed hard copy form. These forms 
are available from the UAB CTNMO. . Information collected will be reviewed and processed by 
the UAB CTNMO. 
The data will be initially reviewed for quality assurance purposes to identify any 
discrepancies or missing data. The staff of the UAB CTNMO will notify the participating site of 


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any data queries and manage the overall data quality of the study. If data received relates to a 
serious adverse event or protocol deviation, the information will be processed for report to the 
UAB CCC DSMB for review. The sponsor- investigator, Luciano Costa, MD and the assigned 
statistician, will also have access to study data for quality assurance and analysis purposes. 
During the course of the study, data quality will be monitored by random inspection of the 
completed forms by a designated monitor.  Any problems detected will be discussed with the PI. 
If necessary, re-training of data collectors will be conducted. 
All data should be substantiated by clinical source documents organized within a patient 
research record. ICH Good Clinical Practices are to be followed.  The study will be subject to a 
yearly internal audit via the UAB CCC Quality Assurance Committee at a minimum and audits 
may occur more frequently at the request of the QA Committee.  


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APPENDIX A:  NCI-CTCAE VERSION 4.0 
 
Common Terminology Criteria for Adverse Events (CTCAE) of the  
National Cancer Institute (NCI) v4.0 
 
Publish Date:  June 14, 2010 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 


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APPENDIX B:  RESPONSE CRITERIA FOR MULTIPLE MYELOMA 
 
 
Response category 
Criteria 
Stringent complete  
response (sCR)    
 
• CR as defined below plus all of the following  
• Normal serum FLC ratio   
• Absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence 
Complete response (CR) 
• Negative immunofixation of the serum and 
urine   
• If only the measurable non-bone marrow 
parameter was  FLC,  
normalization of FLC ratio  
• < 5% plasma cells in bone marrow   
• Disappearance of any soft tissue 
plasmacytomas. 
 
Very good partial  
response (VGPR) 
• PR as defined below plus all of the following:  
• Serum and urine M-component detectable by 
immunofixation but not on  
electrophoresis or  
• If at on study, serum measurable, ≥ 90% or 
greater reduction in serum M-  
component   
• Urine M-component <100 mg per 24 hour 
Partial response (PR) 
One of the following: 
• If serum and urine measurable, ≥ 50% 
reduction of serum M-protein and reduction in 
24-hour urinary M-protein by ≥ 90% or to < 200 
mg per 24 hour. 
• If only serum measurable (but urine not), a ≥ 
50% reduction of serum M-protein. 
• If urine measurable (but serum not), a 
reduction in 24-hour urinary M-protein by ≥ 
90% or to < 200 mg per 24 hour. 
• If only the measurable non-bone marrow 
parameter was  FLC, a ≥ 50% decrease in the 
difference between involved and uninvolved 
FLC  
levels  or a 50% decrease in level of involved 
FLC with 50% decrease in ratio  
• If the bone marrow was only measurable 
parameter, ≥ 50% reduction in bone marrow 
plasma cells is required in place of M-protein,  
provided baseline percentage was ≥ 30%  
• In addition to the above criteria, if  a 
plasmacytoma is present at baseline, ≥  
50% reduction in the size of soft tissue 
plasmacytomas is also required. 
 


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Stable Disease (SD) 
Not meeting criteria for CR, VGPR, PR or PD 
 
Progressive Disease (PD) 
Increase of 25% from lowest response value in 
any of the following: 
• Serum M-component (absolute increase must 
be > 0.5 g/dL), and/or 
• Urine M-component (absolute increase must 
be > 200mg/24 h), and/or 
• Only in patients without measureable serum 
and urine M-protein levels: the difference 
between involved and uninvolved FLC levels 
(absolute increase must be > 10mg/dL) 
• Only in patients without measureable serum 
and urine M protein levels and without 
measurable disease by FLC levels, bone marrow 
PC percentage (absolute percentage must be 
10%) 
• Definite development of new bone lesions or 
soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft 
tissue plasmacytomas 
• Development of hypercalcemia (corrected 
serum calcium > 11.5 mg/dL) that can be 
attributed solely to the PC proliferative disorder 
 
 
 


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APPENDIX C:  FOLLOW UP FORM 
Submit this form electronically to ljcosta@uabmc.edu   and pamdixon@uab.edu for patients in the 
follow up phase at least once a year (due 12 months from entering follow up phase or 12 months from 
last report) or every time there is progression, initiation of new anti-myeloma therapy, death or 
completion of MRD testing performed as part of routine care of the patient. 
 
Subject identifier: __ __ __ - __ __ 
 
Date of submission: ___/___/___ 
 
 
Patient status at time of submission: 
 
(  ) Alive 
(  ) Dead. Date of death _________________ 
 
Did patient experience IMWG-defined disease progression: 
 
(  ) No 
(  ) Yes. Date of progression _________________ 
 
 
Did patient have any ClonoSEQ® MRD evaluation (performed as part of routine care of the patient) 
since entering follow up phase or since last form submitted 
 
(  ) No 
(  ) Yes. Please submit deidentified report to ljcosta@uabmc.edu and pamdixon@uab.edu 
 
 
Patient current anti-MM therapy status 
 
(  ) None, on observation 
(  ) On lenalidomide maintenance, starting date _________________ 
(  ) On lenalidomide, initiated due to resurgence of MRD, starting date _________________ 
(  ) On another drug/combination, initiated due to resurgence of MRD 
 
Starting date _________________; Regimen ________________ 
(  ) On another drug/combination, initiated due to Progression 
 
Starting date _________________; Regimen ________________ 
(  ) Not applicable, patient deceased.