Phase II Trial of Daratumumab for Transplant-Eligible Multiple Myeloma Patients
Phase: PHASE2
Conditions: Plasma Cell Myeloma
Sponsor: Mayo Clinic

 
 
 
 
 
MC1785 / 17-004126 
 
 
Phase II Trial of Daratumumab for Transplant-Eligible Multiple 
Myeloma Patients 
 
 
NCT03477539 
 
 
Document Date: 01/12/2022 

1 
 
 
 
 
Protocol Version Date: 12Jan2022 
 
 
Mayo Clinic Cancer Center 
 
MC1785: Phase II Trial of Daratumumab for Transplant-Eligible Multiple Myeloma Patients 
 
 
 
Study Chairs: 
Sikander Ailawadhi, MD 
Mayo Clinic 
4500 San Pablo Rd 
Jacksonville, FL 32256 
904 953 6468 
 
Aneel Paulus, MD 
Mayo Clinic 
4500 San Pablo Rd 
Jacksonville, FL 32256 
904 953 2607 
 
Study Co-chairs: 
Asher Chanan-Khan, MD 
Vivek Roy, MD 
Sonikpreet, MD 
 
Statistician: 
Gabriela Perez Burbano MS√ 
 
√Study contributor(s) not responsible for patient care 
 
Drug Availability 
Commercial Agents: Daratumumab, Lenalidomide 
Drug Company Supplied: None 
 
 
 
 
Document History 
(Effective Date) 
Activation 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
April 9, 2018 
June 13, 2018 
October 30, 2018 
July 24, 2019 
May 7, 2020 
Amendment 5 
Amendment 6 
Amendment 7 
June 22, 2020 
October 06, 2020 
December 01.2020 
Amendment 8 
Amendment 9 
 
February 26, 2021 
  Pending 
 
 
 
 
 

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Protocol Version Date: 12Jan2022 
 
 
Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Heidi Ganz , Quality Assurance Specialist II 
Phone: 507-293-1465 
Email: Ganz.Heidi@mayo.edu  
Drug administration, infusion pumps, 
nursing guidelines 
Lisa Kottschade, RN 
Phone: 507-284-0207 
Email: kottschade.lisa@mayo.edu 
Forms completion and submission 
Dustin Chapin 
Phone: 904-953-3768 
Email: Chapin.Dustin@mayo.edu 
Protocol document, consent form, 
regulatory issues 
Nichole Plouffe, Senior Research Protocol 
Specialist 
Phone: 904-953-8030 
Email: sanders.jessica1@mayo.edu 
Serious Adverse Events 
Patricia G McNamara, SAE Coordinator 
Phone: 507-266-3028 
E-mail: mcnamara.patricia@mayo.edu 
*No waivers of eligibility 

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Protocol Version Date: 12Jan2022 
 
 
Table of Contents 
Phase II Trial of Daratumumab for Transplant Eligible Multiple Myeloma Patients 
1 
Protocol Resources 
3 
Table of Contents 
4 
Study Schema 
5 
1.0 
Background 
7 
2.0 
Goals 
10 
3.0 
Patient Eligibility 
12 
4.0 
Test Schedule 
14 
5.0 
Grouping Factor: 
18 
6.0 
Registration/Randomization Procedures 
18 
7.0 
Protocol Treatment 
20 
8.0 
Dosage Modification Based on Adverse Events 
21 
9.0 
Ancillary Treatment/Supportive Care 
27 
10.0 
Adverse Event (AE) Reporting and Monitoring 
28 
11.0 
Treatment Evaluation 
40 
12.0 
Descriptive Factors 
47 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
47 
14.0 
Body Fluid Biospecimens 
49 
15.0 
Drug Information 
49 
16.0 
Statistical Considerations and Methodology 
57 
17.0 
Pathology Considerations/Tissue Biospecimens 
57 
18.0 
Records and Data Collection Procedures 
63 
19.0 
Budget 
64 
20.0 
References 
65 
Appendix I 
ECOG Performance Status Scale 
67 
Appendix II 
Creatinine Clearance (CrCl) Calculation 
68 
Appendix III 
New York Heart Association Classification of Congestive Heart Failure 69 
Appendix IV 
Mayo Risk Stratification 
70 
Appendix V 
Patient Medication Diary 
71 

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Protocol Version Date: 12Jan2022 
 
 
 
Registration 
Being Considered for Stem Cell Transplant with detectable MRD in bone marrow 
 
 
Day 100* 
 
 
Event Monitoring 
Treatment Cycle 3 (or 5†) (Consolidation 2)* 
Autologous Stem Cell Transplant** 
Treatment Cycles 1-2 (or 1-4†) (Consolidation 1)* 
Daratumumab: IV or injection Q week X 2 cycles** 
Daratumumab: IV or injection Q 2 week X 2 cycles (optional in 
order to accommodate unexpected delays in transplant) 
Treatment Cycles 16 (or 18†) and Beyond (Maintenance) 
Daratumumab IV or injection Q 3 months till disease progression or unwanted adverse 
Treatment Cycles 4-15 (or 6-17†) (Maintenance)* 
Lenalidomide: 10 mg PO daily Days 1-21 
Daratumumab: IV or injection Q monthly X 12 
*MRD Assessment (Day 100 or before the start of Maintenance if patient receives optional consolidation treatments) : 
Peripheral Blood (Next Generation Sequencing; NGS): Prior to cycle 1, 3 (or 5 in case cycles 3 and 4 given), at Day 100, prior to 
cycle 8, 12, 16, 18, 20 (or cycle 10, 14, 18, 20, 22 in case cycles 3 and 4 given) 
Bone Marrow (Multiparameter Flow Cytometry; MPF and NGS): Prior to cycle 1, 3 (or 5 in case cycles 3 and 4 given), at Day 100, 
prior to cycle 16 (or 18 in case cycles 3 and 4 given) 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
At any time: 
Disease progression/Intolerable adverse events/Patient Refusal 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
**Cycle 1 (to 3, as the case may be for that patient) = 28 days (4 weeks) 
Cycle 2 (or 4, as the case may be for that patient) = Up to 84 days (4 weeks treatment + window period up to 8 
weeks between Consolidation 1 and ASCT) 
Cycle 3 =Up to 124 days (Day 100 visit of ASCT occurs 90-110 days after ASCT + window period up to 14 days 
between Day 100 visit and start of Maintenance) 
Cycles 4-15 (or 6-17, as the case may be for that patient) = 28 days (4 weeks) 
Cycles 16 and beyond (or 18 and beyond as the case may be) = 90 days (3 months) 
†In case patient given cycle 3 and 4 optional treatment in consolidation 1, the subsequent cycle numbers will be 
adjusted accordingly. 

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Protocol Version Date: 12Jan2022 
 
Confirmation of PD is not required. However, treatment may be discontinued for progressive disease that is 
unconfirmed per physician discretion. In this case, an objective status of PD should be entered on the measurement 
form and progressive disease should be reported on the event monitoring form. 
 
 
Generic name: Daratumumab 
Brand name(s): Darzalex® 
Mayo Abbreviation: Dara 
Availability: Commercial 
Generic name: Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: REVLIMID 
Availability: Commercial 

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Protocol Version Date: 12Jan2022 
 
 
1.0 
Background 
1.1 
Multiple Myeloma 
Multiple myeloma (MM) is a malignant disorder of the plasma cells, characterized by 
uncontrolled and progressive proliferation of a plasma cell clone. The disease leads to 
progressive morbidity and eventual mortality by lowering resistance to infection and 
causing significant skeletal destruction (with bone pain, pathological fractures, and 
hypercalcemia), anemia, renal failure, neurological complications and hyper viscosity 
syndrome. 
 
The majority of patients with MM produce a monoclonal protein, also called paraprotein, 
M-protein or M-component, which is an immunoglobulin (Ig) or a fragment of one that 
has lost its function.1,2 Normal immunoglobulin levels are compromised, leading to 
susceptibility of infections. The proliferating MM cells displace the normal bone marrow 
leading to dysfunction in normal hematopoietic tissue and destruction of the normal bone 
marrow architecture, which is reflected by clinical findings such as anemia, paraprotein 
in serum or urine, and bone resorption seen as diffuse osteoporosis or lytic lesions shown 
in radiographs.3 Furthermore, hypercalcemia, renal insufficiency or failure, and 
neurological complications are frequently seen.4 A small minority of patients with MM 
are non-secretory. 
 
At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that 
varies on the basis of both disease- and host-related factors (e.g., age, renal function, 
stage, chromosomal abnormalities). Multiple myeloma causes significant morbidity and 
mortality. It accounts for approximately 1% of all malignancies and 13% of hematologic 
cancers. Approximately 50,000 patients per year are diagnosed with multiple myeloma in 
the EU and US, and 30,000 patients per year die due to multiple myeloma. 
 
1.2 
Treatment for Multiple Myeloma 
Treatment choices for MM vary with age, performance status, comorbidity, the 
aggressiveness of the disease, and related prognostic factors.5 Newly diagnosed patients 
with MM are typically categorized into 2 subpopulations usually defined by their age and 
suitability for the subsequent approach to treatment. Younger patients will typically 
receive an induction regimen followed by consolidation treatment with high-dose 
chemotherapy and autologous stem cell transplantation (ASCT). For those not considered 
suitable for high-dose chemotherapy and ASCT, longer-term treatment with multi-agent 
combinations including alkylators, high-dose steroids, and novel agents are currently 
considered as standards of care. 
 
Over the past few years several novel treatments (immunomodulatory drugs; IMiDs and 
proteasome inhibitors) have become available for patients with MM. Although higher 
percentages of patients are achieving remission, all patients eventually relapse and 
become resistant to therapy. Novel agents and new combinations regimens are needed for 
improved outcome in this disease. There is an increasing body of evidence suggesting 
that clinical or laboratory parameters may be important in selecting specific treatment 
options for patients with MM.5 This is further important since the novel agents being 
used for the treatment of MM have their own inherent side effect profiles that are unique 
and need specific management as against the more expected adverse events from 
conventional chemotherapeutic agents. This is especially true in elderly patients who may 

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Protocol Version Date: 12Jan2022 
 
 
have other comorbidities, since the median age at diagnosis for MM is 70 years. Thus, 
there is a constant need to develop newer, better-tolerated agents/regimens that can keep 
the disease controlled for prolonged durations as well as be safe with respect to low 
cumulative toxicities. 
 
1.3 
Role of Daratumumab in Multiple Myeloma 
Daratumumab is an immunoglobulin G1 kappa (IgG1k) human monoclonal antibody 
(mAb) that binds to a unique CD38 epitope on CD38-expressing cells with high affinity. 
It was developed by the immunization of human immunoglobulin transgenic mice with 
recombinant CD38 protein.6 CD38 is a 46-kDa type II transmembrane glycoprotein that 
is highly expressed on MM cells.7 CD38 has various mechanisms including 
ectoenzymatic activity, receptor-mediated regulation of cell adhesion and signal 
transduction.8 Preclinical studies have shown that daratumumab induces MM cell death 
through several mechanisms, including complement-dependent cytotoxicity (CDC), 
antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular 
phagocytosis (ADCP), and FcR mediated-crosslinking inducing apoptosis.6 In a 
combined analysis of GEN501 and SIRIUS studies including 148 patients, the Overall 
Response Rate (ORR) was 31 %, and at a median follow-up of 14.8 months, the 
estimated Overall Survival (OS) was 19.9 months.9 These trials demonstrated that 
daratumumab is active as monotherapy in patients with heavily pre-treated and 
relapsed/refractory myeloma (RRMM) alongside maintaining its anti-myeloma activity in 
previously treatment refractory patients as evident by ORR 33 and 29.7 % in GEN501and 
SIRIUS, respectively.9 Preclinical studies have shown that Daratumumab in combination 
with other agents enhances the antimyeloma activity and now there are reported multiple 
phase II /III trials to study the same. These include data from the CASTOR and POLLUX 
trials of the combination of daratumumab and dexamethasone with bortezomib and 
lenalidomide, respectively, showing enhanced efficacy of these regimens in patients with 
early relapsed MM (2nd or 3rd line) and low minimal residual disease (MRD) states 
leading to the FDA approval of these regimens.10,11 
 
1.4 
Role of ASCT and Post-ASCT Maintenance Therapy in Multiple Myeloma 
ASCT is the standard of care in transplant-eligible MM patients based on several phase 
III trials and meta-analyses depicting significant improvement in progression free 
Survival (PFS), CR, and OS.12 Attal et al in IFM-90 trial reported superior outcomes of 
high-dose chemotherapy (HDC) followed by ASCT compared to conventional 
chemotherapy alone, with improved OS (57%), CR (22%) and event-free survival (EFS) 
(16%), and median OS 57 months versus 44 months.13 The majority of post-ASCT 
patients relapse with median PFS around 36 months. Relapses are harder to treat and 
prognosis gets worse with each relapse. Multiple studies have suggested a survival 
advantage from attaining a deeper response to induction chemotherapy and ASCT, and 
sustained CR was shown to be a surrogate for OS in MM population.13,14 The clinical 
significance of MRD negativity using highly sensitive methods has been reviewed and 
goal of MRD is to stratify the risk and evaluate the response to novel agents.15 Despite 
remarkable improvement in treatment outcome in MM with the use of IMiDs and novel 
agents, it remains an incurable disease. Multiple studies in the last few years have 
examined the role of consolidation and/or maintenance to eliminate MRD after HDC- 
ASCT in MM. Post-ASCT consolidation and/or maintenance strategies have been studied 
in multiple trials including single and combination agents including interferon-alpha, 

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Protocol Version Date: 12Jan2022 
 
glucocorticoids, thalidomide, lenalidomide, bortezomib and combination regimens to 
determine compare PFS and OS to improve long term outcomes.16 
 
1.5 
Minimal Residual Disease (MRD) in Multiple Myeloma 
CR is defined as disappearance of clonal plasma cells in the bone marrow, and absence of 
paraprotein in urine and serum by immunofixation. Stringent CR (sCR) as defined by 
International Myeloma Workshop includes above mentioned paramenters along with a 
normal kappa/lambda free light chain ratio.17 Molecular CR (mCR) defined as absence of 
detectable disease by polymerase chain reaction (PCR) for Ig gene rearrangement was 
associated with prolonged PFS and OS in allogeneic transplant patients and this extent of 
response was not achieved in autologous transplant patients.17 With the use of novel 
therapies, there was necessity to develop sensitive assays to detect and monitor MRD that 
will have prognostic implication in PFS and OS to compare between different 
consolidation and/or maintenance agents. Various methods include allele-specific 
oligonucleotide PCR (ASO-PCR), next-generation sequencing (NGS) and multiparameter 
flow cytometry (MPF) capable of detecting 1 clonal cell in 106 and 1 clonal cell in 104 
normal cells, respectively.17 In a study of 102 MM patients, a comparison of CR detection 
by negative immunofixation (CR), normal serum free light chain ratio (sCR), and 
undetectable myeloma cells by MPF (immunophenotyping CR-iCR) treated with novel 
agents showed that 43% patients achieved CR, 30% achieved sCR, and 30% achieved 
iCR. Patients in iCR showed significantly improved PFS and TTP as compared to sCR 
versus CR with no significant survival difference between sCR versus CR patients.18 In 
this study ASO-PCR and MPF were able to detect MRD in 17 and 11 patients, 
respectively. PFS for those patients without versus with MRD detected by ASO-PCR was 
34 versus 15 months, respectively (P=.04) and by MPF was 27 versus 10 months, 
respectively (P=.05). In order to predict unsustained CR, a study was conducted in 241 
patients in CR at Day-100 after ASCT.19 It was found that presence of baseline high-risk 
cytogenetics by fluorescent in situ hybridization (HR 17.3; P<.01), and persistent MRD 
by MPF at day-100 after ASCT (HR 8.0; P<.01) were the only independent factors that 
predicted for unsustained CR and a poor outcome with a median OS of 39 months. 
Another study assessed MRD using MPF in post-induction and at day-100 post SCT as 
well as post-induction in transplant ineligible patients.20 This study demonstrates clinical 
utility of MPF as the patients with MRD had inferior outcomes as compared to those 
without detectable MRD. The same study also showed that maintenance therapy benefits 
the patients with MRD negativity and also can convert patients to MRD negative status. 
MRD may serve as a biomarker to inform MM therapy and MRD negativity becomes a 
goal of future studies. 
 
1.6 
Rationale of Daratumumab as a Consolidation Therapy before SCT and Maintenance 
Therapy in Post-SCT Settings for MRD Assessment 
Our primary endpoint is to determine the percentage of patients with MRD negativity at 
Day 100 post SCT and at post-maintenance treatment for 1 year. Phase II multicenter 
single arm study was conducted in 10 IFM centers in France in 2009 to evaluate response 
after lenalidomide, bortezomib and dexamethasone (RVD) induction followed by SCT 
followed by 2 RVD consolidations and 1-year lenalidomide maintenance in 31 untreated 
transplant eligible MM patients.21 At the time of consolidation, 97% achieved PR, 87% at 
least VGPR, including 50% who achieved CR and among 26 evaluable patients, 15 
(58%) were MRD negative. They evaluated MRD by bone marrow aspirate at post- 
induction/pre-ASCT, post-ASCT, post-consolidation and end of treatment regardless of 

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Protocol Version Date: 12Jan2022 
 
 
response. With lenalidomide, 5 patients experienced MRD improvement and after all 
treatment sequences, 21 patients (68%) achieved MRD negativity. Overall, there were 
high response rates and depth of response increased over the course of the transplantation 
program. Rate of VGPR increased from 58% after induction to 70% and 87% after 
transplant and consolidation, respectively. 1-year lenalidomide maintenance further 
improved MRD negativity. 3-year PFS was 100% for MRD negative patients. Further 
studies evaluated that MRD negativity is a major prognostic factor for clinical outcome 
and MRD negativity should be the goal for treatment of ASCT eligible patients in MM.21- 
24 Another study was conducted in 241 MM patients in 2 PETHEMA/GEM trials, 
GEM2000 (VBMCP [vincristine, carmustine, doxorubicin and dexamethasone followed 
by HDT/SCT and 2-year IFN and prednisone maintenance; n=140) and GEM-2005 <65 y 
(randomized induction with the same chemotherapy plus bortezomib in the last 2 cycles 
or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by 
HDT/SCT and 3-year maintenance with IF-2alphab or thalidomide or 
thalidomide/bortezomib; n= 101).19 TTP (median 71 months) and OS (71% at 5 years) 
were longer in CR patients than in less than CR patients at Day-100 after HDT/SCT 
(TTP; median 47 months and OS: 60% at 5 years). Multivariate analysis showed that the 
best predictive parameters for TTP were immunophenotypic CR status (MRD by MFC) 
and FISH cytogenetics. 16% of CR patients had high-risk disease and showed a 
significantly inferior TTP (3 years, 40% vs. 80%) and borderline OS (3 years, 73% vs. 
96%) compared with standard risk patients. Persistent MRD in 87 (36%) out of 241 CR 
patients showed significantly inferior TTP (3 years 58% vs. 86%) and OS (3 years 80% 
vs. 90%). They further explored clinical impact of the immunophenotypic CR in standard 
and high-risk disease. Best prognosis was for patients with both standard-risk 
cytogenetics and achievement of immunophenotypic CR (3 years: TTP 94%, OS 100%), 
whereas worse outcome occurred in both high-risk disease and persistent MRD (3 years: 
TTP 0%, OS 32%). Of 241 patients, 29 (12%) were in unsustained CR within 1 year had 
persistent MRD by MFC (66% vs. 32%) as compared with the remaining patients. 
 
 
1.7 
Trial Design 
This will be a phase II, open label, prospective clinical trial in MM patients with any 
induction treatment, who are considered eligible for an SCT and have detectable MRD. 
So far there have not been any clinical trials to determine the effect of daratumumab on 
MRD as a consolidation therapy in pre-ASCT setting and as maintenance therapy in post- 
ASCT setting. The reason to include patients with MM who have received any induction 
is that the aim of this trial is to assess the efficacy of daratumumab in the pre- and post- 
ASCT settings in improving the MRD-status of patients. Treatment dose in the 
maintenance portion (daratumumab+lenalidomide) will be fixed based on other prior 
clinical trials using this combination. 
 
2.0 
Goals 
2.1 
Primary Objective: 
To determine the percentage of patients achieving MRD negativity by MPF after 
autologous stem cell transplant (SCT) (at Day 100) using pre-SCT daratumumab 
consolidation. 
2.2 
Secondary Objectives: 

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Protocol Version Date: 12Jan2022 
 
2.21 
To determine percentage of patients achieving MRD negativity by MPF after 1 
year of daratumumab+lenalidomide-based maintenance therapy. 
2.22 
To determine progression-free survival (PFS) for peri-SCT treatment with 
daratumumab. 
2.23 
To determine percentage of MRD negativity by MPF after pre-SCT consolidation 
with daratumumab. 
2.24 
To determine safety profile of peri-SCT daratumumab with lenalidomide. 
2.25 
To determine the overall response rate (ORR) of patients receiving peri-SCT 
daratumumab for MM. 
2.26 
To determine the overall survival (OS) for patients receiving peri-SCT 
daratumumab for MM. 

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Protocol Version Date: 12Jan2022 
 
 
 
3.0 
Patient Eligibility 
3.1 
Inclusion Criteria 
3.11 
Age ≥18 years and considered transplant eligible. 
3.12 
Diagnosis: Pathologically confirmed diagnosis of multiple myeloma who are 
transplant eligible and have received any prior induction therapy (with or without 
maintenance). 
3.13 
Measurable MRD in bone marrow within 28 days prior to registration (MPF 
method) 
 
3.14 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix I) at registration. 
 
3.15 
The following laboratory values obtained ≤14 days prior to registration: 
• 
Absolute neutrophil count (ANC) ≥1,000 cell/mm3 without growth factor 
support 
• 
Platelets ≥50,000 cells/mm3 for patients who have bone marrow 
plasmacytosis <50% or ≥30,000 cells/mm3 for patients who have bone 
marrow plasmacytosis of ≥50% 
• 
Calculated or measured creatinine clearance ≥30 ml/min (see Appendix II) 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert’s 
syndrome, in which case the direct bilirubin must be ≤1.5 X ULN. 
• 
Aspartate aminotransferase (AST)/SGOT and alanine aminotransferase 
(ALT)/SGPT ≤3 x ULN 
• 
PT/INR ≤1.5 X ULN 
• 
Negative Urine or serum pregnancy test for women of childbearing potential. 
NOTE: Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program. 
 
3.16 
Provide informed written consent. 
 
3.17 
Measureable disease of multiple myeloma as defined in section 11.1 at the time 
specified by one of the following: 
• 
If no relapse prior to transplant, values obtained at the time of diagnosis 
• 
If disease relapse prior to transplant and the patient did not have treatment for the 
relapsed disease prior to transplant, the values obtained at the time of relapse 
immediately prior to the transplant. 
• 
If disease relapse prior to transplant and the patient did have treatment for the 
relapsed disease prior to transplant, the values obtained prior to this therapy, ie, 
the time of relapse. 
 
3.2 
Exclusion Criteria 
3.21 
Any previous ASCT for MM. EXCEPTION: Patient had autologous stem cell 
transplant > 3 years ago without any related adverse events. (NOTE: Patient may 
have had prior stem cell collection before registration on the study) 
 
3.22 
Any prior therapy with daratumumab 

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Protocol Version Date: 12Jan2022 
 
3.23 
Non-secretory MM or known AL amyloidosis 
 
3.24 
Clinically significant active infection requiring intravenous antibiotics (≤14 days 
prior to registration). 
 
3.25 
≥Grade 3 neuropathy and/or POEMS syndrome (plasma cell dyscrasia with 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes). 
 
3.26 
Other prior malignancy. 
EXCEPTIONS: 
• 
Adequately treated basal cell or squamous cell skin cancer 
• 
Any in situ cancer 
• 
Adequately treated Stage I or II cancer from which the patient is currently in 
complete remission, or 
• 
Any other cancer from which the patient has been disease free for at least 
three years 
 
3.27 
Concurrent therapy considered investigational. 
NOTE: Patients must not be planning to receive any radiation therapy (except 
localized radiation for palliative care that must be completed prior to starting 
Cycle 1, Day 1). 
 
3.28 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women (lactating females are eligible provided that they agree not to 
breast feed while taking lenalidomide) 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.29 a 
Major surgery ≤4 weeks prior to registration. 
 
3.29b History of stroke/intracranial hemorrhage ≤6 months prior to registration. 
 
3.29c 
Clinically significant cardiac illness including New York Heart Association 
(NYHA) Class III or Class IV heart failure (Appendix III), unstable angina 
pectoris, myocardial infarction within the past 6 months, or ≥Grade 3 cardiac 
arrhythmias noted ≤ 14 days prior to registration. 
 
 
3.29d Known HIV+ patients 
 
3.29e 
Known Hepatitis B or Hepatitis C infection. 
 
3.29f 
Exhibiting clinical signs of meningeal involvement of multiple myeloma. 
 
3.29g Known severe chronic obstructive pulmonary disease or asthma defined as forced 
expiratory volume (FEV1) in 1 second less than <60% of expected. 

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Protocol Version Date: 12Jan2022 
 
 
 
4.0 
Test Schedule 
4.1 
Test schedulea 
 
 
 
 
 
Tests and Procedures 
≤28 days 
prior to 
registration 
≤14 days prior 
to registration 
Cycle 
1, Day 
1 
Cycle 1, 
Day 15 
Cycle 2 
(to 4†), 
Day 1 
Cycle 2 (or 
4†): 
≤14 days prior 
to ASCT 
Cycle 3 (or 5†): 
Day 100 visit of 
ASCT 
(occurs 90-110 days 
after ASCT) 
Cycle 4 (or 
6†) and 
beyond (end 
of each cycle) 
End of Treatment 
Complete medical and 
disease history 
 
X 
 
 
X 
X 
X 
X 
 
Physical examinationb 
 
X 
 
 
X 
X 
X 
X 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
 
 
Performance status 
(ECOG scale)(Appendix 
1) 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
CBC with differential 
 
X 
Xc 
X 
X 
X 
X 
X 
X 
Type and Screen 
 
 
X 
 
 
 
 
 
 
Prothrombin time (PT) 
and INR 
 
X 
Xc 
X 
X 
X 
X 
 
 
Blood chemistries: 
sodium, chloride, 
potassium, magnesium, 
phosphate, uric acid, 
BUN, glucose, ALT/AST 
(SGPT/SGOT), alkaline 
phosphatase, total protein, 
Direct bilirubin, total 
bilirubin, albumin, serum 
creatinine, and estimated 
creatinine clearance 
(Appendix II), calcium 
and lactate dehydrogenase 
(LDH) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Xc 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 

15 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
 
 
Tests and Procedures 
≤28 days 
prior to 
registration 
≤14 days prior 
to registration 
Cycle 
1, Day 
1 
Cycle 1, 
Day 15 
Cycle 2 
(to 4†), 
Day 1 
Cycle 2 (or 
4†): 
≤14 days prior 
to ASCT 
Cycle 3 (or 5†): 
Day 100 visit of 
ASCT 
(occurs 90-110 days 
after ASCT) 
Cycle 4 (or 
6†) and 
beyond (end 
of each cycle) 
End of Treatment 
Bone marrow 
aspirate/biopsy with 
standard testing (including 
but not limited to 
myeloma FISH and flow 
cytometry) d 
 
X 
 
 
 
 
 
 
Xd 
 
 
X 
 
 
X 
 
Bone marrow MRD 
Assessment by MPF, d 
X 
 
 
 
 
X 
X 
X 
 
Peripheral blood MRD 
testinge 
X 
 
 
 
 
X 
X 
X 
 
Electrophoresis of serum 
and urine (SPEP/UPEP) 
 
X 
 
 
Xl 
Xl 
Xl 
Xl 
X* 
*Serum immunoglobulinsd  
X 
 
 
X 
X 
X 
X 
X* 
*Immunofixation serum 
and urine (IF) 
 
X 
 
 
X 
X 
X 
X 
X* 
*Immunoglobulin free 
light chain (FLC) 
 
X 
 
 
X 
X 
X 
X 
X* 
*Serum β2-microglobulin  
X 
 
 
 
 
 
 
 
Skeletal bone survey 
 
X 
 
 
 
 
 
 
 
PET scang  
X 
 
 
 
 
 
 
X 
 
Adverse Event 
monitoringf 
 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy teste 
 
X 
 
 
 
 
 
X 
 
Registered in the 
REVLIMID REMS™ 
programh 
 
 
 
 
 
 
 
X 
 
 
Pill Diaryi 
 
 
 
 
 
 
 
X 
 
 
Cycle 1 (to 3, as the case may be for that patient) = 28 days (4 weeks) 
Cycle 2 (or 4, as the case may be for that patient) = Up to 84 days (4 weeks treatment + window period up to 8 weeks between Consolidation 1 and ASCT) 
Cycle 3 (or 5, as the case may be for that patient) = Up to 124 days (Day 100 visit of ASCT occurs 90-110 days after ASCT + window period up to 14 days 
between Day 100 visit and start of Maintenance) 
Cycles 4-15 (or 6-17, as the case may be for that patient) = 28 days (4 weeks) 
Cycles 16 and beyond (or cycle 18 and beyond, as the case may be for that patient) = 90 days (3 months) 

16 
 
Protocol Version Date: 12Jan2022 
 
 
 
†In case patient given cycle 3 and 4 optional treatment in consolidation 1, the subsequent cycle numbers and Day 100 ASCT visit will be adjusted accordingly. 
 
All tests and procedures are clinically indicated, unless noted with an R to indicate funding by research 
a) All scheduled visits will have a window of ±3 days, Cycle 1, Day 1, unless otherwise stated, all procedures to be completed within 3 days prior to 
commencing subsequent treatment cycle. (±3 days does not apply to daratumumab treatment in cycles 1-4; consolidation 1) 
b) To include blood pressure, pulse rate, temperature, weight. Height to be documented ≤14 days prior to registration 
c) Labs are not required to be repeated if done ≤14 days prior to registration. 
d)  Standard of care procedure: Prior to Cycle 1, pre-ASCT, at Day 100, prior to Cycle 16 or if considered clinically indicated at any other time during the 
study. Bone marrow biopsy during cycle 2 can be done any tiem between days 28 and 84. 
e) To coincide with standard of care blood sample collection at: Prior to Cycle 1, pre-ASCT, at Day 100, prior to cycles 8, 12, 16, 18, and 20. NOTE: To 
coincide with the day of MRD testing by bone marrow biopsy, if occurring at that time point. 
f) 
Serum immunoglobulins to include IgG, IgA and IgM for all patients and IgD or IgE where clinically indicated. NOTE: bone marrow testing prior to 
registration must be after the last anti-myeloma treatment but ≤ 28 days of registration. 
g) A PET scan should be done within 28 days prior to registration, prior to Cycle 16 treatment and whenever else considered clinically necessary. PET 
scan done when CR considered to assess imaging response. 
h) During treatment period, at end of treatment visit. The patient should be contacted by a nurse 30 days after the last dose of study treatment (or at the 
time of initiation of subsequent treatment if started before 30 days) to check if the patient has experienced any late adverse events. Grade 3 or higher 
adverse events at least possibly related to study treatment and deaths due to any cause should be reported as a late adverse event on the Survival and 
Disease Status Follow-Up/Event Monitoring form if they were not already reported on the Adverse Event form for the last cycle and they occurred prior 
to any subsequent treatment and 30 days post-end of treatment 
i) 
For females of childbearing potential, a negative pregnancy test (urine or serum) must be documented within 14 days of starting treatment on the study 
and for patients starting Cycle 4 (daratumumab+lenalidomide) in accordance with the REVLIMID REMSTM program. A female of childbearing 
potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
j) 
Patients starting Cycle 4 treatment (daratumumab+lenalidomide) prior to starting treatment with REVLIMID 
k) To be collected at the end of every cycle of maintenance therapy while the patient is receiving lenalidomide 
l) 
UPEP testing required at baseline only. Subsequent testing will be as needed per physician discretion.  
*Repeat Electrophoresis of serum and urine, Serum immunoglobulins, Immunofixation serum and urine, and Immunoglobulin free light chain only if the 
assessments were not completed 14 days prior to End of Treatment visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Version Date: 12Jan2022 
 
4.2 
Event Monitoring/Survival Follow-up 
 
 
Event Monitoring Phase1 
Q 3 months until 
PD or subsequent 
treatment 
At PD 
or subsequent 
therapy 
After PD or 
subsequent therapy 
Q 6 months 
 
 
Death 
 
 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
  
 
1. 
If a patient is still alive 3 years after registration, no further follow-up is required 

18 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
 
5.0 
Grouping Factor: 
None 
6.0 
Registration/Randomization Procedures 
6.1 
Registration Procedures 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at (507) 284- 
2753 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://ccswww.mayo.edu/training/) and detail the process 
for completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions. It is the responsibility of 
the individual and institution registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Prior to accepting the registration, registration/randomization application 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 
 
6.13 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 507-284-0885). If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 

19 
 
Protocol Version Date: 12Jan2022 
 
 
 
6.14 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a medical oncologist/hematologist. 
 
6.15 
Treatment cannot begin prior to registration and must begin ≤ 28 days after 
registration. 
 
6.16 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.17 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
 
6.18 
Study drug is available on site. 

20 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
7.0 
Protocol Treatment 
Daratumumab may be administered within ±1 day of the scheduled dose if there are any logistical 
challenges (holiday, patient transport or other logistics, scheduling availability, etc.) 
7.1 
Treatment Schedule 
7.11 
Consolidation 1 (Cycles 1-2 or 1-4, as the case may be for that patient) 
 
 
Agent 
Dose 
Route 
Day 
Cycles 
Daratumumab 
16 mg/Kg* (IV) 
1,800 mg (Injection) 
IV or injection 
1, 8, 15, 22 
Cycle 1-2 
Daratumumab 
16 mg/Kg* (IV) 
1,800 mg (injection) 
IV or injection 
1, 15 
Cycle 3-4 
Cycle 1 (to 3, as the case may be for that patient) length = 28 days; 
Cycle 2 (or 4, as the case may be for that patient) length = up to 84 days (4 weeks 
treatment + window period up to 8 weeks between Consolidation 1 and ASCT) 
Treatment Window (for patients receiving treatment through a local medical 
doctor)= ±5 days 
*Any dose-adjustments will be made as per the prescriber information. 
Daratumumab administration as per prescriber information and institutional 
guidelines. 
 
7.12 
Consolidation 2 (Cycle 3 or 5, as the case may be for that patient) 
• 
All patients enrolled in the trial after completing consolidation 1 treatment 
will proceed to a SCT with Day 0 of SCT within 8 weeks of completing 
cycle 2 (or 4, as the case may be for that patient), Day 28 of consolidation 1. 
• 
Stem cell collection could have been completed prior to initiating 
consolidation 1 or may be performed within the up to 8-week period between 
completion of Cycle 2 (or 4, as the case may be for that patient), Day 28 and 
Day 0 of SCT. 
• 
Consolidation 1 should not be interrupted for the purpose of stem cell 
collection. 
• 
SCT procedures should be completed as per institutional standards. 
• 
Consolidation 2 period will be considered up until the Day 100 visit (±10 
days as per institutional BMT program scheduling). 
• 
Cycle 3 (or 5, as the case may be for that patient) length = Up to 124 days 
(Day 100 visit of ASCT occurs 90-110 days after ASCT + window period up 
to 14 days between Day 100 visit and start of Maintenance) 
7.13 
Maintenance (Cycles 4 and Beyond, or cycle 6 and beyond as the case may 
be for that patient) 
• 
All patients will be initiated on maintenance therapy as below within 14 days of 
completing Day 100 visit post-SCT. 
 
 
Agent 
Dose 
Route 
Day 
Cycles 
 
Daratumumab 
16 mg/Kg* (IV) 
1,800 mg (Injection) 
IV or 
Injecti 
on 
 
1 
Cycle 4-15 
(or 6-17) 
Lenalidomide 
10 mg* 
PO 
1-21 
Cycle 4-15 

21 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
 
 
 
(or 6-17) 
Cycles 4-15 (or 6-17) length = 28 days 
*Any dose-adjustments will be made as per the prescriber information. 
Daratumumab administrations as per prescriber information and institutional 
guidelines. 
Note: Thromboprophylaxis is required as standard of care (see Section 9.3) for 
all patients on maintenance treatment. 
• 
NOTE: Prior to Cycle 16 (or 18), patients who are still maintaining response will 
proceed to maintenance with single-agent daratumumab every 3 months till 
disease progression or unwanted adverse events, if any. Cycles 16 and beyond 
length = 90 days (3 months). 
• 
In the event of disease progression, intolerable adverse event or patient refusal 
for continued therapy, they will proceed to event monitoring without any 
additional anti-MM therapy. 
• 
Considering that there are newer immunotherapy compounds being made 
available for the treatment of multiple myeloma, based on the initial results of 
this clinical trial, amendments may be put in place to add more arms to the study 
with newer, proven safe combination regimens, especially for maintenance 
treatment. 
7.2 
Treatment by a local medical doctor (LMD) allowed. 
When it has been determined that a patient’s malignant disease is stable and the patient is 
tolerating therapy without excessive toxicity at a stable dose level, the patient may continue 
treatment via the patient’s Local Medical Doctor (LMD). The patient will be required to return to 
Mayo Clinic for all study visits. 
7.3 
Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose. Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame and 
documented as clinical sequelae to an overdose. 
There has been no experience of overdosage with daratumumab in clinical studies. Doses 
up to 24 mg/kg have been administered intravenously in a clinical study without reaching 
the maximum tolerated dose. There is no known specific antidote for daratumumab 
overdose. In the event of an overdose, the subject should be monitored for any signs or 
symptoms of adverse effects and appropriate symptomatic treatment be instituted 
immediately. 
Refer to Section 10 for further information regarding AE reporting. 
 
8.0 
Dosage Modification Based on Adverse Events 
Any adverse event noted in the study and its resultant dose-modifications should be managed as 
per the prescribing information of daratumumab and/or lenalidomide as per which of these two 
drugs the adverse event is attributable to. 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
General Considerations: 
a) Missed doses for lenalidomide are to be omitted rather than made up, unless the dose 
was forgotten and remembered on the same day, in which case the dose can be taken 

22 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
that day. Any doses missed on a particular day are not to be made up the next day. 
Doses that are considered to be vomited are not to be made up and a mention about the 
time of dose and time of vomiting episode should be made in the pill diary. 
b) Daratumumab may be administered within ±1 day of the scheduled dose if there are any 
logistical challenges (holiday, patient transport or other logistics, scheduling availability, 
etc.) 
c) If multiple toxicities are experienced, dose modifications will be based on the toxicity 
requiring the largest dose reduction. 
d) Reductions are based on the dose given in the preceding cycle and are based on 
toxicities with an attribution of possible, probable, or definite that were observed since 
the prior toxicity evaluation. 
e) If a drug is omitted due to specific adverse events and the patient is on combination 
therapy (maintenance therapy), the other agents, considered unrelated to the adverse 
event may be continued. 
f) If a patient cannot be administered a dose of daratumumab during Consolidation 1 
(Cycles 1-2 or 1-4, as the case may be for that patient) for >28 days due to adverse 
events or any other reason, the patient should be removed from the study treatment and 
go to event monitoring. (NOTE: Patients on maintenance therapy (cycles 4 and beyond, 
or cycle 6 and beyond as the case may be for that patient) may be continued on 
treatment with single-agent daratumumab or lenalidomide in case the other agent has to 
be permanently discontinued in absence of disease progression. If a patient on 
maintenance treatment must discontinue both, lenalidomide and daratumumab, they 
should be removed from the protocol therapy and proceed to event monitoring. 
8.2 
Lenalidomide Dose Modifications 
 
Lenalidomide 
(Days 1-21) 
Starting dose 
10mg 
-1 
5 mg 
-2 
Discontinue 
 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified  
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 

23 
 
Protocol Version Date: 12Jan2022 
 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count 
decreased 
Grade 4 
Lenalidomide 
*Omit dose until AE has resolved to 
Grade 1 or better 
• Follow CBC weekly 
• If thrombocytopenia <30,000/mm3 
recurs, reduce dose by one dose level 
(by 5 mg) and continue therapy when 
platelet count ≥30,000/mm3 
If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 1 within 4 weeks, then the 
patient may continue on single-agent 
daratumumab till the completion of 
maintenanceand then proceed to 
Event Monitoring 
Neutrophil count 
decreased 
Grade 4 
*Omit dose until AE has resolved to 
Grade 2 or better 
• Follow CBC weekly 
* If neutropenia has resolved to 
≤Grade 2, resume dose at one level 
lower 
*If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 1 within 4 weeks, then the 
patient may continue on single-agent 
daratumumab till the completion of 
maintenance and then proceed to 
Event Monitoring 
Blood and lymphatic 
system disorders 
Anemia 
Grade 4 
*Omit dose until AE has resolved to 
Grade 2 or better 
• Follow CBC weekly 
* If anemia has resolved to ≤Grade 2, 
resume dose at one level lower 
*If, after lenalidomide has been 
omitted, and the AE does not return to 
≤Grade 1 within 4 weeks, then the 
patient may continue on single-agent 
daratumumab till the completion of 
maintenance and then proceed to 
Event Monitoring 
Febrile neutropenia 
≥Grade 3 
• Omit dose and follow CBC weekly 
• If neutropenia has resolved to 
≤Grade 2, resume dose at same level 
with GCSF support (See Section 9.6) 

24 
 
Protocol Version Date: 12Jan2022 
 
 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Cardiac disorders 
Sinus bradycardia/ 
other cardiac 
arrhythmia 
Grade 2 
Lenalidomide 
Omit dose and follow at least weekly 
until resolution 
• If AE resolves to ≤Grade 1, reduce 
dose by one dose level (by 5mg) and 
continue therapy 
≥ Grade 3 
• Discontinue study treatment and go 
to event monitoring 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
• Omit dose and start anticoagulation; 
restart at investigator’s discretion 
(maintain dose level) 
Immune system 
disorders 
Allergic reaction 
Grade 2-3 
• Omit dose and follow at least 
weekly until resolution 
• If AE resolves to ≤Grade 1, reduce 
dose by 5 mg and continue therapy 
Anaphylaxis 
Grade 4 
• Discontinue study treatment and go 
to event monitoring 
Skin and 
subcutaneous tissue 
disorders 
Erythema multiforme 
≥Grade 3 
Discontinue study treatment and go to 
event monitoring 
Skin ulceration 
≥Grade 2 
Discontinue study treatment and go to 
event monitoring 
Other: Non-blistering 
rash Grade 3 
• If Grade 3 omit dose and follow 
weekly until resolution 
• If AE resolves to ≤Grade 2 continue 
therapy 
Other: Non-blistering 
rash Grade 4 
• Discontinue study treatment and go 
to event monitoring 
Other AEs 
Non-hematologic AE 
assessed as related to 
lenalidomide 
≥Grade 3 
• Omit dose and follow at least 
weekly until resolution 
• If the AE resolves to ≤Grade 2, 
implement one dose reduction step 
and continue therapy (per Table 8.2) 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
** Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient does not 
make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does make up 
the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
 
If lenalidomide has been omitted and the toxicity does not return to ≤Grade 2 within 28 days during 
Consolidation 1 (Cycles 1-2), may continue on single-agent daratumumab till the completion of 
maintenance and then proceed to Event Monitoring. 
 
8.21 
Lenalidomide dose adjustment for renal function 

25 
 
Protocol Version Date: 12Jan2022 
 
 
 
Lenalidomide dose will be adjusted as per standard of care guidelines in the prescribing 
information of lenalidomide for multiple myeloma patients. 

26 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
8.3 
Daratumumab Dose Modifications (NOTE: Only if any of the following criteria are met 
and the event cannot be ascribed to lenalidomide or to any other concurrent medication 
that the patient may be on, the daratumumab administration must be held/omitted as 
specified below to allow for recovery from toxicity). 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specied  
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Neutrophil count decreased 
Grade 4 lasting >7 days 
Platelet count decreased 
Grade ≥3 with bleeding 
Daratumumab Hold (Day 1) or Omit (Days 8, 15, or 22) 
Daratumumab** until recovery to Grade ≤2 
or baseline 
May restart at same dose at the next 
planned dosing date. 
Blood and 
lymphatic 
system disorders 
Febrile neutropenia 
≥Grade 3 
Neutropenia with infection, 
of any grade 
 
Hold (Day 1) or Omit (Days 8, 15, or 22) 
Daratumumab** until recovery to Grade ≤2 
or baseline 
May restart at same dose at the next 
planned dosing date. 
Gastrointestinal 
disorders 
Nausea Grade 2 (if 
persistent for >7 days 
despite optimal antiemetic 
therapy) 
Vomiting ≥Grade 3 (if 
persistent for >7 days 
despite optimal antiemetic 
therapy) 
 
Hold (Day 1) or Omit (Days 8, 15, or 22) 
Daratumumab** until recovery to Grade ≤1 
or baseline 
May restart at same dose at the next 
planned dosing date. 
 
Diarrhea ≥Grade 3 (if 
persistent for >7 days 
despite optimal anti- 
diarrheal therapy) 
 
 
Other (Non- 
hematologic)**** 
Any other Grade 4 AE or 
any unmanageable Grade 3 
AE that was present at 
baseline or lasts for >7 days 
after the last administration 
of daratumumab 
 
Hold (Day 1) or Omit (Days 8, 15, or 22) 
Daratumumab** until recovery to Grade ≤1 
or baseline 
May restart at same dose at the next 
planned dosing date. 
Additional Adverse Events: 
** If Daratumumab is omitted in the middle of the cycle and the toxicity resolves, patient 
can re-start the drug but the days of drug treatment missed do not need to be caught-up 
and can be omitted in order to maintain the cycle schedule. 
• 
Dose omission: Daratumumab may be omitted for adverse event considerations 
for a maximum of 28 consecutive days during Consolidation 1 (Cycle 1-2 or 1-4, 
as the case may be for that patient). Patients on maintenance therapy may be 
continued on treatment with single-agent daratumumab or lenalidomide in case 
the other agent has to be permanently discontinued in absence of disease 
progression. If a patient on maintenance treatment must discontinue both, 

27 
 
Protocol Version Date: 12Jan2022 
 
 
 
lenalidomide and daratumumab, they should be removed from the protocol 
therapy and proceed to event monitoring. 
• 
If multiple adverse events are seen, administer dose based on the greatest 
reduction required by any single adverse event observed. 
• 
Dose modifications are for adverse events attributed to study treatment only. 
Dose modifications are not required for adverse events if they are deemed 
unrelated and/or unlikely related to study treatment. 
• 
Reductions apply to treatment given in the preceding cycle and are based on 
adverse events observed since the prior dose. 
**** If cough, dyspnea, and other pulmonary symptoms occur, a chest x-ray and high- 
resolution chest CT scan should be obtained. Incentive spirometry studies (to include 
DLCO) should be considered. Consider Pneumocystis pneumonia or viral pneumonitis. 
Patients who experience a deep vein thrombosis (DVT), pulmonary embolus (PE), or 
other clotting event should have all study drugs temporarily omitted while full-dose 
anticoagulation is initiated (other than warfarin or other Vitamin K antagonist). There 
should not be a delay of more than 28 days in reinitiating the study treatment. 
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction 
at the start of the next cycle, then the dose will remain lowered for that entire remaining 
length of the study treatment. 
NOTE: In the event patient is benefitting from treatment and the delay was 
unrelated to treatment toxicity, patient may remain on study with approval of study 
PI. 
 
 
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full Supportive Care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Bisphosphonates 
Patients may receive concurrent treatment with a bisphosphonate. 
 
9.3 
Thrombophylaxis 
Due to the increased risk of deep vein thrombosis (DVT) for multiple myeloma patients, 
thromboprophylaxis is to be used as standard of care on this regimen according to the 
International Myeloma Working Group guidelines 
(http://jco.ascopubs.org/content/32/6/587.full).25 
 
9.4 
Prohibited medications 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment 
• 
Any cytotoxic chemotherapy 

28 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
· 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy. NOTE: Radiation therapy administered with 
palliative intent to control localized symptoms from MM is permitted provided the 
symptoms are not considered due to disease progression. 
9.5 
Anti-emetics 
Anti-emetics may be used at the discretion of the attending physician 
9.6 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (42) Update of 
Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: Evidence- 
Based, Clinical Practice Guidelines.26 
9.7 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
9.8 
Concomitant medications 
Any systemic, anti-myeloma therapy or steroids other than those prescribed by the 
protocol are prohibited while on protocol therapy. Guidelines for selection and use of 
other concomitant medications should be derived from the lenalidomide and 
daratumumab prescribing information. Other than study medications, administration of 
any therapeutic or diagnostic investigational agent (for any indication) is prohibited while 
on study. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 

29 
 
Protocol Version Date: 12Jan2022 
 
 
 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study 
(please read entire section for specific instructions): 
 
 
WHO: 
WHAT form: 
WHERE to send: 
 
 
All sites 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic 
applications/docs/PregnancyReportFormUpdated.p 
df 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 
 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
http://livecycle2.mayo.edu/workspace/?startEndpoin 
t=MC4158-56/Processes/MC4158-56- 
Process.MC4158-56 
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa 
nualsForms/Forms/UCM048334.pdf 
 
 
 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo.edu 

30 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor). 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4). 
e. Determine if other reporting is required (see Section 10.5). 
 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 

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10.2 
Expected vs. Unexpected Events 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan). 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions. 
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 

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occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0 
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe 
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor 
ms/UCM387002.pdf 
 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event. 
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
 
 
Gastrointestinal Disorders 
Diarrhea 
≤Grade 3 
Nausea 
≤Grade 3 
Vomiting 
≤Grade 3 
General disorders and 
administration site 
conditions 
 
Fatigue 
 
≤Grade 3 
 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
Neutrophil count decreased 
≤Grade 4 

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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
 
2) 
A life-threatening adverse event 
 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
 
5) 
A congenital anomaly/birth defect. 
 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be expeditedly reported1 
 
Platelet count decreased 
≤Grade 4 
 
White blood cell count 
decreased 
 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed. 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer.] 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention 1, 2 
 

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1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the Reportable Event coversheet and appropriate 
documentation to CANCERCROSAFETYIN@mayo.edu. The Mayo Regulatory 
Affairs Office will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 

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• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
 
 
10.55 Pregnancy, Fetal Death, and Death Neonatal 
Pregnancy reporting for Celgene/Revlimid REMS™ program 
Females of reproductive potential must adhere to scheduled pregnancy testing as 
required in the Revlimid REMS™ program. 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on lenalidomide, or within 28 days of the subject’s last dose of lenalidomide, 
are considered immediately reportable events. Lenalidomide is to be discontinued 

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immediately. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Celgene Drug Safety immediately by facsimile or other 
appropriate method using the Pregnancy Initial Report Form. The female subject 
should be referred to an obstetrician-gynecologist (not necessarily one with 
reproductive toxicity experience) or another appropriate healthcare professional 
for further evaluation. 
 
The Investigator will follow the female subject until completion of the 
pregnancy, and must notify Celgene Drug Safety immediately about the outcome 
of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form or equivalent form. 
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an 
SAE to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, and 
the pregnant female partner should be advised to call their healthcare provider 
immediately. 
 
Pregnancy reporting Mayo Clinic 
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 

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NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna 
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC. 

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10.6 
Required Routine Reporting 
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation. 
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
 
System Organ Class 
(SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Anemia 
 
X 
Skin and subcutaneous 
tissue disorder 
Rash Maculo-papular 
 
X* 
 
General disorders and 
administration site 
conditions 
Infusion related reaction 
 
X 
Injection site reaction 
 
X 
 
Fatigue 
 
X 
 
X 
Investigations 
Neutrophil count decreased 
 
X 
Platelet count decreased 
 
X 
*Only for evaluations during cycles 4-15 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 

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10.8 
Adverse Events of Special Interest (AESI) 
 
Specific adverse events, or groups of adverse events, will be followed as part of standard 
safety monitoring activities. These events (regardless of seriousness) will be reported to 
Pharmacyclics Drug Safety per SAE reporting timelines. 
 
10.81 Major Hemorrhage 
 
Major hemorrhage is defined as any of the following: 
 
• 
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*. Any 
treatment-emergent serious adverse events of bleeding of any grade 
• 
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as 
grade 3 or higher AE per CTCAE v4.0. 
 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 10.8 above. 
 
11.0 
Treatment Evaluation - The International Myeloma Working Group (IMWG) uniform response 
criteria (Kumar et al, 201617) will be used to assess response to therapy 
11.1 
Terms and definitions 
 
• M-protein: synonyms include M-spike, monoclonal protein and myeloma 
protein, paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in 
cases where the SPEP is felt to be unreliable. 
• M-proteins migrating in the β-region (usually IgA M-proteins) 
• Cases in which the M-protein is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin 
level (by greater than 1500 mg/dL) due to technical staining properties 
of the agarose gel. 
• Cases in which there are multiple peaks of same M-protein (aggregates 
or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine 
M-protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted, with the exception that 
quantitative IgG may not be used. However, this must be explicitly reported 
at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-protein values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably. 
 
Urine M-protein measurement is estimated using 24-h UPEP only. Random 
or 24 h urine tests measuring kappa and lambda light chain levels are not 

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reliable and are not recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, 
The Binding Site Limited, UK). Patients with kappa/lambda FLC ratio <0.26 
are defined as having monoclonal lambda FLC and those with ratios >1.65 as 
having a monoclonal kappa FLC. The monoclonal light chain isotype is 
considered the involved FLC isotype, and the opposite light chain type as the 
uninvolved FLC type. 
 
• Response terms: The following response terms will be used: stringent 
Complete Response (sCR), complete response (CR), very good partial 
response (VGPR), partial response (PR), Minimal Response (MR), stable 
disease (SD), and progressive disease (PD). 
 
In addition, for each response category, there will be an “unconfirmed” 
response category, which will be for internal use, for the purpose of guiding 
decision making and test ordering. These designations will be applied at the 
time of the first measurement at which the quantitative aspect of the response 
category has been satisfied without the confirmation step having been 
satisfied. The designation “u” will precede the standard abbreviations, and 
will include usCR, uCR, uVGPR, uPR, uMR, uPD. 
 
• Measurable disease: Patients who have a measurable serum or urine M- 
protein. 
 
o Serum M-protein ≥1 g/dl 
NOTE: Quantitative IgG may not be used for defining measurable disease 
o Urine M-protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥ 10 mg/dl provided serum FLC 
ratio is abnormal 
o Bone marrow plasma cells ≥ 30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response 
to therapy in patients who have oligo-secretory or non-secretory disease and 
should be used in assessing response only if the baseline serum and/or urine 
M proteins are not “measurable” as above, and the baseline level of the 
involved FLC is “measurable.” When using this assay, it is important to note 
that the FLC levels vary considerably with changes in renal function and in 
patients with renal insufficiency, the levels of both the kappa and lambda may 
remain elevated, but the ratio normalizes with achievement of CR. Thus, both the 
level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be 
considered in assessing response. Patients included on the study on the basis of 
FLC alone (i.e., no measurable serum/urine M-protein) should be the only ones 
who are evaluated using FLC response criteria. The others should follow usual 
criteria and ignore FLC results with the exception of defining stringent complete 

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response. 
 
• Evaluable disease: Patients who do not have a “measurable” serum M- 
protein, serum free light chain, or urine M-protein. 
 
• Oligosecretory myeloma: Patient with multiple myeloma who has NEVER 
had “measurable” serum M-protein or urine M-protein, but has had a 
detectable M-protein in his/her serum and/or urine and/or measurable serum 
free light chain. 
 
• Non-secretory myeloma: Patient with multiple myeloma who has NEVER 
had a detectable M-protein in his/her serum and/or urine. 
 
 
11.2 
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on 
the characteristics of their disease at on study. 
 
Table 11.2 
Tests Required To Assess Response (Must Be Done At Each Disease 
Measurement Visit except as indicated1,2) 
On Study Baseline Value 
SPEP4 
24 hr 
UPEP2 
Ig 
FLC 
BM 
Bx 
Serum M-protein ≥1 g/dl, and urine M- 
protein≥ 200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but urine M- 
protein < 200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and urine M- 
protein≥ 200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein < 
200 mg/24 hrs, but involved Ig FLC is ≥10 
mg/dL 
 
 
 
X 
 
Serum M-protein < 1 g/dl, urine M-protein< 
200 mg/24 hrs, involved Ig FLC is <10 
mg/dL, bone marrow ≥30% plasma cells 
 
 
 
 
X3 
1 SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone 
marrow biopsy are required to document CR regardless of registration values, 
and in addition FLC measurement and bone marrow immunophenotyping is 
required to document sCR. SPEP and UPEP are required to document VGPR 
regardless of registration values. 
2 For serum measurable patients, 24 hour urine does not need to be confirmed 
(i.e. repeated after documented response) for any response category 
3 At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response. Bone marrow biopsy results do not need to be repeated 
after documented response. 

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4 If serum M-protein is being followed by quantitative immunoglobulin levels 
derived from nephelometry or turbidometry, quantitative immunoglobulins are 
required. SPEP is only required to document CR or VGPR. 
 
11.3 
Confirmed response 
 
In order to be classified as a hematologic response, confirmation of serum M- 
protein, serum immunoglobulin free light chain (when primary determinant of 
response) and urine M- protein (when primary determinant of response) results 
must be made by verification on two consecutive determinations. 
• Bone marrow aspirate and biopsy are only required to document CR or 
sCR, except for patients with evaluable disease only, where a bone 
marrow is required to document all response categories including 
progression. However, a second confirmatory bone marrow is not required 
to confirm response in any case. 
• Radiographic studies are not required to satisfy these response 
requirements; however, if radiographic studies were performed there 
should be no evidence of progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 
11.2 
 
11.4 
Bone progression 
 
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone. Compression fracture does not exclude continued 
response and may not indicate progression. When progression is based on 
skeletal disease alone, it should be discussed with the Study Chair before 
removing the patient from the study. 
 
11.5 
Response and Progression 
 
Criteria for response and progression are listed in Table 11.5. Progressive disease 
for all patients as defined in Table 11.5. 
 
Baseline values for disease assessment: All disease response measurements 
will be based on the values obtained at the time of diagnosis if there has been 
no relapse prior to transplant. If patients had a disease relapse prior to 
transplant, the baseline values will be those obtained at the time of relapse 
immediately prior to the transplant. If patient had treatment for the relapsed 
disease prior to transplant, the values will be from prior to this therapy, ie, 
the time of relapse. 

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Table 11.5 
IMWG MRD 
NEGATIVITY 
CATEGORY 
 
RESPONSE CRITERIA a 
Flow MRD k 
Absence of phenotypically aberrant clonal plasma cells by MPF 
on bone marrow aspirates using the EuroFlow standard 
operation procedure for MRD detection in multiple myeloma 
(or validated equivalent method) with a minimum sensitivity of 
1 in 105 nucleated cells or higher 
Imaging + 
MRD-negative 
MRD negative as defined by MPF or NGS PLUS 
Disappearance of every area of increased tracer uptake found at 
baseline or a preceding PET/CT or decrease to < mediastinal 
blood pool 
Standard uptake value or decrease to less than that of 
surrounding normal tissue 
STANDARD IMWG 
RESPONSE 
CATEGORY 
 
RESPONSE CRITERIA a 
Stringent Complete 
Response (sCR) b 
CR as defined plus 
Normal FLC ratio and 
• Absence of clonal PCs by immunohistochemistry or 2- to 4- 
color flow cytometry i 
Complete Response 
(CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• <5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d 
Very Good Partial 
Response (VGPR) 
• Serum and urine M-protein detectable by immunofixation but 
not on electrophoresis c or 
• ≥90% reduction in serum M-protein and urine M-protein 
<100 mg/24 h c 
• If the only measurable disease is FLC, a >90% reduction in 
the difference between involved and uninvolved FLC levels 
Partial Response (PR) 
• If present at baseline, ≥ 50% reduction of serum M-protein 
and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24hrs c 
• If the only measurable disease is FLC, a ≥50% reduction in 
the difference between involved and uninvolved FLC levels 
• If the only measurable disease is BM, a ≥ 50% reduction in 
BM PCs (provided the baseline PCs was ≥ 30%) 
• If present at baseline, ≥ 50% reduction in the size (SPD) of 
soft tissue plasmacytomas j 
Minor Response (MR) 
• If present at baseline, ≥25% but ≤ 49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
• If present at baseline, ≥50% reduction in the size (SPD) of 
soft tissue plasmacytoma j 

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Stable Disease (SD) 
• Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
Progressive Disease 
(PD) b, h 
Increase of 25% from lowest value in any of the following f, g: 
• 
Serum M-protein (absolute increase must be ≥ 0.5 g/dL) 
and/or 
• 
Urine M-protein (absolute increase must be ≥ 200 mg/24 
hrs) and/or 
• 
If the only measurable disease is FLC, the difference 
between involved and uninvolved FLC levels (absolute 
increase must be >10 mg/dL) and/or 
• 
If the only measurable disease is BM, bone marrow PC 
percentage (absolute increase must be ≥ 10%) e 
Or any one or more of the following: 
• 
Development of new bone lesion or soft tissue 
plasmacytoma or ≥50% increase from nadir in the size 
(SPD) of existing bone lesions or soft tissue plasmacytoma 
or ≥ 50% increase in the longest diameter of a previous 
lesion >1 cm in short axis j 
• 
50% increase in circulating plasma cells (minimum of 200 
cells per L) if this is the only measure of disease 
Clinical Relapse 
One or more of the following direct indicators of increasing 
disease and/or end-organ dysfunction that are considered 
related to the underlying plasma cell proliferative disorder: 
1. Development of new soft tissue plasmacytomas or bone 
lesions on skeletal survey, magnetic resonance imaging, or 
other imaging 
2. Definite increase in the size of existing plasmacytomas or 
bone lesions. A definite increase is defined as a 50% (and at 
least 1 cm) increase as measured serially by the sum of the 
products of the cross-diameters of the measurable lesion 
3. Hypercalcemia (>11.5 mg/dL; >2.875mM/L) 
4. Decrease in hemoglobin of more than 2 g/dL (1.25mM) or 
to less than 10 g/dL 
5. Rise in serum creatinine by more than or equal to 2 mg/dL 
(≥177mM/L) 
6. Hyperviscosity 
 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at 
any time before the institution of any new therapy. MRD tests should be done as specified per the test 
schedule. sCR, CR, VGPR, PR, MR and SD categories and MRD require no known evidence of 
progressive or new bone lesions or extramedullary plasmacytomas if radiographic studies were 
performed. However, radiographic studies are not required to satisfy these response requirements. Bone 
marrow assessments need not be confirmed. Each category, except for stable disease, will have a working 
subcategory of “unconfirmed” [prefix ‘u”] to designate first time point at which response category MAY 
have been achieved if confirmed. The date of the initial test is considered as the date of response for 
evaluation of time dependent outcomes such as duration of response. 

46 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD. A 
positive immunofixation alone is not sufficient. If a patient has already achieved a complete response 
prior to registration as a result of the induction therapy, the patient will be considered a continued 
complete response if they continue to meet the complete response criteria at the next assessment. 
Reconfirmation of complete response is not required. 
 
c If more than one M protein spike meets the criteria for measurable disease at baseline, then both need to 
be followed for response. Otherwise, only follow the measurable M protein spike for response. 
 
d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a 
normal FLC ratio of 0.26-1.65 in addition to the CR criteria listed above. 
 
e Bone marrow criteria for PD are only to be used in patients without measurable disease by M protein and 
by FLC; 
 
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, 
soft tissue plasmacytoma or hypercalcemia. The lowest value does not need to be a confirmed value. If 
the lowest serum M-protein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define 
disease progression. 
 
g In the case where a value is felt to be a spurious result per physician discretion (for example, a possible 
lab error), that value will not be considered when determining the lowest value. 
 
h Progressive disease should be confirmed on two consecutive evaluations, where the timing of 
confirmation is per the treating physician and can be done immediately within the same cycle or on the 
next cycle. However, treatment may be discontinued for progressive disease that is unconfirmed per 
physician discretion. In this case, an objective status of PD should be entered on the measurement form 
and progressive disease should be reported on the event monitoring form. 
 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/l of 4:1 or 1:2. 
 
j Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be 
measured with a ruler. Measurement of tumor size will be determined by the sum of the products of the 
maximal perpendicular diameters of measured lesions (SPD). 
 
k Requires a complete response as defined in the table. MRD tests should be done as specified per the test 
schedule. MRD requires no known evidence of progressive or new bone lesions if radiographic studies 
were performed. However, radiographic studies are not required to satisfy these response requirements. 
NOTE: An objective status of MRD negative should be reported on the treatment measurements 
form only when flow MRD by bone marrow is negative. 
 
11.6 
Criteria for engraftment (for hematopietic stem cell transplant studies only) 
Engraftment is defined as: 
• The first day of three consecutive days on which the absolute neutrophil 
count (ANC) >500/mm3 and 
• The first of three consecutive days with an untransfused platelet count 
>20,000/mm3. 

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Protocol Version Date: 12Jan2022 
 
 
 
12.0 
Descriptive Factors 
12.1 
Depth of Response at registration: MRD positive sCR vs. MRD positive CR vs. VGPR 
vs PR vs SD 
 
12.2 
MM risk categories (As per Appendix IV): High vs. standard/intermediate vs. unknown. 
 
12.3 
Immediately prior treatment was maintenance: yes vs. no 
 
12.4 
Prior number of anti-myeloma regimens: 1 vs. >1 (NOTE: Any maintenance therapy 
given after an induction regimen is considered a part of that induction therapy and thus, 1 
regimen) 
 
12.5 
Parameters followed for hematologic response (pick one) as per the time specified in 
section 3.18 : serum M-spike ≥1 g/dL and urine M-spike ≥200 mg/24 hours vs. serum M- 
spike ≥1g/dL only vs. urine M-spike ≥200 mg/24 hours only vs. serum immunoglobulin 
free light chain ≥10 mg/dL vs. bone marrow cells ≥30%. Distinguish between SPEP 
measurements versus quantitative IgA measurements versus quantitative IgD 
measurements for serum M-spike. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Patients who are responding 
Patients who are sCR, CR, VGPR, PR, MR, or SD (or usCR, uCR, uVGPR, uPR, uMR) 
will continue treatment per protocol. Treatment may continue until disease progression as 
long as the patient continues to respond and does not have any unacceptable toxicity. 
13.3 
Criteria for Initiation of Event Monitoring 
Patients who go off protocol treatment for the following reasons will go to the event- 
monitoring phase per Section 4.2: 
 
• 
Progressive multiple myeloma at any time on the clinical trial 
• 
Patient requests to discontinue study treatment 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation 
• 
A dose omission of more than 28 days beyond the scheduled date of retreatment for 
daratumumab or lenalidomide 
 
All attempts should be made to complete the End of Study procedures if a patient goes 
off treatment early. 
13.4 
Criteria for Study Discontinuation 
The study may be temporarily or permanently discontinued at any site and at any time. 
Reasons for study discontinuation may include, but are not limited to, the following: 
• 
Safety concerns 
• 
Poor enrollment 

48 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
• 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 
 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons. In the case of such termination, the 
Investigator will notify the IRB. 
13.5 
Ineligibles 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable). 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per the protocol. 
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.6 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 4.2 of the protocol. 
13.7 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 

 
Protocol Version Date: 12Jan2022 
 
14.0 
Body Fluid Biospecimens 
None. 
15.0 
Drug Information 
15.1 
Daratumumab (Darzalex Faspro™, Darzalex™, JNJ-54767414) 
15.11 Background: Daratumumab is an antineoplastic agent that is an antibody against 
the CD-38 antigen expression on cells including multiple myeloma. 
 
SQ formulation: Daratumumab and hyaluronidase-fihj injection is a sterile, 
preservative-free, colorless to yellow, and clear to opalescent solution supplied 
in a single-dose vial for subcutaneous administration. Each 15 mL single-dose 
vial contains 1800 mg daratumumab and 30,000 units hyaluronidase, L-histidine, 
L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, sorbitol, 
and Water for Injection, USP. 
 
IV formulation: Daratumumab drug product is a colorless to yellow liquid 
concentrate. It is presented at a target concentration of 20 mg/mL in a 6R or 25R 
vial with a nominal fill volume of 5 mL or 20 mL, respectively. It is administered 
by the intravenous (IV) route after dilution in a sterile, pyrogen-free 
physiological saline solution (0.9% NaCl) provided by the investigation site. The 
diluent is a commercially available product approved by the competent authority 
of the relevant country. 
 
Daratumumab drug product is formulated as a concentrate of 20.0 mg/mL ± 2.0 
mg/mL in an isotonic buffer consisting of sodium acetate, sodium chloride, 
mannitol and polysorbate 20 at pH 5.5. 
 
15.12 Storage and handling: 
 
The daratumumab vials should be stored in the original carton in a refrigerator at 
2ºC to 8ºC and must not be utilized after the expiry date printed on the label. The 
product must be protected from light and must not be frozen. Since daratumumab 
does not contain preservatives, any unused portion remaining in the vial must be 
discarded. 
 
IV: Daratumumab will be diluted in a sterile, pyrogen-free physiological saline 
solution (0.9% NaCl) prior to IV administration. 
 
SQ: Daratumumab and hyaluronidase-fihj SC injection is directly drawn 
from the vial into a syringe and is compatible with polypropylene or 
polyethylene syringe material; polypropylene, polyethylene, or polyvinyl 
chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and 
injection needles. After the solution is withdrawn into the syringe, replace 
the transfer needle with a syringe cap. To avoid needle clogging, attach 
the hypodermic injection needle or subcutaneous infusion set to the 
syringe immediately prior to injection. 
 
15.13 Administration: 

50 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
• 
IV Administration: Administer the diluted solution by intravenous 
infusion using an infusion set fitted with a flow regulator and with an in- 
line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) 
filter (pore size 0.22 or 0.2 micrometer). Polyurethane (PU), 
polybutadiene (PBD), PVC, PP or PE administration sets must be used. 
 
Infusion should be completed within 15 hours 
 
Refer to the Infusion rates in the table below 
 
Do not store any unused portion of the infusion solution for 
reuse. Any unused product or waste material should be disposed 
of in accordance with local requirements. 
 
Do no infuse daratumumab concomitantly in the same 
intravenous line with other agents 
 
• 
SQ administration: Utilizing a hypodermic injection needle or 
subcutaneous infusion set, inject 15 mL of the daratumumab and 
hyaluronidase-fihj solution into the subcutaneous tissue of the abdomen 
approximately 3 inches to the right or left of the navel over 
approximately 3-5 minutes. No data are available on performing the 
injection at other sites of the body. 
 
Daratumumab has been administered as monotherapy at doses up to 24 mg/kg 
and as combination therapy at doses up to 16 mg/kg. The daratumumab infusion should 
be intravenously administered at the appropriate initial infusion rate, as presented in the 
table below. Incremental escalation of the infusion rate should be considered only if the 
previous infusion of daratumumab was well tolerated as defined in the table 
below.Infusion Rates for Daratumumab Administration via IV 
 
 
Dilution 
Volume 
Initial Infusion 
Rate (first hr) 
Increments of 
Infusion Rate 
Maximum 
Infusion rate 
First Infusion 
1000 ml 
100 mL/hr 
50 mL/hr every hr 
200 mL/hr 
Second infusiona 
500 ml 
50 mL/hr 
50 mL/hr every hr 
200 mL/hr 
Subsequent infusionsb 
500 ml 
50 mL/hr 
50 mL/hr every hr 
200 mL/hr 
 
aModified rates should only be used if the first infusion of daratumumab was well-tolerated as 
defined by an absence of > Grade 1 IRRs during the first 3 hours. 
bModified rates should only be used if the first 2 infusions of daratumumab were well-tolerated as 
defined by an absence of > Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr. 
 
 
15.14 Pharmacokinetic information: 
Pharmacokinetic (PK) data are available from GEN501, MMY2002 and 
MMY1002 monotherapy studies. Doses across these studies ranged from 0.005 
to 24 mg/kg. The PK profile was consistent with target-mediated disposition with 
rapid target-related clearance at low doses and slower clearance at higher doses. 
Preliminary PK data from Study GEN503 show that following both the first dose 
and multiple repeated doses, the PK profile of daratumumab in combination with 
lenalidomide and dexamethasone is similar to what was observed in Study 
GEN501 following the same dose and schedule. The data suggest that 
lenalidomide and dexamethasone do not affect the PK profile of daratumumab. 

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Protocol Version Date: 12Jan2022 
 
 
 
Overall, biomarker assessments evaluated to date provided evidence of NK cell 
reduction with daratumumab single agent or combination treatment. Increases in 
T-cell counts and clonality were observed providing preliminary evidence of the 
immunomodulatory effects of daratumumab that needs further investigation. No 
significant changes in other immune subsets were observed with daratumumab 
treatment. A large overlap in baseline CD38 expression was observed between 
responders and non-responders along with its reduction with daratumumab 
treatment irrespective of response. 
 
Following the administration of the recommended dose of 1,800 mg 
daratumumab and 30,000 units hyaluronidase subcutaneously once weekly for 8 
weeks, the mean ± standard deviation (SD) maximum trough concentrations 
(Ctrough following the 8th dose) were 593±306 μg/mL compared to 522±226 
μg/mL for daratumumab 16 mg/kg administered intravenously, with a geometric 
mean ratio of 108% (90% CI: 96, 122). The estimated median daratumumab area 
under the concentration-time curves (AUC0-7 days) and daratumumab peak 
concentration (Cmax) following the 8th dose were comparable between 
subcutaneous and intravenous daratumumab (4017 μg/mL•day vs. 4,019 
μg/mL•day for AUC0-7 days and 592 μg/mL vs. 688 μg/mL for Cmax). 
The absolute bioavailability of daratumumab-hyaluronidase is 69%, with peak 
concentrations occurring around 3 days (Tmax). The estimated mean (coefficient 
of variation, CV) volume of distribution for the central compartment is 5.2 L 
(37%) and peripheral compartment was 3.8 L with the daratumumab- 
hyaluronidase formulation. Daratumumab is cleared by parallel linear and 
nonlinear saturable target mediated clearances. The estimated mean (CV%) linear 
clearance of daratumumab is 119 mL/day. The estimated mean (CV%) 
elimination half-life associated with linear clearance is 20 days (22%). 
 
Body Weight (BW): After administration of 1,800 mg daratumumab and 30,000 
units hyaluronidase subcutaneously once weekly for 8 weeks, the mean 
maximum Ctrough was 12% lower in the higher body weight group (>85 kg) while 
the mean maximum Ctrough was 81% higher in the lower BW group (≤ 50 kg) 
compared to the corresponding BW groups in the intravenous daratumumab arm. 
 
15.15 Known potential toxicities: 
• 
Very Common (≥10%): 
Blood and lymphatic system disorders: neutropenia, 
thrombocytopenia, anemia, lymhopenia 
Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation 
Infections and infestations: upper respiratory tract infection, 
bronchitis, pneumonia, nasopharyngitis 
Injury, poisoning and procedural complications: infusion related 
reaction 
Metabolism and nutrition disorders: hypokalemia, hyperglycemia, 
decreased appetite 
Musculoskeletal and connective tissue disorder: muscle spasms, back 
pain, arthralgia, pain in extremity, bone pain, musculoskeletal chest 
pain 
Nervous system disorders: dizziness, headache, tremor 
Psychiatric disorders: Insomnia, anxiety 

52 
 
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Respiratory, thoracic and ediastinal disorders: cough, dyspnea, nasal 
congestion 
Vascular disorders: hypertension 
General disorders and administration site conditions: fatigue, pyrexia, 
chills, peripheral edema, asthenia, non-cardiac chest pain, pain 
• 
Common (1 to <10%): 
General disorders and administration site conditions: injection site 
reaction, peripheral edema 
Infections and infestations: respiratory tract infection, influenza, lower 
respiratory tract infection, sepsis, sinusitis, rhinitis, pharyngitis, viral 
respiratory tract infection, nasopharyngitis, respiratory syncytial virus 
infections, laryngitis, tonsillitis, lung infection, herpes zoster 
Blood and lymphatic disorders: febrile neutropenia 
Cardiac disorders: atrial fibrillation 
Respiratory, thoracic, and mediastinal disorders: pulmonary edema, 
hypoxia, laryngeal edema, pneumonitis, bronchospasm 
 
• 
Uncommon and rare known potential toxicities, <1%: 
Infections and infestations: metapneumovirus infection, tracheitis, acute 
sinusitis, bronchiolitis, epiglottitis, oropharyngeal candidiasis, rhinovirus 
infection, tracheobronchitis, upper respiratory tract bacterial infection, 
infectious bronchitis, infectious laryngitis, infectious pharyngitis, viral 
rhinitis, respiratory syncytial virus, infectious pneumonia 
Blood and Lymphatic Disorders: neutropenic sepsis, neutropenic 
infection 
 
Please refer to the prescribing information or package insert for a more complete 
comprehensive list of treatment-related adverse events 
 
15.16 Drug procurement: Drug will be procured from the commercial supply of 
daratumumab. 
 
15.17 Special populations: 
• 
Geriatric use: Of the 237 subjects treated with daratumumab monotherapy 
in clinical studies, 44% were 65 years and over. No overall differences in 
safety or effectiveness were observed between these subjects and younger 
subjects, and other reported clinical experience has not identified differences 
in responses between the elderly and younger subjects, but greater sensitivity 
of some older individuals cannot be ruled out. Based on population PK 
analysis, age (range: 31 to 84 years) had no clinically important effect on the 
PK of daratumumab, and the exposure of daratumumab was similar between 
younger (age <65 years, n=127) and older patients (age ≥65 years, n=96). No 
dose adjustments are considered necessary. 
• 
Renal impairment: No formal studies of daratumumab in subjects with 
renal impairment have been conducted. Changes in renal function are 
unlikely to have an effect on the elimination of daratumumab since 
daratumumab is not excreted via renal pathways. Based on a population 
pharmacokinetic (PK) analysis no dosage adjustment is necessary for 
subjects with renal impairment. Daratumumab has not been studied in 

53 
 
Protocol Version Date: 12Jan2022 
 
 
 
subjects with severe renal impairment (creatinine clearance <20 mL/min) or 
on hemodialysis. 
• 
Hepatic Impairment: No formal studies of daratumumab in subjects with 
hepatic impairment have been conducted. Changes in hepatic function are 
unlikely to have any effect on the elimination of daratumumab since IgG1 
molecules such as daratumumab are not metabolized through hepatic 
pathways. Based on a population PK analysis, no dosage adjustments are 
necessary for subjects with mild hepatic impairment (Total Bilirubin [TB] 
1.0× to 1.5× upper limit of normal [ULN] or aspartate aminotransferase 
[AST] >ULN). Daratumumab has not been studied in subjects with moderate 
to severe hepatic impairment (TB >1.5× ULN and any AST). 
15.18 Nursing Guidelines 
• 
Daratumumab can cause severe infusion reactions, usually during the first 
infusion. Patients who have experience a reaction may experience further 
reactions with subsequent infusions. Most reactions occur during or within 4 
hours of infusion, however, may occur up to 48 hourse after an infusion. 
Warn patient of this possibility. Monitor patient throughout infusion for 
bronchospasm, hypoxia, SOB, and hypertension. Patients may also 
experience symptoms of anaphylaxis. Administer emergency medication as 
ordered. 
• 
Patients may experience infections, including URI and pneumonia. Patients 
who have an ongoing infection should not receive agent. 
• 
Patients may experience gastrointestinal side effects including diarrhea and 
nausea. Treat sympotomatically and monitor for effectiveness. 
• 
Warn patients about the possibility of peripheral neuropathy, dizziness, and 
insomnia. 
• 
Fatigue is common. Instruct patient in energy conserving lifestyle. 
• 
Rarely patients may experience cardia issues including, atrial-fibrillation, 
peripheral edema, and hypertension. Instruct patient to report any chest pain, 
heart palpitations, and swelling to the study team. 
• 
Monitory CBC w/diff as cytopenias (thrombocytopenia, neutropenia, anemia, 
and lymphopenia) have been seen. Instruct patient to report any unusual, 
bruising, bleeding, and/or infections/fever to the study team. 
15.2 
Lenalidomide for Oral Administration (Revlimid®) 
15.21 Background: Lenalidomide has antineoplastic, immunomodulatory and 
antiangiogenic characteristics via multiple mechanisms. Lenalidomide selectively 
inhibits secretion of proinflammatory cytokines (potent inhibitor of tumor 
necrosis factor-alpha secretion); enhances cell-mediated immunity by stimulating 
proliferation of anti-CD3 stimulated T cells (resulting in increased IL-2 and 
interferon gamma secretion); inhibits trophic signals to angiogenic factors in 
cells. Lenalidomide inhibits the growth of myeloma cells by inducing cell cycle 
arrest and cell death. 
 
15.22 Formulation and Dispensing: Commercially available for oral administration 
as: Capsules: 5 mg, 10 mg, 15 mg and 25 mg 
Lenalidomide is approved for marketing only under a FDA approved, restricted 
distribution program called Revlimid REMS. Physicians, pharmacies, and 
patients must be registered; a maximum 28-day supply may be dispensed; a new 

54 
 
Protocol Version Date: 12Jan2022 
 
 
Boxed Warnings: 
1. Potential for human birth defects 
2. Hematologic toxicity (neutropenia and thrombocytopenia) 
3. Deep Venous Thrombosis and Pulmonary Embolism 
 
 
prescription is required each time it is filled; pregnancy testing is required for 
females of childbearing potential. 
 
15.23 Preparation, storage, and stability: Store oral capsules at controlled 
room temperature between 15ºC and 30ºC (59 ºF and 86 ºF). Refer to 
labeling on the bottle for expiration date of the commercial tablets. 
 
15.24 Administration: Refer to the treatment section for specific administration 
instructions. Administer with water. Swallow capsule whole; do not break, open, 
or chew. 
 
15.25 Pharmacokinetic information: 
Absorption: Rapid 
Metabolism: Approximately two-thirds of Lenalidomide is eliminated 
unchanged through urinary excretion. 
Protein binding: ~30% 
Time to peak, plasma: Healthy volunteers: 0.6-1.5 hours; Myeloma 
patients: 0.5-4 hours 
Half-life elimination: ~3 hours 
Excretion: Urine (~67% as unchanged drug) 
 
15.26 Potential Drug Interactions: 
Increased Effect/Toxicity: Abatacept and Anakinra may increase the risk 
of serious infection when used in combination with Lenalidomide. 
Lenalidomide may increase the risk of infections associated with vaccines 
(live organism). 
Decreased Effect: Lenalidomide may decrease the effect of vaccines 
(dead organisms). 
Herb/Nutraceutical Interactions: Avoid echinacea (has 
immunostimulant properties; consider therapy modifications). 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
 
Common known potential toxicities, >10%: 
Cardiovascular: Peripheral edema 
Central nervous system: Fatigue, pyrexia, dizziness, headache 
Dermatologic: Pruritus, rash, dry skin 
Endocrine & metabolic: Hyperglycemia, hypokalemia 
Gastrointestinal: Diarrhea, constipation, nausea, weight loss, dyspepsia, 
anorexia, taste perversion, abdominal pain 
Genitourinary: Urinary tract infection 
Hematologic: Thrombocytopenia, neutropenia, anemia, myelosuppression 
is dose-dependent and reversible with treatment interruption and/or dose 
reduction 
Neuromuscular & skeletal: Muscle cramp, arthralgia, back pain, tremor, 
weakness, paresthesia, limb pain 

55 
 
Protocol Version Date: 12Jan2022 
 
 
 
Ocular: Blurred vision 
Respiratory: Nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, 
upper respiratory infection, pneumonia 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Edema, deep vein thrombosis, hypertension, chest pain, 
palpitation, atrial fibrillation, syncope 
Central nervous system: Insomnia, hypoesthesia, pain, depression 
Dermatologic: Brusing, cellulitis, erythema 
Endocrine & metabolic: Hypothyroidism, hypomagnesemia, hypocalcemia 
Gastrointestinal: Vomiting, xerostomia, loose stools 
Genitourinary: Dysuria 
Hematologic: Leukopenia, febrile neutropenia, Lymphopenia 
Hepatic: ALT increased 
Neuromuscular & skeletal: Myalgia, rigors, neuropathy 
Respiratory: Sinusitis, rhinitis, bronchitis, pulmonary embolism 
Miscellaneous: Night sweats, diaphoresis 
Rare known potential toxicities, <1% (Limited to important or life- 
threatening): 
Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 
Tumor Lysis Syndrome 
 
15.28 Drug procurement: As a requirement of the REMS program, access to 
Lenalidomide is restricted. Lenalidomide is approved for marketing only under a 
FDA approved, restricted distribution program called REVLIMID REMS 
(www.REVLIMIDREMS.com) formerly known as the RevAssist program. 
Physicians, pharmacies, and patients must be registered; a maximum 28-day 
supply may be dispensed; a new prescription is required each time it is filled; 
pregnancy testing is required for females of childbearing potential. 
 
15.29 Nursing Guidelines: 
• 
Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. Instruct 
patient to report any unusual bruising or bleeding (thrombocytopenia); signs 
and symptoms of infection (neutropenia); and energy conserving lifestyle 
(anemia). 
• 
Lenalidomide can have thrombotic adverse events (i.e DVT and PE). Instruct 
patient to report any limb swelling or pain, and to seek medical attention for 
shortness of breath or chest pain. 
• 
Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing therapy. 
Males must be instructed to use a latex condom during any sexual contact 
with a woman of child bearing potential (even if they have had a vasectomy), 
because it is unknown if lenalidomide is present in semen. 
• 
Patents may experience pruritus, rash and dry skin. Because of the rare risk 
of Steven’s Johnson Syndrome, patients should immediately report any rash 
to their provider. 
• 
Drug may cause hyperglycemia. Patients with diabetes or impaired fasting 
glucose may need to have their glucose levels monitored more closely. 

56 
 
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• 
Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patient symptomatically and 
monitor for effectiveness. 
• 
Patients may experience myalgias, arthralgias, and other generalized pain. 
Administer analgesics as ordered and monitor for their effectiveness. 
• 
Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can be 
seen. Manage symptomatically and monitor for effectiveness. 

57 
 
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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This is a phase II study of Daratumumab for transplant eligible multiple myeloma 
patients. This study is designed to assess the rate of minimal residual disease (MRD) 
negativity using a one stage phase II study design with an interim analysis in patients 
with transplant eligible multiple myeloma. 
 
16.11 Primary Endpoint: The primary endpoint of this study is the rate of MRD 
negative response after ASCT. MRD negative response after ASCT is defined as 
achievement of MRD negative status in the bone marrow by flow cytometry 
(MPF) at the day 100 post ASCT visit. All patients meeting the eligibility 
criteria, who have signed a consent form and have begun treatment will be 
evaluable for response, unless they are determined to be a major violation. 
 
16.12 Sample Size: The one stage study design with an interim analysis to be used is 
fully described below. A minimum of 20 and a maximum of 45 evaluable 
patients will be accrued total onto this phase II study unless undue toxicity is 
encountered. We anticipate accruing an additional 5 patients to account for 
ineligibility, cancellation, major treatment violation, or other reasons for a total 
of 50 patients overall. 
 
16.13 Accrual Rate and Study Duration: The anticipated accrual rate is 2 evaluable 
multiple myeloma patients per month. Therefore, the accrual period for this 
phase II study is expected to be about 2 years. The maximum total study duration 
is expected to be approximately 5 years, or until the last patient accrued has been 
observed at least for 3 years after registration. 
 
16.3 
Statistical Design: 
16.31 Decision Rule: 
Previous studies of evaluation of minimal residual disease in multiple myeloma 
have been limited and have included small numbers of patients. In one previous 
study of lenalidomide, bortezomib and dexamethasone (RVD) induction 
followed by ASCT followed by 2 cycles of RVD consolidation and 1-year 
Lenalidomide maintenance in 31 untreated transplant eligible MM patients, an 
MRD negative response rate of 54% by flow cytometry was seen post ASCT in 
26 evaluable patients tested. A MRD negative response rate of 65% by bone 
marrow flow cytometry would be of interest for this study. 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 45%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 65%. The following one–stage design with an interim 
analysis is based on a two-stage Simon optimum design28 and requires 45 
evaluable patients to test the null hypothesis that the true success proportion in 
this patient population is at most 45%. 
 
16.311 Interim Analysis: Enter 20 evaluable patients into the study. If 9 or fewer 
successes are observed in the first 20 evaluable patients, we will consider 
this regimen ineffective in this patient population and terminate the 

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Protocol Version Date: 12Jan2022 
 
 
 
 
study. Otherwise, if the number of successes is at least 10, we will 
continue accrual. 
 
16.312 Final Decision Rule: Enter an additional 25 evaluable patients into the 
study. If 24 or fewer successes are observed in the first 45 evaluable 
patients, we will consider this regimen ineffective in this patient 
population and terminate this study. Otherwise, if the number of 
successes is at least 25, this will be considered evidence of promising 
activity and the treatment may be recommended for further testing in 
subsequent studies in this population. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process. 
 
16.314 NOTE: We will not suspend accrual at the interim analysis to allow the 
first 20 patients to become evaluable, unless undue toxicity is observed. 
Given the limited overall sample size and the inclusion of an adverse 
events stopping rule, we feel it is ethical to not halt accrual for the 
interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
 
16.32 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping at the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is... 
0.45 
0.50 
0.55 
0.60 
0.65 
Then the probability of declaring 
that the regimen warrants further 
study is… 
 
0.09 
 
0.25 
 
0.49 
 
0.74 
 
0.90 
And the probability of stopping at 
the interim analysis is… 
0.59 
0.41 
0.25 
0.13 
0.05 
 
16.33 Other considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.4 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.2) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is all patients have been 

59 
 
Protocol Version Date: 12Jan2022 
 
 
 
followed at least through the day 100 post ASCT visit (approximately 8 months) or have 
discontinued study treatment prior to ASCT. 
 
16.41 Primary Outcome Analysis: 
16.411 Definition: The primary endpoint of this trial is the rate of MRD negative 
response after ASCT. MRD negative response after ASCT is defined as 
achievement of MRD negative status in the bone marrow by flow 
cytometry (MPF) at the day 100 post ASCT visit. All patients meeting 
the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response, unless they are determined to be 
a major violation. 
16.412 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Ninety- 
five percent confidence intervals for the true success proportion will be 
calculated according to the approach of Duffy and Santner. 
16.413 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals 
 
16.42 Secondary Outcome Analyses 
 
The rate of MRD negative response after pre-SCT consolidation with Daratumumab will 
be estimated by the number of patients who achieve MRD negative status by flow 
cytometry (MPF) in the bone marrow after pre-SCT consolidation with Daratumumab 
divided by the total number of evaluable patients. Exact binomial 95% confidence 
intervals for the true rate of MRD negative response after pre-SCT consolidation with 
Daratumumab will be calculated. 
 
 
The rate of MRD negative response after 1 year (12 cycles) of Daratumumab and 
lenalidomide maintenance will be estimated by the number of patients who achieve 
MRD negative status by flow cytometry (MPF) in the bone marrow after 1 year of 
maintenance therapy divided by the total number of evaluable patients. Exact binomial 
95% confidence intervals for the true rate of MRD negative response after 1 year of 
maintenance will be calculated. 
 
 
Progression-free survival time is defined as the time from registration to the time of 
progression or death due to any cause. Patients who are alive and progression-free will 
be censored on the date of their last disease assessment. Patients who receive subsequent 
treatment for myeloma before disease progression will be censored on the date of their 
last disease assessment prior to initiation of the subsequent treatment. The distribution 
of progression-free survival will be estimated using the method of Kaplan-Meier. 

60 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
 
Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier. 
 
 
The overall response rate at day 100 post ASCT will be estimated by the 
number of patients with an objective status of sCR, CR, VGPR, or PR at 
the day 100 post ASCT assessment divided by the total number of 
evaluable patients. Response assessment will be in comparison to values 
obtained at the disease assessment at the time registration. Exact 
binomial 95% confidence intervals for the true overall response rate at 
day 100 post ASCT will be calculated. 
 
 
Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
 
16.43 Exploratory Outcomes Analyses 
 
16.431 To evaluate the correlation of MRD assessment between blood and bone 
marrow, patients will be categorized as positive vs. negative MRD for 
each measure. The number of patients who have agreement between the 
2 measures (both positive or both negative) will be assessed. 
 
16.432 To evaluate the correlation of MRD assessment between flow cytometry 
(MPF) and NGS, patients will be categorized as positive vs. negative 
MRD for each measure. The number of patients who have agreement 
between the 2 measures (both positive or both negative) will be assessed. 
 
16.433 Immune repertoire profiling (Section 1.74) will be assessed as 
continuous variables and their mutual change over time as assessed on 
the pre-specified time points will be correlated with response category to 
the treatment. 
 
16.434 ADCP and ADCC (Section 1.75) will be assessed as continuous 
variables and their mutual change over time as assessed on the pre- 
specified time points will be correlated with response category to the 
treatment 
 
16.5 
Data and Safety Monitoring: 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.52 Adverse Event Stopping Rules: 

61 
Protocol Version Date: 12Jan2022 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that 
satisfy one of the following: 
•
If 5 or more patients in the first 15 treated patients experience a grade 4 or
higher non-hematologic adverse event at least possibly related to treatment.
•
If after the first 15 patients have been treated, 30% of all patients experience
a grade 4 or higher non-hematologic adverse event at least possibly related to
treatment.
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.6 
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 3 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time all patients registered have been 
followed at least through the day 100 post ASCT visit (approximately 8 months) or have 
discontinued study treatment prior to ASCT. 
16.7 
Inclusion of Women and Minorities: 
16.71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.73 The geographical region served by MCCC has a population which includes 
approximately 5% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 5-7% of patients will be classified as minorities by 
race and about 40% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 

62 
Protocol Version Date: 12Jan2022 
Accrual Estimates by Gender/Ethnicity/Race 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
20 
29 
49 
Ethnic Category: Total of all subjects 
20
30
50
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian
0 
0
0
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White
19 
29
48
Racial Category: Total of all subjects 
20
30
50
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
0BNot Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
17.0 
Pathology Considerations/Tissue Biospecimens: None. 

63 
Protocol Version Date: 12Jan2022 
18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.2 and data submission table for the event monitoring/survival follow-up 
schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis prior to study entry as well as 
for evidence of response to study therapy and progression after study therapy. For 
patients with any previous ASCT for MM, provide a clinic note including ASCT history 
or transplant records (E.g. central registry records) . Supporting documentation for 
diagnosis will include either a pathology report or a laboratory report demonstrating 
multiple myeloma (including SPEP, UPEP, FLC, Serum and Urine Immunofixation, 
Bone Marrow Biopsy and Aspirate, skeletal bone survey, PET scan, Plasma Cell 
Proliferation and Assessment and FISH). These reports should be uploaded into the 
Supporting Documentation: Baseline form within 14 days of registration. 
For progression of disease prior to study entry, supporting documentation includes the 
evidence needed to determine the patient’s progression prior to enrollment. These 
documents should be uploaded into the Supporting Documentation: Baseline form within 
14 days of registration. 
For response to treatment, supporting documentation may include SPEP, UPEP, FLC, 
Serum and Urine Immunofixation, Bone Marrow Biopsy and aspirate, skeletal bone 
survey, and PET scan. These documents should be uploaded into the Supporting 
Documentation form. 
For patients who progress after study therapy supporting documentation may include any 
of the following: SPEP, UPEP, FLC, serum and urine immunofixation, bone marrow 
biopsy and aspirate, skeletal bone survey, and PET scan. These documents should be 
uploaded into the Supporting Documentation form. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 

64 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
18.8 
Overdue lists 
A list of overdue materials is automatically available to each site at any time. The 
appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
 
18.9 
Correction forms 
If a correction is necessary the QAS will query the site. The query will be sent to 
the appropriate site to make the correction in the database and respond back to the 
QAS. 
19.0 
Budget 
19.1 
Costs charged to patient: All routine clinical care. Lenalidomide and daratumumab 
procurement. 
19.2 
Tests to be research funded:  None. 
19.3 
Other budget concerns: Protocol administration, study coordinator time, data 
management, and statistical analysis efforts will be funded by the Division of 
Hematology-Oncology. 

65 
 
Protocol Version Date: 12Jan2022 
 
 
 
20.0 
References 
1. 
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia. 2009;23(1):3-9. 
2. 
Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for 
the management of multiple myeloma patients ineligible for standard high-dose chemotherapy 
with autologous stem cell transplantation. Leukemia. 2009;23(10):1716-1730. 
3. 
Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed 
multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33. 
4. 
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060. 
5. 
Dingli D, Ailawadhi S, Bergsagel PL, et al. Therapy for Relapsed Multiple Myeloma: 
Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. Mayo Clin 
Proc. 2017;92(4):578-598. 
6. 
Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: a first-in-class CD38 
monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol. 2016;9(1):51. 
7. 
McEllistrim C, Krawczyk J, O'Dwyer ME. New developments in the treatment of 
multiple myeloma - clinical utility of daratumumab. Biologics. 2017;11:31-43. 
8. 
Malavasi F, Deaglio S, Ferrero E, et al. CD38 and CD157 as receptors of the immune 
system: a bridge between innate and adaptive immunity. Mol Med. 2006;12(11-12):334-341. 
9. 
Usmani S, Weiss B, Bahlis N, et al. Clinical Efficacy of Daratumumab Monotherapy in 
Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Blood 2015;126:29 
(Abstract). 
10. 
Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and 
Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319-1331. 
11. 
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754-766. 
12. 
Mohty M, Harousseau JL. Treatment of autologous stem cell transplant-eligible multiple 
myeloma patients: ten questions and answers. Haematologica. 2014;99(3):408-416. 
13. 
Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials 
for multiple myeloma: update of protocols conducted by the intergroupe francophone du 
myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin 
Oncol. 2010;28(7):1209-1214. 
14. 
Lonial S, Anderson KC. Association of response endpoints with survival outcomes in 
multiple myeloma. Leukemia. 2014;28(2):258-268. 
15. 
Paiva B, van Dongen JJ, Orfao A. New criteria for response assessment: role of minimal 
residual disease in multiple myeloma. Blood. 2015;125(20):3059-3068. 
16. 
Sengsayadeth S, Malard F, Savani BN, Garderet L, Mohty M. Posttransplant maintenance 
therapy in multiple myeloma: the changing landscape. Blood Cancer J. 2017;7(3):e545. 
17. 
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple myeloma. 
Lancet Oncol. 2016;17(8):e328-e346. 
18. 
Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for 
minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow 
cytometry. Leukemia. 2014;28(2):391-397. 
19. 
Paiva B, Gutierrez NC, Rosinol L, et al. High-risk cytogenetics and persistent minimal 
residual disease by multiparameter flow cytometry predict unsustained complete response after 
autologous stem cell transplantation in multiple myeloma. Blood. 2012;119(3):687-691. 

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20. 
Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum 
free light chain, and immunophenotyping for response evaluation and prognostication in multiple 
myeloma. J Clin Oncol. 2011;29(12):1627-1633. 
21. 
Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program 
with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation 
followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by 
the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712-2717. 
22. 
Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the 
most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell 
transplantation. Blood. 2008;112(10):4017-4023. 
23. 
Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by 
multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical 
Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540-2547. 
24. 
Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al. Minimal residual disease monitoring 
in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time 
quantitative polymerase chain reaction and flow cytometry. Haematologica. 2005;90(10):1365- 
1372. 
25. 
Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and 
lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-423. 
26. 
Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of 
hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American 
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27. 
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus 
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28. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 
1989;10(1):1-10. 

 
Protocol Version Date: 12Jan2022 
 
Appendix I 
ECOG Performance Status Scale 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649- 
655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
From http://www.ecog.org/general/perf stat.html 

68 
 
Protocol Version Date: 12Jan2022 
 
 
 
 
Appendix II 
Creatinine Clearance (CrCl) Calculation 
 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females = 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 

 
Protocol Version Date: 12Jan2022 
 
Appendix III New York Heart Association Classification of Congestive Heart Failure 
 
 
 
NYHA 
Class 
 
Symptoms 
 
I 
 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
no shortness of breath when walking, climbing stairs etc. 
 
II 
 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
 
III 
 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g. walking short distances (20–100 m). Comfortable only at rest. 
 
IV 
 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart 
Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the 
heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association , Inc. Diseases of the Heart 
and Blood Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown 
and Co. 1964, p 114. 

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Protocol Version Date: 12Jan2022 
 
 
 
 
Appendix IV Mayo Risk Stratification 
 
 
High Risk 
 
FISH deletion 17p 
FISH t(14; 16) 
FISH t(14; 20) 
 
GEP (if done) High-risk signature 
 
 
Intermediate Risk 
 
FISH t(4:14) 
 
Metaphase cytogenetic del 13 
Hypodiploidy 
 
 
Standard Risk 
 
All others including: 
 
FISH t(11; 14) 
 
FISH t(6; 14)