Response Adapted Therapy With Bortezomib/Dexamethasone Followed by Addition of Lenalidomide in Non Responders as Initial Treatment for Patients With Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma (MM)
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
PaQe 1 of 61 
 
 
 
 
Response Adapted Therapy with Bortezomib/Dexamethasone Followed by Addition of 
Lenalidomide in non Responders as Initial Treatment for Patients with Multiple Myeloma 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
I  Principal Investigator/Department: 
 
 
I  Hani Hassoun, MD 
I
Medicine 
 
Co-Principal 
Investigator(s)/Department: 
Heather Landau, MD 
Medicine 
Investigator(s)/Department: 
Sergio Giralt, MD 
David Straus, MD 
David Chung, MD, PhD 
Alexander Lesokhin, MD 
Nikoletta Lendvai, MD, PhD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Matthew Matasar, MD 
Alison Moskowitz, MD 
Craig Moskowitz, MD 
Ariela Noy, MD 
M. Lia Palomba, MD 
Carol Portlock, MD 
Craig Sauter, MD 
Andrew Zelenetz, MD, PhD 
Ola Landgren, MD, PhD 
Eric Smith, MD, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Regina Byrne, APN 
Janet Cogswell, CRN 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Avni Desai, MD 
Jahan Ahgalar, MD 
Sham Mailankody, MBBS 
Krysti Corrado, CRN 
Medicine 
Medicine 
Medicine 
Nursing 
Kenneth Ng, MD 
Pamela Drullinsky, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Treso-Sandoval, MD 
Erin Scansarole, CRN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Philip Caron, MD PhD 
Gloria Wasilewski, CRN 
Medicine 
Nursing 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
PaQe 2 of 61 
 
 
 
Jason Konner, CRN 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Virginia Klimek, MD 
Marina Shcherba, MD 
Neha Korde, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Sean M. Devlin, PhD 
Ewa Chauvin, NP 
Maesa Koeber, NP 
Shani Irby, NP 
Megan Heavey Scott, NP 
Abigail Cohen, NP 
Nicole Lestrange, NP 
Tara Wolff, NP 
Michelle Wisniewski, PA 
Allison Sams, NP 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine 
Nursing 
Consenting 
Professional( s)/Department: 
Sergio Giralt, MD 
David Straus, MD 
Hani Hassoun, MD 
David Chung, MD, PhD 
Heather Landau, MD 
Alexander Lesokhin, MD 
Nikoletta Lendvai, MD, PhD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Matthew Matasar, MD 
Alison Moskowitz, MD 
Craig Moskowitz, MD 
Ariela Noy, MD 
M. Lia Palomba, MD 
Carol Portlock, MD 
Craig Sauter, MD 
Andrew Zelenetz, MD, PhD 
Eric Smith, MD, PhD 
Ola Landgren, MD, PhD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Medicine 
Medicine 
Medicine 
Avni Desai, MD 
Jahan Ahgalar, MD 
Sham Mailankody, MBBS 
Medicine 
Medicine 
Medicine 
Kenneth Ng, MD 
Pamela Drullinsky, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Philip Caron, MD PhD 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
PaQe 3 of 61 
 
 
I 
 Ridge 
 
I 
 
 
 
 
 
 
 
 
 
 
 
Westchester 
OneMSK Sites 
 
Marina Shcherba, MD 
Neha Korde, MD 
Medicine 
Medicine 
Jason Kanner, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Medicine 
Medicine 
Medicine 
 
 
 
MSK Alliance Clinical Trials Sites 
Pl's Name 
Site's Role 
Hartford HealthCare 
W. Jeffrey Baker, MD 
Data Collection 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
Page 4 of 61 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 9 
Secondary objectives: .................................................................................................................... 9 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 9 
3.1 
Overview on First Line Treatment of Multiple Myeloma .................................................... 9 
3.1.1 
Induction therapy .................................................................................................... 1O 
3.1.2 
Autologous Stem Cell Transplantation .................................................................... 1O 
3.2 
Rationale for the Concept of the Current Clinical Trial .................................................... 10 
3.3 
Rationale for the Drugs and doses chosen in the Current Clinical Trial. ......................... 12 
3.3.1 
Clinical Experience with Lenalidomide and Dexamethasone in NDMM ................... 12 
3.3.2 
Clinical experience with bortezomib ........................................................................ 12 
3.3.3 
Clinical Experience with Bortezomib Plus Lenalidomide and Dexamethasone ........ 16 
3.4 
Rationale for the Concept of the Correlatives for this Clinical Trial. ................................ 17 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 18 
4.1 
Design ........................................................................................................................... 18 
4.2 
Intervention .................................................................................................................... 18 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 19 
5.1.2 Preparation, Handling, Storage, and Destruction of Drugs ........................................... 20 
5.1.3 
Bortezomib Administration ...................................................................................... 21 
5.1.4 
Subcutaneous Administration ................................................................................. 21 
5.1.5 
Packaging, and Labeling......................................................................................... 21 
Bortezomib will be supplied in vials as open-label stock. Both the box label and vial label will fulfill all 
requirements specified by governing regulations .................................................................. 21 
5.2 
Lenalidomide ................................................................................................................. 22 
5.2.1 
Preparation, Handling, Storage, and Destruction of Drugs ...................................... 22 
5.2.2 
Lenalidomide Administration ................................................................................... 23 
5.2.3 
Prescribing lnformation ........................................................................................... 23 
5.2.4 
Packaging ............................................................................................................... 23 
5.3 
Dexamethasone ............................................................................................................. 23 
5.3.1 Preparation, Handling, Storage .................................................................................... 23 
5.3.2 
Administration ......................................................................................................... 24 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 24 
6.1 
Subject Inclusion Criteria ............................................................................................... 24 
6.2 
Subject Exclusion Criteria .............................................................................................. 25 

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7.0 
RECRUITMENT PLAN ...................................................................................................... 27 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 27 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 28 
9.1 
TreatmentPlan ............................................................................................................... 28 
9.1.1 
Initial first 2 cycles of treatment: .............................................................................. 28 
9.1.2 
Treatment beyond the first 2 cycles: ....................................................................... 28 
9.1.3 
Stem cell collection ................................................................................................. 29 
9.2 
Pre-Treatment Criteria ................................................................................................... 29 
9.2.1 
Criteria for initiation of New Cycle of BD or RVD Therapy (Day 1) .......................... 30 
9.2.2 
Criteria for intra-cycle Therapy (Days 4, 8 and 11) .................................................. 30 
9.3 
Dose Modifications/Delays ............................................................................................. 30 
9.3.1 
General Guidelines ................................................................................................. 30 
9.3.2 
Dose Reduction Steps and Guidelines .....................................................................31 
9.3.3 
Dose Modification Guidelines for Specific Drug-Associated Adverse Events ...........32 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 36 
10.1 Evaluation During the Treatment Phase ........................................................................ 36 
10.1.2 Correlative Studies ....................................................................................................... 37 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 38 
11.1 Potential Risks of Bortezomib ........................................................................................ 38 
11.2 Potential Risks of Lenalidomide ..................................................................................... 45 
11.3 Potential Risks of Dexamethasone ................................................................................ 45 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 46 
12.1 Definition of Measurable Disease ................................................................................... 46 
12.2 Methods for Evaluation of Measurable Disease ............................................................. 46 
12.3 International Myeloma Working Group Response Criteria .............................................. 46 
12.4 QOL Questionnaire ........................................................................................................ 48 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 48 
14.0 BIOSTATISTICS ............................................................................................................... 49 
14.1 Primary Endpoint. ............................................................................................................. 49 
14.2 Secondary Endpoints ....................................................................................................... 49 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES50 
15.1 Research Participant Registration .................................................................................. 50 
15.2 Randomization ............................................................................................................... 50 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 50 
16.1 Quality Assurance ......................................................................................................... 50 

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IRB Number: 13-064 A(22) 
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16.2 Data and Safety Monitoring ............................................................................................51 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 51 
17.1 Privacy ...........................................................................................................................52 
17.2 Serious Adverse Event (SAE) Reporting .........................................................................52 
17.2.1 
Serious Event Reporting to Millennium ................................................................... 53 
Definitions ................................................................................................................................ 53 
Adverse Event Definition ....................................................................................................... 53 
Serious Adverse Event Definition ........................................................................................... 54 
Procedures for Reporting Serious Adverse Events (SAEs)....................................................... 55 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events.......................... 56 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 56 
19.0 REFERENCES .................................................................................................................. 58 
20.0 APPENDICES ....................................................................................................................61 

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IRB Number: 13-064 A(22) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Primary Objective: 
The primary objective of the study is to determine the overall response rate (defined as 
Partial Response 
(PR) after 4 cycles of response-adapted sequential therapy using bortezomib and dexamethasone, followed by 
the addition of lenalidomide in suboptimal responders. 
Patient Population 
Patients diagnosed with symptomatic multiple myeloma based on the revised International Myeloma Working 
Group (IMWG) diagnostic criteria. The following criteria must be met at screening time prior to initiation of 
protocol therapy: 1) Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven 
bony or extramedullary plasmacytoma; 2) Any one or more of the following myeloma defining events: Clonal 
bone marrow plasma cell percentage 60%, lnvolved:Uninvolved serum free light chain ratio 100, >1 focal 
lesions on MRI studies (each focal lesion must be 5 mm or more in size), presence of organ damage related to 
the myeloma as defined by the CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions); 3) 
Measurable monoclonal protein (M-protein) present in the serum and/or urine as per IMWG criteria. Non 
transplant candidates are eligible. 
Study Design 
This is a phase II, single center clinical trial designed to evaluate the response rate and toxicity of a response­ 
adapted, sequential therapy, using bortezomib and dexamethasone, followed by the addition of lenalidomide in 
non-responders, in patients with untreated MM. According to the statistical plan detailed in section 14, a 
Simon's optimal two-stage design will be implemented where an overall response rate of 70% after four cycles 
of therapy is considered unpromising and a rate of 90% is considered promising. The maximum sample size 
for the trial is 28 patients. 
Treatment Plan (See schema below) 

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IRB Number: 13-064 A(22) 
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Lenalidomide added (RVD) 
to Bortezomib + 
Dexamethasone x 2 cycles 
 
  
> VGPR  
 
 
Continue Bortezomib and 
Dexamethasone X 4 
cycles 
Lenalidomide added RVD 
to Bortezomib + 
Dexamethasone X 4 cycles 
Response assessment after total of 4 cycles 
Continue Bortezomib and 
Dexamethasone 
X 2 cycles 
Multiple Myeloma 
- Untreated 
- Non ASCT candidate or those who opt to 
forgo ASCT as part of first line therapy 
SC Bortezomib and 
Dexamethasone X 2 cycles 
Response assessment after total of 4 cycles 
 
Response assessment after total of 8 cycles 
 
 
Continue RVD 
X 4 cycles 
SCHEMA 
 
 
 
 
R 
1 
 
 
 
 
 
 
Note 
 
• 
Lenalidomide may be added to the patient's regimen at any time if there is evidence of hematologic 
disease progression. 
• 
 Patients could proceed with stem cell collection after at least 4 cycles if adequate response ( PR) has 
been achieved, at the discretion of the treating physician. These patients may resume treatment on 
study after stem cell collection for addition cycles (not to exceed a total of 8 cycles on study). All other 
patients will continue therapy on study up to 8 cycles. 
PR 
<P

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
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• 
 All patients including those who proceed to stem cell collection or are removed from treatment for 
reasons other than POD, will return for follow-up once every 2 months until progression of disease 
(POD). 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objective: 
 
• 
To determine the overall response rate (defined as.:::_ PR) after 4 cycles of response-adapted 
sequential therapy using bortezomib and dexamethasone (BD) followed by the addition of 
lenalidomide in suboptimal responders. 
Secondary objectives: 
• 
To determine the overall response rate for the entire population after up to 8 cycles of 
response-adapted sequential therapy 
• 
To determine the CR, VGPR, PR after 4 cycles and after 8 cycles (for those completing 8 
cycles) of response adapted sequential therapy 
• 
To determine the toxicity of response-adapted sequential therapy 
• 
To measure quality of life (QOL) using this response adapted sequential therapy 
• 
To determine the PFS of patients after response adapted sequential therapy 
Correlatives: 
• 
Aim 1: Characterization of genomic mutations of targetable genes 
• 
Aim 2: Characterization of immunomodulatory checkpoint pathways in multiple 
myeloma 
 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Overview on First Line Treatment of Multiple Myeloma 
 
Multiple myeloma (MM) is a malignant plasma cell disorder that accounted for an estimated 20,180 (1.32%) 
new cancer cases in the United States (US) in 2010, as well as approximately 10,650 deaths1. Although 
multiple myeloma is uniformly fatal, treatment has dramatically improved over the last several decades with the 
introduction of cytotoxic drugs, high-dose therapy and autologous transplant, and the development of novel 
agents. 
Based on the United Kingdom (UK) Myeloma Forum and the Nordic Myeloma Study Group recommendations2 
and National Comprehensive Cancer Network (NCCN) Practice Guidelines3, chemotherapy is indicated for the 
management of MM presenting with myeloma-related organ damage (a condition referred to as symptomatic 
myeloma as opposed to asymptomatic myeloma). Organ damage includes hypercalcemia, renal failure, 
anemia, and bone disease (CRAB). 
Standard first line treatment for patients with symptomatic MM deemed eligible for transplantation consists of 2 
phases of treatment: The first is referred to as the induction therapy and consists of various combinations of 
therapeutic agents. The second consists of high dose melphalan followed by autologous stem cell 
transplantation (HDM/ASCT)4-6. For patients who are considered ineligible for HDM/ASCT because of 

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advanced age or co-morbidities, the treatment has included an induction treatment followed by a maintenance 
regimen, often consisting of the same drugs used during induction but administered at lower doses and slightly 
modified schedule, for a variable period of time7-17. 
3.1.1 
Induction therapy 
 
MM is sensitive to a number of cytotoxic drugs such as alkylating agents, anthracyclines, and corticosteroids 
for initial treatment. Melphalan plus prednisone (MP) has been the standard chemotherapy regimen. Other 
older chemotherapy regimens still recommended in the NCCN guidelines include single-agent 
dexamethasone3; VAD (vincristine-adriamycin-dexamethasone); and DVd (liposomal doxorubicin, vincristine, 
and dexamethasone). The last several years, however, have witnessed the introduction of several newer 
agents such as bortezomib, thalidomide, and lenalidomide that have been effective in the treatment of multiple 
myeloma, as demonstrated by improved response rates and, in the case of bortezomib, improved 5-year 
survival17. Combination chemotherapy regimens with these newer agents currently recommended in the NCCN 
guidelines include: VMP (bortezomib, melphalan, prednisone)7•17; MPT (melphalan, prednisone, 
thalidomide )8•18; Thal-Dex (thalidomide-dexamethasone)19-22; RevDex (lenalidomide/low-dose 
dexamethasone23; V-Dex (bortezomib-dexamethasone)24•25; and bortezomib, dexamethasone, and either 
lenalidomide26 or thalidomide27. Despite the marked increase in the number of therapeutic options, the disease 
remains incurable and there remains a need for new and better agents as well as a better understanding of 
when and how to combine effective or novel agents. 
3.1.2 
Autologous Stem Cell Transplantation 
 
There have been several large prospective trials in France (IFM 90)4•28-30 and in UK (MRC 9)5, and one large 
retrospective study of myeloma patients in Nordic countries31, showing a survival benefit for HDM/ASCT 
compared to conventional chemotherapy. In the larger study, IFM 90, newly diagnosed untreated patients less 
than 65 years of age with OS stage II or Ill MM were randomized to either SCT after up to 6 cycles of VMCP 
alternating with BVAP or conventional chemotherapy with 18 cycles of VMCP alternating with BVAP. 
Recombinant interferon alpha (IFNa) was administered to patients in both groups until relapse. By intent-to­ 
treat, SCT patients had a significantly higher response rate (CR+VGPR 38% versus 14%) than those 
receiving conventional chemotherapy. At a median follow-up of 37 months in the chemotherapy group and 41 
months in the SCT group, the latter had significantly longer PFS and OS. The other studies have confirmed 
these results. Based on these trials, autologous stem cell transplantation using melphalan 200 mg/m2 has 
become part of the standard treatment of symptomatic multiple myeloma patients eligible for the procedure. 
Smaller studies have reached similar conclusions. 
 
Although HDM/ASCT has improved response rate and in some trials overall survival rate in patients with 
MM, all patients eventually relapse and the disease remains incurable and relapse occurs in almost all 
patients, with a median survival period of 5 to 7 years. Although ASCT remains a cornerstone of therapy 
following induction chemotherapy in transplant eligible patients, the high response rates reported with novel 
agents in transplant eligible and ineligible patients has raised the question of the utility of early ASCT in 
newly diagnosed multiple myeloma (NDMM) and there currently is an interest in clinical trials that delay 
ASCT until disease progression. 
3.2 
Rationale for the Concept of the Current Clinical Trial 
 
The aggressive approach to first line treatment of MM, which has lead to the incorporation of ASCT, has 
also been adopted during the induction phase of the treatment. Investigators have strived to develop 

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successive combination regimens aiming at achieving ever higher response rates. While the combination 
of dexamethasone, doxorubicin, and vincristine (VAD) was standard induction for a long time, achieving 
75% ORR and 10% >VGPR, several new induction regimens have included novel drugs (proteasome 
inhibitors and immunomodulators). These combinations have proven more effective, achieving higher 
ORR than their predecessors. They consisted initially of doublets like thalidomide/dexamethasone22•32, 
lenalidomide/dexamethasone23•33, and bortezomib/dexamethasone34•35, but were expanded to include triplet 
and quadruplet drug regimens. Several phase Ill trials8•9•36-4° of thalidomide plus melphalan and 
prednisone (MPT) versus melphalan and prednisone (MP) showed increased ORR with MPT in 
patients ineligible for ASCT, with OS benefit shown in some trials. Likewise, the phase Ill VISTA trial 
demonstrated superior efficacy with bortezomib plus melphalan and prednisone (VMP) versus MP in 
previously untreated patients ineligible for ASCT15-17. Cavo et al, in a randomized study for ASCT 
eligible patients showed the combination of dexamethasone, bortezomib and thalidomide (VTD) to 
achieve still greater results with 93% ORR and 60% >VGPR41A2.  Recently, Richardson et al 
demonstrated that the combination of lenalidomide, bortezomib and dexamethasone (RVD) 
administered to 66 transplant and non-transplant patients resulted in 49 patients achieving at least a 
PR after 4 cycles of treatment (6% CR/nCR; 5% VGPR, and 64% PR). Improvement in response by at 
least one response category was noted in 75% of the 56 patients that continued on therapy from cycle 
4 through cycle 8, with further improvement in response noted in 20 of 37 patients who continued 
beyond cycle 8 with maintenance therapy resulting in 100% ORR and 74% >VGPR26A3. Hence, it has 
become fairly common practice for patients to receive more aggressive induction regimens whether 
eligible for ASCT or not. 
 
However, this aggressive approach to therapy, whether pertaining to ASCT or to induction, is not 
without controversy. Regarding ASCT, Fermand et. al demonstrated that the OS of patients receiving 
ASCT as first-line therapy is identical to OS of those who receive it at relapse, suggesting that the 
perceived benefit to the ASCT arm over the conventional therapy arm in the randomized phase Ill trial 
mentioned above, may well be ascribed to the availability of an additional treatment modality rather 
than to the aggressive upfront approach combining induction to ASCT44. Further supporting this 
concept, a meta-analysis by Koreth comparing ASCT to conventional chemotherapy showed advantage in 
PFS but not OS45. This data indicates that although more aggressive therapy in the form of ASCT may lead 
to improved ORR and PFS, it may not necessarily translate into improved OS. In this context, an 
international trial is currently evaluating the need for ASCT upfront in the era of novel agents, comparing 
RVD with and without upfront ASCT. 
 
Likewise, regarding the induction phase, and although the improved ORR of multiple drug regimens 
has been ascertained, it is not universally accepted that this improved ORR translates into improved 
long term outcome, i.e. OS. This uncertainty becomes even more important when one considers the 
toxicity profile associated with multi-drug regimens that expose patients simultaneously to several drugs 
with distinct and sometimes additive side effects. 
 
Whether patients should be exposed to doublet, triplet, or quadruplet combinations during induction 
remains one of the major unanswered questions haunting physicians treating MM patients, whether 
transplant candidates or not. While improved ORR associated with simultaneous exposure to multiple 
drugs has been established, it is conceivable that such a benefit could be retained while toxicity profile 
improved by a response adapted sequential introduction of drugs. 

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IRB Number: 13-064 A(22) 
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In the proposed trial we would like to test the efficacy and the toxicity of such a sequential response adapted 
approach, starting therapy with subcutaneous Bortezomib and dexamethasone, adding Revlimid based on the 
response to Bortezomib/Dexamethasone. 
3.3 
Rationale for the Drugs and doses chosen in the Current Clinical Trial 
 
Several clinical studies have established the effectiveness of bortezomib, the first proteasome inhibitor, and 
lenalidomide in the treatment of new diagnosed multiple myeloma. Since these agents have differing 
mechanisms of action, clinical trials of 2- and 3-drug regimens incorporating proteasome inhibition 
(bortezomib), IMiD (lenalidomide), and dexamethasone have been conducted in NDMM. These combinations 
have been shown to be effective with phase 3 combination trials ongoing. 
 
 
3.3.1 
Clinical Experience with Lenalidomide and Dexamethasone in NDMM 
Lenalidomide is a thalidomide analogue that has significant clinical activity in multiple myeloma. Lenalidomide 
in combination with dexamethasone is approved by the FDA for the treatment of multiple myeloma patients 
who have received at least 1 prior therapy. Based on the activity of this combination in the relapse/refractory 
setting, clinical trials have been completed in patients with NDMM. The Eastern Cooperative Oncology Group 
(ECOG) conducted a randomized phase 3, multicenter, open-label study (E4A03) in 445 patients with 
NDMM23. The primary outcome of the trial was to determine whether low-dose dexamethasone (40 mg on 
Days 1, 8, 15, and 22 of a 28-day cycle) plus lenalidomide (Ld) was noninferior to high-dose dexamethasone 
(40 mg on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle) plus lenalidomide (LO). After 
4 cycles of therapy, patients could either discontinue the planned protocol therapy to undergo a stem-cell 
transplant or continue on protocol therapy until disease progression. Results showed that Ld is associated with 
better overall survival and a lower toxicity profile compared to LO. At the 1-year, second interim analysis, 
overall survival was 96% (95% Cl 94-99) in the Ld group compared with 87% (82-92) in the LD group (p = 
0.0002) and toxicity was higher in the high dose group. Consequently, the trial was stopped and patients on 
high-dose therapy were crossed over to low-dose therapy. 
 
The Southwest Oncology Group (SWOG) conducted a randomized, phase 3, double-blind, crossover, placebo­ 
controlled, multicenter study in patients with NDMM33. The primary endpoint was to compare the progression­ 
free survival (PFS) of patients treated with dexamethasone plus lenalidomide or placebo. The target accrual 
was 500 patients; however the study closed early with an accrual of 198 after results of the ECOG trial E4A03 
reported improved survival using Ld versus LO. The estimated 1-year PFS was 77% in the 100 patients treated 
with lenalidomide-dexamethasone and 55% in the 98 with dexamethasone plus placebo; however, 1-year 
overall survival was similar in both groups (93% vs 91%). The response rate was 85.3% (22.1% CR) versus 
51.3% (3.8% CR) in the groups respectively. 
3.3.2 
Clinical experience with bortezomib 
It is estimated that as of June 2011, more than 300,000 patients have been treated with bortezomib, including 
patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the US NCI Cancer 
Therapy Evaluation Program (CTEP), and with commercially available drug. Bortezomib has been 
commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-limiting toxicity (DLT) 
of bortezomib in a number of therapeutic settings involving subjects with various advanced malignancies. In a 
phase 1 trial in patients with refractory hematologic malignancies, the MTD for a twice weekly dosing for 4 

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weeks of a 42-day cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, hypokalemia, 
fatigue, and malaise46. The toxicity was greatest during the 3rd and 4th weeks of therapy. In the 3-week 
schedule of bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the 
DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with peripheral sensory 
neuropathy). Therefore, the MTD at this schedule was 1.3 mg/m2/dose. In a 35-day treatment cycle with 4 
weekly doses of bortezomib monotherapy, the MTD was 1.6 mg/m2/dose and DLT included hypotension, 
tachycardia, diarrhea, and syncope. 
In phase 1 clinical studies, antitumor activity was reported in subjects with Non-Hodgkin Lymphoma (NHL), 
MM, Waldenstrom's Macroglobulinemia, squamous cell carcinoma of the nasopharynx, bronchoalveolar 
carcinoma of the lung, renal cell carcinoma, and prostate cancer46•49. 
The safety and efficacy of bortezomib in subjects with MM were investigated in two phase 2 clinical studies, 
studies M34100-024 (subjects with first relapse)50 and M34100-025 (subjects with second or greater relapse 
and refractory to their last prior therapy)51. In M34100 025, 202 heavily pretreated subjects with refractory MM 
after at least 2 previous treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day 
treatment cycle. The European Group for Blood and Marrow Transplant (EBMT) response criteria, as 
described by Blade were utilized to determine disease response. Complete responses (CRs) were observed in 
4% of subjects, with an additional 6% of patients meeting all criteria for CR but having a positive 
immunofixation test. Partial response (PR) or better was observed in 27% of subjects, and the overall 
response rate (CR, PR, and minor response [MR] combined) was 35%. Seventy percent of subjects 
experienced stable disease or better. 
The phase 3 study (M34101-039)25, also referred to as the APEX study, was designed to determine whether 
bortezomib provided benefit (time to progression [TTP], response rate, and survival) to patients with relapsed 
or refractory MM relative to treatment with high-dose dexamethasone. The study was also designed to 
determine the safety and tolerability of bortezomib relative to high-dose dexamethasone, and whether 
treatment with bortezomib was associated with superior clinical benefit and quality of life relative to high-dose 
dexamethasone. A total of 669 patients were enrolled and 663 patients received study drug (bortezomib: 331; 
dexamethasone: 332). Patients randomized to bortezomib received 1.3 mg/m2 IV push twice weekly on Days 
1, 4, 8, and 11 of a 3-week cycle for up to 8 treatment cycles as induction therapy, followed by 1.3 mg/m2 
bortezomib weekly on Days 1, 8, 15, and 22 of a 5-week cycle for 3 cycles as maintenance therapy. Patients 
randomized to dexamethasone received oral dexamethasone 40 mg once daily on Days 1 to 4, 9 to 12, and 17 
to 20 of a 5-week cycle for up to 4 treatment cycles as induction therapy, followed by dexamethasone 40 mg 
once daily on Days 1 to 4 of a 4-week cycle for 5 cycles as maintenance therapy. The EBMT response criteria 
were utilized to determine disease response. There was a 78% increase in TTP for the bortezomib arm. 
Median TTP was 6.2 months for the bortezomib arm and 3.5 months for the dexamethasone arm (p < 0.0001). 
CR + PR was 38% with bortezomib versus 18% with dexamethasone (p < 0.0001). CR was 6% with 
bortezomib versus 1% with dexamethasone (p < 0.0001). The CR + nCR (near CR) rate was 13% with 
bortezomib versus 2% with dexamethasone. In patients who had received only 1 prior line of treatment 
(bortezomib: 132; dexamethasone: 119), CR + PR was 45% with bortezomib vs 26% with dexamethasone (p 
= 0.0035). With a median 8.3 months of follow up, overall survival was significantly longer (p = 0.0013) for 
patients on the bortezomib arm versus patients on the dexamethasone arm. The probability of survival at 1 
year was 80% for the bortezomib arm versus 66% for the dexamethasone arm, which represented a 41% 
decreased relative risk of death in the first year with bortezomib(p = 0.0005). In patients who had received 
only 1 prior line of treatment, the probability of survival at 1 year was 89% for the bortezomib arm versus 72% 
for the dexamethasone arm, which represented a 61% decreased relative risk of death in the first year with 
bortezomib(p = 0.0098). Updated response rates and survival data were reported in abstract form in 2005 for 

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M34101-039. The updated CR+ PR rate was 43% with bortezomib. The CR+ nCR rate was 16% with 
bortezomib. With a median 22 months of follow up, overall survival was significantly longer for patients on the 
bortezomib arm versus patients on the dexamethasone arm. The median overall survival was 29.8 months 
(95% Cl: 23.2, not estimable) for the bortezomib arm vs 23.7 months (95% Cl: 18.7, 29.1) for the 
dexamethasone arm (hazard ratio= 0.77, p = 0.0272). The probability of survival at 1 year was 80% for the 
bortezomib arm versus 67% for the dexamethasone arm (p = 0.0002). 
The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma (MCL) were investigated 
in an international, phase 2, multicenter study M34103-053, also referred to as the PINNACLE study52. The 
single-arm study was designed to evaluate the response rates, duration of response (DOR), TTP, overall 
survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma. 
For 141 evaluable patients, the response rate was 31% (8% CR/unconfirmed CR [Cru]). Median time to 
response was 40 days (range 31-204 days). The median number of cycles administered across all patients 
was 4; in responding patients, the median number of cycles was 8. The median DOR by algorithm was 9.2 
months and 13.5 months in patients with CR/CRu. Median TTP for both groups was 6.2 months. With a 
median follow-up of 13.4 months, overall survival had not been reached. The most commonly reported 
adverse events (AEs) were fatigue, peripheral neuropathy, and gastrointestinal events. A time-to-event update 
to the PINNACLE study was reported in abstract form in 2007 after a median follow-up of 26.4 months. TTP 
was 6.7 months for all patients, 12.4 months in all responders. The median DOR was 9.2 months in all 
responders and had not been reached in patients achieving CR/Cru. Overall survival was 23.5 months in all 
patients and 36 months in patients with CR/Cru. Survival at 12 months was 69% overall and 91% in 
responding patients. 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and efficacy of the 
combination of bortezomib, melphalan, and prednisone in previously untreated multiple myeloma patients who 
were not candidates for stem cell transplant53. The study was designed to determine the benefit of adding 
bortezomib to MP (melphalan and prednisone) as assessed by TTP. Patients (682) were randomized to 
receive nine 6-week cycles of melphalan 9mg/m2 and prednisone 60 mg/m2 on Days 1 to 4, alone or in 
combination with bortezomib1.3 mg/m2 by IV bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 to 
4, and on Days 1, 8, 22, and 29 during Cycles 5 to 9. Response was evaluated every 3 weeks using the 
EBMT criteria. At a preplanned interim analysis, the independent data monitoring committee recommended 
that the study be stopped since the prespecified statistical boundary end point of TTP had been crossed. 
Response rates were 30% with 4% CR. The rates of partial response or better were 71% in the bortezomib 
(VMP) group compared to 34% in the MP group (p = 0.001). With follow-up of 16.3 months, the TTP for the 
VMP group was 24 months compared to 16.6 months in the MP group (p = 0.000001) and was associated with 
a 52% reduced time to progression. The median DOR was 19.9 months in the VMP group and 13.1 months in 
the MP group. Overall survival had not been reached in either group. Hematologic toxicity was similar in both 
groups. The incidence of peripheral sensory neuropathy and gastrointestinal symptoms was higher in the VMP 
group. The incidence of herpes zoster was 3% in patients in the VMP group who received antiviral 
prophylaxis. Fifteen percent of patients in the VMP group discontinued therapy due to AEs compared to 14% 
in the MP group. 
The VISTA study update after extended follow-up of 25.9 months17, confirmed a survival benefit for the VMP 
group. Overall survival was not reached in either group: VMP group (75) deaths, 3 year OS 72%; MP group 
(111) deaths, 3 year OS 59% (p = 0.0032). Patients on VMP were less likely to start second-line therapy (VMP 
38% vs MP 57% at the time of data cut-off) with a longer time to next therapy (TNT) and treatment free interval 
(TFI). Of the MP patients who received subsequent therapy, 43% went on to receive bortezomib. 

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Based on investigator-reported best responses to subsequent therapies, patients relapsing after therapy with a 
novel agent were not intrinsically more resistant than after receiving a traditional agent. 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS. Patients were successfully 
treated with subsequent IMiD-based therapy and retreated with bortezomib. After 36.7 months follow-up, OS 
continued to be superior for VMP. The OS for VMP had not yet been reached compared to MP (43.1 
months)17. In an abstract updated analysis of overall survival based on 387 deaths (median follow-up 60.1 
months) performed in 2011, the median overall survival for VMP was 56.4 months and the MP was 43.1 
months, with a hazard ration of 0.695 (95% Cl: 0.57, 0.85). 
SUBCUTANEOUS ADMINISTRATION 
 
A randomized Phase 1 pilot study in 24 subjects with multiple myeloma demonstrated that both the IV and SC 
routes of bortezomib administration have similar systemic drug exposure and proteasome inhibition. 
Importantly, SC and IV administration of bortezomib appeared to result in similar efficacy profiles (ie, response 
rate) and similar safety profiles. The pilot study also provided preliminary evidence of good local tolerance for 
SC injection of bortezomib, when administered at 1 mg/ml concentration54. 
The data from the Phase 1 pilot study formed the basis of the design of a randomized, Phase 3 study that 
compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1.3 mg/m2 
dose and twice per week schedule in patients with relapsed multiple myeloma55. 222 patients were randomly 
assigned in a 2:1 ratio to receive either subcutaneous (n=148) or intravenous (n=74) bortezomib. The 
response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous 
group. Patients received a median of eight cycles (range one to ten) in both groups. 
The ORR (CR+PR) after 4 cycles of treatment, assessed by computer algorithm implementation of EBMT 
response criteria, was 42 % in both the SC and IV treatment groups for the response-evaluable population. 
The ORR after 4 cycles in the IV arm was consistent with what was observed in historical single-agent 
bortezomib trials with relapsed multiple myeloma subjects. The stratified Mantel Haenszel estimate of the 
relative risk of achieving response for SC treatment group versus IV treatment group was 0.99 with 95% Cl 
(0.71, 1.37). The 95% Cl for ORR_SC - 0.6 ORR_IV was (6.1, 27.1), which excludes 0. Thus the study met the 
noninferiority objective (p-value for the noninferiority hypothesis was 0.00201). Results in the ITT population 
were similar; noninferiority of SC versus IV was also demonstrated. 
The CR rate after 4 cycles of treatment was 6% in the SC treatment group and 8% in the IV treatment group; 
the nCR rate after 4 cycles of treatment was 6% in the SC treatment group and 5% in the IV treatment group; 
the VGPR rate after 4 cycles of treatment was 4% in the SC treatment group and 3% in the IV treatment group. 
Therefore, 17% subjects in the SC treatment group and 16% subjects in the IV treatment group had obtained 
at least VGPR after the first 4 cycles. 
The ORR (CR+PR) after 8 cycles of treatment was 52% in both the SC and IV treatment groups for the 
response-evaluable population. The stratified Mantel-Haenszel estimate of the common relative risk of 
achieving response for SC versus IV was 1.00 with 95% Cl (0.77, 1.31). Twenty-five percent of subjects in the 
SC treatment group and 25% of subjects in the IV treatment group had obtained at least VGPR during the first 
8 cycles. 
The median TTP (Kaplan-Meier estimate) was 10.4 months in the SC treatment group and 9.4 months in the IV 
treatment group. The hazard ratio was 0.839 with 95% Cl (0.564, 1.249), and the p=0.3866 (stratified log-rank 
test), indicating similar results between the SC and IV arm. 

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The median PFS (Kaplan-Meier estimate) was 10.2 months in the SC treatment group and 8.0 months in the 
IV treatment group. The hazard ratio was 0.824 with 95% Cl (0.574, 1.183), and the p=0.2945 (stratified log­ 
rank test), indicating comparable results between the SC and IV arm. 
After a median follow-up of 11.8 months, the 1-year survival rate was 72.6% in the SC arm and 76.7% in the IV 
arm. The p-value for the difference in 1-year survival rate was 0.5037, indicating similar results between the 
SC and IV arm. 
The median time to first response (Kaplan-Meier estimate) was 3.5 months for both the SC and IV treatment 
groups. The hazard ratio was 1.059 with 95% Cl (0.716, 1. 567), and the p=0.7725 (stratified log-rank test), 
indicating similar results between the SC and IV arm. Among the responders, the median time to first response 
was 1.4 months (44 days) in the SC arm and 1.4 months (43 days) in the IV arm. Among the responders, the 
median duration of response (Kaplan-Meier estimate) was 9.7 months in the SC treatment group, compared 
with 8.7 months in the IV treatment group. 
Overall, similar efficacy results were observed in the SC and IV treatment groups, and the study demonstrated 
that bortezomib SC administration is not inferior to bortezomib IV administration55. 
The value of the addition of dexamethasone to the bortezomib therapeutic regimen was assessed in patients 
who participated in phase 2 studies M34100-025 (SUMMIT)56 and M34100-024 (CREST)57. Patients with PD 
after the first 2 cycles or stable disease (SD) after 4 cycles of bortezomib monotherapy were permitted to add 
dexamethasone 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle. Additional 
responses were observed in 28 of 100 patients. The toxicities reported during combination therapy were 
manageable, and their incidence was not increased compared with single-agent bortezomib therapy. Similarly, 
patients administered bortezomib SC or IV in Study 26866138-MMY-3021 were permitted to receive 
dexamethasone after completion of 4 cycles of treatment if they had no response and had not progressed. 
Eighty-two (68%) SC-treated patients and 39 (32%) IV-treated patients received dexamethasone starting in 
Cycle 5. The addition of dexamethasone improved response in both groups: of patients with no response at the 
end of Cycle 4, 30% in both SC- and IV-treated groups obtained a partial response later; patients with a PR at 
the end of Cycle 4 improved to CR later in 13% of patients in both the SC- and IV-treated groups. 
3.3.3 
Clinical Experience with Bortezomib Plus Lenalidomide and Dexamethasone 
Evidence to support combining bortezomib with immunomodulatory analogues, includes preclinical data 
demonstrating synergistic effects on apoptosis, clinical efficacy seen with the combination of bortezomib, 
lenalidomide, and dexamethasone in relapsed/ refractory disease, and the clinical activity of these agents in 
NDMM patients. Richardson and colleagues conducted a phase 1/2 study combining lenalidomide, bortezomib, 
and dexamethasone in NDMM patients26. The primary end points were to determine the MTD of this 
combination (phase 1) and to evaluate response rate (> PR) to the combination (phase 2). Response 
assessments were done after 4 and 8 cycles of therapy. Patients received lenalidomide on Days 1 through 14, 
bortezomib on Days 1, 4, 8, and 11, and dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, and 12, for eight 21-day 
cycles. Patients with a CR or nCR/PR after Cycle 4 could proceed at any point to stem cell mobilization and 
transplantation. Patients with stable or responding disease without unacceptable toxicity at the completion of 
Cycle 8, were allowed to continue onto the maintenance phase of the study which comprised of 3-week cycles 
of bortezomib on Days 1 and 8, lenalidomide on Days 1 through 14 at the doses tolerated at the completion of 
cycle 8, and dexamethasone 10 mg the day before and after bortezomib (Days 1, 2, 8, and 9). In the phase 1 
portion of the study, the combination of lenalidomide 25mg, bortezomib1 .3 mg/m2, with reduced 
dexamethasone (20/10 mg), was determined to be the MTD of the combination and the RP2D. Overall 66 
patients were enrolled to this study (Phase 1 n=31; Phase 2 n=35). Results indicated that the combination of 

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lenalidomide, bortezomib, and dexamethasone was highly active in patients with NDMM, with all patients 
(100%) achieving at least a pre-ASCT response of PR and high rates of VGPR or better (CR + nCR + VGPR). 
In both the phase 2 population and overall, 74% and 67% respectively achieved a VGPR or better. Overall, 49 
patients achieved at least a PR after 4 cycles of treatment (6% CR/nCR; 5% VGPR, and 64% PR). 
Improvement in response by at least one response category was noted in 75% of the 56 patients that 
continued on therapy from cycle 4 through cycle 8, with further improvement in response noted in 20 of 37 
patients who continued beyond cycle 8 with maintenance therapy. With a median follow-up of 21 months, 
neither the median DOR nor median OS has been reached. The authors concluded the bortezomib, 
lenalidomide and dexamethasone (VRD) combination was a highly effective regimen for patients with NDMM. 
 
In the proposed trial, we will be using this latter phase II trial as benchmark for comparison and hypothesize 
that the sequential, response adapted approach proposed in this trial will lead to comparable response rates 
after 4 and also after 8 cycles with lesser exposure to drugs and associated side effects. 
 
3.4 
Rationale for the Concept of the Correlatives for this Clinical Trial 
As the development of molecularly targeted and immune based therapies continues, incorporating knowledge 
of mutational and immune checkpoint "status" into clinical practice will enable rapid identification of patients 
eligible for clinical trials with genetically- and immunophenotypically-defined entry criteria. 
 
Aim 1: Characterization of genomic mutations of targetable genes: In recent years candidate gene and 
genome-wide studies have identified somatic genetic alterations that may contribute to hematopoietic 
transformation in a wide spectrum of hematopoietic malignancies. Moreover, in many cases these newly 
discovered lesions have therapeutic and/or prognostic significance, such as the identification of BRAF V600E 
mutations in a subset of myeloma, which may be potentially amenable to therapy with available drugs. 
Although a small set of genetic alterations, most commonly gene mutations or chromosomal translocations, 
have found tangible applications in the clinical arena, the clinical significance of many recently identified 
genetic alterations are not well understood. Indeed, for the majority of genetic alterations in MM, there are few 
retrospective or prospective studies available to allow clinicians and researchers to determine if these 
mutations have clinical value. Thus, additional studies, which cast a broad net across pharmacologically 
targetable genes, may be a more pragmatic and fruitful means to realize the potential of personalized 
molecularly targeted therapies for individual patients with MM. The first goal of the correlative studies being 
proposed is to pursue such an approach using next generation sequencing of known targetable genes. Using 
serially obtained samples in the context of a response adjusted Vd followed by VRd treatment program we will 
Characterize and correlate mutational frequency with treatment outcome using Nimblgen capture followed by 
next-generation sequencing of all exons of a set of 600 genes known to be important to the pathogenesis of 
hematopoietic malignancies. 
 
 
Aim 2: Characterization of immunomodulatory checkpoint pathways in multiple myeloma: In the past decade, 
immune checkpoint blockade has emerged as a promising means to achieve durable disease control through 
enhanced anti-tumor immunity. lpilimumab, which blocks the function of CTLA-4, was the first drug in this class 
to gain FDA approval for the treatment of melanoma based on a doubling of overall survival reported in a 
phase Ill study in 2010. In the past several years, promising results with PD-1 pathway blockade and 
combined CTLA-4/PD-1 blockade have further demonstrated the therapeutic potential of targeting immune 
regulatory receptors. To date, therapeutics targeting 8 distinct pathways are in various stages of clinical 
development and offer the possibility to fine tune adaptive immunity to effectively eradicate malignancies. 

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In MM, the PD-1 checkpoint pathway is felt to play a role in pathogenesis based on an observed greater 
expression of the PD-1 ligand (PD-L1) on malignant plasma cells than normal plasma cell counterparts. 
However, data on the role of other checkpoint blockade molecules in the natural history of multiple myeloma 
is lacking. Furthermore, little is known about the sensitivity of MM to therapeutic manipulation of checkpoint 
pathways. Thus, the goal of this specific aim is to develop an understanding of the natural history of MM 
relative to immunomodulatory checkpoint receptor expression status. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase II, single center clinical trial designed to evaluate the response rate and toxicity of a response­ 
adapted, sequential therapy, using bortezomib, dexamethasone, and lenalidomide, in patients with untreated 
MM. The patients will be started on bortezomib and dexamethasone (BO) for 2 cycles. The response will be 
evaluated at the end of every cycle. Lenalidomide will be added (RVD) to the subsequent cycles if PR has not 
been achieved after 2 cycles of BO or if VGPR has not been achieved after 4 cycles of BO. Lenalidomide may 
be added to the patient's regimen at any time if there is evidence of hematologic disease progression. Patients 
could proceed with stem cell collection after at least 4 cycles if adequate response ( PR) has been achieved, 
at the discretion of the treating physician. These patients may resume treatment on study after stem cell 
collection at the discretion of the treating physician (not to exceed a total of 8 cycles on study). All patients will 
continue therapy on study up to 8 cycles. All patients, whether completing the 8-cycles, or are removed from 
treatment for reasons other than POD, will return for follow-up once every 2 months until progression of 
disease (POD). 
According to the statistical plan detailed in section 14, a Simon's optimal two-stage design will be implemented 
where an overall response rate of 70% after four cycles is considered unpromising and a rate of 90% is 
considered promising. The maximum sample size for the trial is 28 patients. 
4.2 
Intervention 
Initial 2 cycles with bortezomib and dexamethasone (BO) 
 
• 
Length of cycle: 35 days 
• 
These cycles will consist of: 
o 
Bortezomib SC (or IV if SC not tolerated) 1.5 mg/m2 on days 1, 8, 15, and 22 
o 
Dexamethasone PO or IV 40mg on days 1, 8, 15, and 22 or on a split-dose regimen (20mg 
BIW). 
• 
The following prophylactic medications are recommended: acyclovir 400mg BID; sulfamethoxazole and 
trimethoprim OS, TIW; fluconazole 100 mg daily; and omeprazole 20 mg daily. Alternative prophylactic 
medications are allowed if sensitivity to the drugs occurs. 
• 
Bisphosphonates are recommended as clinically indicated. 
• 
Erythropoietin is allowed 
 
Treatment cycles beyond cycle 2 may include the addition of lenalidomide (RVD) 
 
Lenalidomide may be added based on the response to prior cycles (if less than PR after 2 cycles of BO or if 
less than VGPR after 4 cycles or as described in the design above and below.) If lenalidomide is not added, 

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the treatment schedule used during the initial 2 cycles will be unchanged. If lenalidomide is added, the 
following schedule will apply: 
• 
Length of cycle: 28 days 
• 
The cycles including Revlimid will consist of: 
• 
Bortezomib SC (or IV if SC not tolerated) 1.3 mg/m2 on days 1, 8, and 15 
• 
Dexamethasone 40 mg PO or IV on days 1, 8, and 15 or on a split-dose regimen (20mg BIW). 
• 
Lenalidomide 15 mg PO (or dose adjusted to renal function as per guidelines) daily on days 1-21. 
If well tolerated, the dose of lenalidomide could be escalated with subsequent cycles incrementally by 5 
mg, not to exceed 25 mg, days 1-21, 
• 
The following prophylactic medications are recommended: acyclovir 400mg BID; sulfamethoxazole and 
trimethoprim OS, TIW; fluconazole 100 mg daily; omeprazole 20 mg daily; and aspirin 325 mg or aspirin 
81mg or prophylactic doses of Low Molecular Weight Heparin (LMWH). Alternative prophylactic 
medications are allowed if sensitivity to the drugs occurs. 
• 
 Bisphosphonates are recommended as clinically indicated. 
Erythropoietin is not recommended because of the risk of thrombosis. 
Lenalidomide may be added to the patient's regimen at any time if there is evidence of hematologic 
disease progression. Patients could proceed with stem cell collection after at least 4 cycles if adequate 
response( PR) has been achieved, at the discretion of the treating physician. These patients may 
resume treatment on study after stem cell collection for additional cycles (not to exceed a total of 8 
cycles on study). All patients will continue therapy on study up to 8 cycles. All patients, whether 
completing the 8-cycles, or are removed from treatment for reasons other than POD, will return for 
follow-up once every 2 months until progression of disease (POD). 
 
• 
 Beyond 8 cycles, the treatment will be left to the discretion of the treating physician. The following 
maintenance treatment is recommended: Lenalidomide maintenance (21 days out of 28 day-cycle) at 
the last tolerated dose for patients who received lenalidomide during the first 8 cycles, and bortezomib 
on a maintenance schedule (every other week or 4 weeks ON followed by 4 weeks OFF) if 
lenalidomide was not added during the first 8 cycles. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Bortezomib 
5.1.1 Scientific Background 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium Pharmaceuticals, 
Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib is currently approved by the 
United States Food and Drug Administration (US FDA) for the treatment of patients with multiple myeloma 
(MM). It is also indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at 
least 1 prior therapy. In the European Union (EU), bortezomib in combination with melphalan and prednisone 
is indicated for the treatment of patients with previously untreated MM who are not eligible for high-dose 
chemotherapy with bone marrow transplant. Bortezomib is indicated as monotherapy for the treatment of 
progressive MM in patients who have received at least 1 prior therapy and who have already undergone or are 
unsuitable for bone marrow transplantation. 

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By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The 
antineoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell 
growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular 
adhesion, migration, and angiogenesis.  Thus, the mechanisms by which bortezomib elicits its antitumor 
activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition 
of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute 
(NCI) in vitro and in vivo assays19.  In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor 
models, both as a single agent and in combination with chemotherapy and radiation.20,21,22,23,24,25,26,27,28,29,30,31,32 
Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated 
growth and resistance to conventional chemotherapeutics.33 
The mechanisms of action leading up to apoptosis have been more clearly defined and include initiation of the 
unfolded protein response and direct/indirect effects on various molecular targets including cell cycle control 
proteins p27 and p21, cyclins, signal transduction molecules, transcription factors c-jun and HIF1-a, tumor 
suppressor protein p53, angiogenesis factors, and many others. Bortezomib is thought to be efficacious in 
multiple myeloma via its inhibition of nuclear factor KB (NF-KB) activation, its attenuation of interleukin-6 (IL-6)­ 
mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.34,35,36,37,38,39,40.41 
5.1.2 Preparation, Handling, Storage, and Destruction of Drugs 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in vials containing 
bortezomib and mannitol at a 1:10 ratio. For example, vials containing 3.5 mg of bortezomib contain 35 mg of 
mannitol. 
Vials containing lyophilized bortezomib for Injection should be stored according to the label requirements. For 
the United States, store at USP Controlled Room Temperature which is 25°C (77°F); for Europe, do not store 
above 30°C (86°F); excursions permitted from 15 to 30°C (59-86°F). To date, stability data indicate that the 
lyophilized drug product is stable for at least 18 months when stored under the recommended conditions. 
Stability studies are ongoing, and Millennium Pharmaceuticals, Inc. will notify the investigator should this 
information be revised during the conduct of the study. 
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and handling 
bortezomib solutions. Cytotoxic drugs should only be handled by staff specially trained in the safe handling of 
such preparations. The use of gloves and other appropriate protective clothing is recommended. In case of 
skin contact, wash the affected area immediately and thoroughly with soap and water for at least 15 minutes. 
If product contacts eye, immediately flush eye thoroughly with water for at least 15 minutes. Always contact a 
physician after any form of body contact. All materials that have been used for preparation should be disposed 
of according to standard practices. A log must be kept of all disposed materials. 
Prior to reconstitution the vials should remain in the cartons to protect them from light. Dissolution is 
completed in approximately 10 seconds. The reconstituted solution is clear and colorless, with a final pH of 5 
to 6. Reconstituted bortezomib should be administered promptly and in no case more than 8 hours after 
reconstitution. 
For commercially-labeled bortezomib for IND-exempt studies, please contact your Millennium Clinical 
Operations representative to arrange for return of study drug. Any unused or expired BORTEZOMIB must be 
returned to Millennium. Be sure to document drug return on your drug accountability logs. 

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5.1.3 Bortezomib Administration 
Drug will be administered only to eligible patients under the supervision of the investigator or identified sub­ 
investigator(s). Patients may be treated on an outpatient basis, if possible. The drug will be prepared under 
the supervision of a pharmacist, or appropriately qualified and trained personnel. The amount (in mg) of drug 
to be administered will be determined based on body surface area. Body surface area is to be calculated 
based on body weight using a standard nomogram or calculation. The dose should be calculated on Day 1 of 
each cycle; the dose administered should remain the same throughout each cycle but should be recalculated 
at the start of the next cycle. If a patient experiences a notable change in weight within a cycle, as determined 
by an unscheduled weight assessment, then the patient's dose should be recalculated at that time based on 
clinical judgment. 
There must be at least 3 days between each dose of bortezomib. 
5.1.4 Subcutaneous Administration 
INTRAVENOUS AND SUBCUTANEOUS ROUTE OF ADMINISTRATION HAVE DIFFERENT 
RECONSTITUTED CONCENTRATIONS. CAUTION SHOULD BE USED WHEN CALCULATING THE 
VOLUME TO BE ADMINISTERED. 
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib. Each vial of bortezomib for 
Injection should be reconstituted under a laminar flow biological cabinet (hood) within eight hours before 
dosing with 1.4 ml of normal (0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted solution 
contains bortezomib at a concentration of 2.5 mg/ml for subcutaneous administration. 
Subcutaneous Administration Precautions: 
 
• 
The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should 
be used in calculating the dose to prevent overdose. 
• 
When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. 
• 
New injections should be given at least one inch from an old site and never into areas where the site is 
tender, bruised, erythematous, or indurated. 
• 
If local injection site reactions occur following bortezomib administration subcutaneously, the IV route of 
administration should be considered. 
• 
In clinical trials of bortezomib IV, local skin irritation was reported in 5% of patients, but extravasation of 
bortezomib was not associated with tissue damage. In a clinical trial of subcutaneous bortezomib, a 
local reaction was reported in 6% of patients as an adverse event, mostly redness. 
5.1.5 Packaging, and Labeling 
Bortezomib will be supplied in vials as open-label stock. Both the box label and vial label will fulfill all 
requirements specified by governing regulations. 
 
5.1.6 
Treatment Compliance 
All drugs will be administered to eligible patients under the supervision of the investigator or identified sub 
investigator(s). The pharmacist will maintain records of drug receipt (if applicable), drug preparation, and 
dispensing, including the applicable lot numbers, , and total drug administered Any discrepancy between the 
calculated dose and dose administered and the reason for the discrepancy must be recorded in the source 
documents. 

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Drug accountability for lenalidomide and dexamethasone (if taken PO) will be assessed with the use of a pill 
diary for each cycle of treatment. 
5.1.7 
Product Complaints 
A product complaint is a verbal, written, or electronic expression which implies dissatisfaction regarding the 
identity, strength, purity, quality, or stability of a drug product. Individuals who identify a potential product 
complaint situation should immediately contact MedComm Solutions (see below) and report the event. 
Whenever possible, the associated product should be maintained in accordance with the label instructions 
pending further guidance from a Millennium quality representative. 
A medication error is a preventable event that involves an identifiable patient and that leads to inappropriate 
medication use, which may result in patient harm. While overdoses and underdoses constitute medication 
errors, doses missed inadvertently by a patient do not. Individuals who identify a potential medication error 
situation should immediately contact MedComm Solutions (see below) and report the event. 
 
For Product Complaints or Medication Errors, 
call MedComm Solutions at 
1-510-740-1273 (international number) 
1-866-835-2233 (for US sites) 
 
Product complaints and medication errors in and of themselves are not AEs. If a product complaint or 
medication error results in an SAE, an SAE form should be completed and sent to PPD (refer to Section 
17.2.1). 
5.2 
Lenalidomide 
5.2.1 Preparation, Handling, Storage, and Destruction of Drugs 
Lenalidomide (L) (REVLIMID®, CC-5013), a thalidomide analogue, is an immunomodulatory agent with anti­ 
angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6- 
dione and it has the following chemical structure: 
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. Lenalidomide is 
an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous 
solvents. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and 
R(+), and is produced as a racemic mixture with a net optical rotation of zero. 
Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration. Each capsule 
contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 

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Lenalidomide should be stored at room temperature away from direct sunlight and protected from excessive 
heat and cold. 
5.2.2 Lenalidomide Administration 
Lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe life-threatening 
human birth defects. Because of this toxicity, and to limit potential fetal exposure to lenalidomide, patients 
must follow the birth control guidelines outlined in Appendix E. All women of childbearing potential must follow 
the protocol-dictated timelines for pregnancy testing. 
Lenalidomide is administered orally. It may be taken with or without food at approximately the same time each 
day. 
5.2.3 Prescribing Information 
Prescriptions must be filled within 14 days, unless the patient is a female of childbearing potential, in which 
case the prescription must be filled within 7 days. Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
Accurate records will be kept of all study drug administration, including dispensing and dosing, in the source 
documents. 
5.2.4 Packaging 
Lenalidomide will be shipped directly to patients. Bottles will contain a sufficient number of capsules for one 
cycle of dosing. 
 
 
5.3 
Dexamethasone 
5.3.1 Preparation, Handling, Storage 
Dexamethasone is a synthetic adrenocortical steroid. Corticosteroids are naturally-occurring chemicals 
produced by the adrenal glands located above the kidneys. Corticosteroids affect the function of many cells 
within the body and suppress the immune system. Corticosteroids also block inflammation and are used in a 
wide variety of inflammatory diseases affecting many organs. 
The molecular weight for dexamethasone is 392.47. It is designated chemically as 9-fluoro-11p,17,21- 
trihydroxy-16a-methylpregna-1,4-diene-3,20-dione. The empirical formula is C22H29FOs and the structural 
formula is: 
 
 
 
 
Dexamethasone is stable in air and almost insoluble in water. 

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Approval date: 11-Apr-2022 
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Dexamethasone is a white to practically white, odorless, crystalline powder. It is available in 2 or 4 mg tablets 
(commercially) for oral administration. Each tablet contains dexamethasone as the active ingredient, and the 
following inactive ingredients: calcium phosphate, lactose, magnesium stearate, and starch. The tablet shell 
may contain the following: D&C Yellow 10, FD&C Yellow 6, and/or FD&C Blue 1. 
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent unauthorized 
access. Dexamethasone should be stored at controlled room temperature, 68-77°F (20-25°C) and not frozen, 
and according to label requirements. 
Dexamethasone should be handled by trained pharmacy staff. The use of gloves and other appropriate 
protective clothing is recommended as necessary. 
Dexamethasone supply will be obtained through commercial supply. 
If Dexamethasone is given PO, it should be taken with food at approximately the same time each day. 
At the end of the study, unused supplies of dexamethasone should be destroyed and documented 
according to institutional policies. 
5.3.2 
Administration 
During initial therapy, each participant will receive dexamethasone as a single oral or IV dose. The 
investigator or designee will order drug supply from commercial supply. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• 
Age 18 or greater at the time of signing the informed consent document. 
• 
 Patients diagnosed with symptomatic multiple myeloma based on IMWG Diagnostic Criteria. According 
to these criteria, patient must have Monoclonal plasma cells in the bone marrow 10% and/or 
presence of a biopsy-proven bony or extramedullary plasmacytoma and any one or more of the 
following myeloma defining events: 
■ 
Clonal bone marrow plasma cell percentage 
60% (Note: clonality should be 
established by showing kappa/lambda-light-chain restriction on flow cytometry, 
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage 
should preferably be estimated from a core biopsy specimen; in case of a disparity 
between the aspirate, the highest value should be used) 
■ 
 lnvolved:Uninvolved serum free light chain ratio 100 (values are based on the serum 
Freelite assay) The involved free light chain must be 
10 mg/dl 
■ 
>1 focal lesions on MRI studies (each focal lesion must be 5 mm or more in size) 
■ 
 [C] Calcium elevation in the blood, defined as serum calcium> 11 mg/dl or> 1 mg/dl 
higher than the upper limit of normal 
■ 
 [R] Renal insufficiency, defined as serum creatinine > 2 mg/di or creatinine clearance < 
40 ml/min 
■ 
[A] Anemia, defined as hemoglobin <10 g/dl or > 2 g/dl below the lower limit of normal 
■ 
 [B] Lytic bone lesions, one or more osteolytic lesions on skeletal radiography, CT, or 
PET-CT (if bone marrow has less than 10% clonal plasma cells, more than one bone 
lesion is required to distinguish from solitary plasmacytoma with minimal marrow 
involvement) 

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Page 25 of 61 
 
 
 
• 
 Patients must have symptomatic multiple myeloma without advanced organ damage (such as multiple 
fractures or advanced bone disease causing immobilization, renal failure, spinal cord compression, or 
organ compromise due to soft tissue plasmacytoma). If immediate therapy with radiation and high­ 
dose steroids (eg, for spinal cord compression) or if triple therapy is clearly advisable from the start, the 
patient is not eligible for this trial. 
 
• 
Patients with measurable disease defined as one or more of the following: serum M-protein 1.0 g/dl, 
urine M-protein 200 mg/24h, and/or serum FLC assay: involved FLC level 10 mg/di with abnormal 
serum FLC ratio. 
 
• 
Only non transplant candidates or those who opt to forgo ASCT during first line therapy are eligible 
 
• 
ECOG performance status .:::_2 
 
• 
Female patients must: 
o 
be postmenopausal for at least 1 year before the Screening visit, OR 
o 
be surgically sterile, OR 
o 
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at 
the same time, from the time of signing the informed consent through 30 days after the last dose 
of study treatment, OR agree to completely abstain from heterosexual intercourse 
 
• 
Male patients, even if surgically sterilized (ie, status post-vasectomy), must: 
o 
Agree to practice effective barrier contraception during the entire study treatment period and 
through 30 days after the last dose of study treatment, OR 
o 
Agree to completely abstain from heterosexual intercourse 
 
• 
 Patients must be able to provide voluntary written informed consent before performance of any study­ 
related procedure not part of normal medical care, with the understanding that consent may be 
withdrawn by the subject at any time without prejudice to future medical care. 
6.2 
Subject Exclusion Criteria 
• 
Participant treated with any prior systemic therapy with the exception of the following: 
o 
Treatment by localized radiotherapy for a specific indication within 2 weeks of initiation of 
treatment. 
o 
Treatment with corticosteroids, not to exceed the equivalent of 160 mg of dexamethasone over 
a four-week period before initiation of protocol therapy. 
 
• 
Presence of Primary or associated amyloidosis (AL) 
 
• 
Participants who plan to proceed with ASCT as part of first line therapy 
 
• 
Poor tolerability or known allergy to lenalidomide, bortezomib and/or dexamethasone or compounds 
that have similar chemical or biologic composition to these study drugs. 

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• 
 Platelet count< 50,000/mm3 within 21 days of initiation of protocol therapy for patients in whom <50% 
of bone marrow nucleated cells are plasma cells; or platelet count <30,000/mm3 for patients in 
whom 50% of bone marrow nucleated cells are plasma cells. Transfusion is not allowed to meet 
platelet eligibility criteria. 
 
• 
 ANC < 1,000 cells/mm3 within 21 days of initiation of protocol therapy. Growth factor administration is 
not allowed to meet ANC eligibility criteria. 
 
• 
Hemoglobin< 8 g/dl within 21 days of initiation of protocol therapy. Transfusion may be used to meet 
hemoglobin eligibility criteria. 
• 
Hepatic impairment, defined as bilirubin > 1.5 x institutional upper limit of normal (ULN) [Patients with 
benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible] or AST (SGOT), or ALT (SGPT), or 
alkaline phosphatase 2 x ULN, within 21 days of initiation of protocol therapy. 
• 
Renal insufficiency, defined as creatinine clearance < 30 ml/min within 21 days of initiation of protocol 
therapy. Creatinine clearance will be the primary eligibility criteria in determining renal insufficiency. 
The Cockcroft-Gault formula (See Appendix) should be used for calculating creatinine clearance 
values. 
 
• 
Active hepatitis B or C infection 
 
• 
HIV 1 or 2 positivity 
 
• 
Female participant who is pregnant or breast-feeding. 
 
• 
Inability to comply with an anti-thrombotic treatment regimen (e.g., administration of aspirin, 
enoxaparin, or low molecular weight heparin administration). 
 
• 
Peripheral neuropathy;:: Grade 2 on clinical examination, within 21 days of initiation of protocol therapy. 
 
• 
Participant who had myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class Ill or IV heart failure, uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities. 
• 
Participant who has hypersensitivity to bortezomib, boron, or mannitol. 
 
• 
Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 
 
• 
 Participant diagnosed or treated for another malignancy within 2 years of enrollment, with the exception 
of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ 
malignancy, or low-risk prostate cancer after curative therapy. Patients who have had prior 
malignancies within the past 2 years but are considered to be "cured" with a low likelihood of 
recurrence may be eligible at the discretion of the Principal Investigator. 
 
• 
 Any other medical condition or laboratory evaluation that, in the treating physician's or principle 
investigator's opinion, makes the patient unsuitable to participate in this clinical trial. 

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IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
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7.0 
RECRUITMENT PLAN 
This study will be conducted at MSKCC. All patients will be recruited from the large pool of newly diagnosed 
patients referred to the myeloma service whether transplant or non-transplant candidates. About 8-10 newly 
diagnosed patients are seen per month at MSKCC main campus and we therefore anticipate no difficulty 
enrolling to this protocol. About 30% of them are non-transplant candidates. Since this protocol is the only trial 
available for non-transplant patients, we anticipate that these patients will constitute the bulk of patients 
enrolled. Efforts will be made to ensure that women and minority groups are adequately represented in this 
trial. All patients will be seen by MSKCC myeloma physicians and associated MSKCC co-investigators, 
enrolled and registered at MSKCC. All co-investigators agree to follow the treatment in the protocol and to 
conduct the proposed investigation according to recognized principles of good clinical practice. Participation is 
voluntary. Each patient must be informed about the neoplastic nature of his/her disease and willingly consent 
to participation in this study. Every patient will be informed of the procedures to be followed, the potential 
benefits, side effects, risks, and discomforts of the trial and of potential therapeutic alternatives. All participants 
will be required to sign statements of informed consent and research authorization that conform to FDA, IRB 
and HIPAA guidelines. Informed consent will be documented by the use of a written consent form that has 
been approved by the MSKCC IRB. 
 
 
8.0 
PRETREATMENT EVALUATION 
The following tests will be performed within 21 days prior to treatment: 
 
• 
History & Physical exam including height and weight for BSA and neurologic examination 
 
• 
Full Symptom assessment 
 
• 
ECOG Performance status (See Appendix) 
 
• 
QOL assessment (See Appendix) 
 
• 
Serum myeloma studies: Serum protein electrophoresis (SPEP), serum immunofixation (IF), 
quantitative immunoglobulins, and serum free light chain assay 
• 
 Urine myeloma studies: Twenty-four hour urine for total volume and total protein (TV, TP), 
immunofixation (IF), protein electrophoresis (UPEP), N-telopeptides, and creatinine clearance 
• 
 CBC with differential, comprehensive metabolic panel, LOH, Mg, Phos, Uric acid, C-reactive protein, 
beta2-microglobulin, PT&APTT, BNP, and troponin. 
• 
Serum -HCG Pregnancy test (for women of childbearing potential) 
 
• 
Urinalysis 
 
• 
Optional blood research sample 
 
The following tests will be performed within 12 weeks prior to patient enrollment: 
• 
Bone marrow examination, including biopsy sample for H & E stain and immunohistochemical staining 
for CD 138, CD20, kappa and lambda light chains; bone marrow aspirate samples for Giemsa staining, 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
Page 28 of 61 
 
 
flow-cytometry, cytogenetic and FISH analysis for myeloma markers, and optional BMA research 
sample 
• 
Electrocardiogram (EKG) 
 
• 
 A skeletal survey that should be reviewed at MSKCC if not performed at MSKCC (Not required if MRI of 
total spine, MRI of the totaty body or PET/CT is performed 
• 
PET/CT (MRI of the total spine or MRI of the total body could be done alternatively) 
The following tests will be performed within 6 months prior to patient enrollment: 
• 
Hepatitis A, B, C serologies 
• 
HIV 1/2 test 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Treatment Plan 
 
9.1.1 Initial first 2 cycles of treatment: 
Patients who have signed the consent form and are deemed eligible for this clinical trial will start therapy with 
bortezomib and dexamethasone (BO) with the following schedule: 
• 
Length of cycle: 35 days 
• 
These cycles will consist of: 
o 
Bortezomib SC (or IV if SC not tolerated) 1.5 mg/m2, days 1, 8, 15, and 22 
o 
Dexamethasone 40 mg PO or IV days 1, 8, 15 and 22 or on a split-dose regimen (20mg BIW). 
• 
The following prophylactic medications are recommended: acyclovir 400mg BID; sulfamethoxazole and 
trimethoprim OS, TIW; fluconazole 100 mg daily; and omeprazole 20 mg daily. Alternative prophylactic 
medications are allowed if sensitivity to the drugs occurs. 
• 
Bisphosphonates are recommended as clinically indicated. 
• 
Erythropoietin is allowed 
 
Patients will be assessed at the end of every cycle as shown in table. 
9.1.2 Treatment beyond the first 2 cycles: 
• 
 Lenalidomide may be added based on the response to prior cycles (if less than PR after 2 cycles of BO 
or if less than VGPR after 4 cycles or POD at any time of induction). If lenalidomide is not added, the 
treatment schedule used during the initial 2 cycles will be unchanged. If lenalidomide is added, the 
following schedule will apply: 
 
• 
Length of cycle: 28 days 
• 
The cycles including Revlimid will consist of: 
o 
Bortezomib SC (or IV if SC not tolerated) 1.3 mg/m2, days 1, 8, and 15 
o 
Dexamethasone 40 mg PO or IV days 1, 8, and 15 or on a split-dose regimen (20mg BIW). 

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IRB Number: 13-064 A(22) 
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o  Lenalidomide 15 mg PO (or dose adjusted to renal function as per guidelines) daily, days 1-21. 
If well tolerated, the dose of lenalidomide can be escalated with subsequent cycles 
incrementally by 5 mg, not to exceed 25 mg, days 1-21. 
 
• 
The following prophylactic medications are recommended: acyclovir 400mg BID; sulfamethoxazole and 
trimethoprim OS, TIW; fluconazole 100 mg daily; omeprazole 20 mg daily; and aspirin 325 mg or aspirin 
81mg or prophylactic doses of LMWH. Alternative prophylactic medications are allowed if sensitivity to 
the drugs occurs. 
• 
Bisphosphonates are recommended as clinically indicated. 
 
► All other patients will continue treatment with BO with the schedule detailed above. 
 
► All patients will receive at least a total of 4 cycles of treatment. 
 
Patients could proceed with SC collection after at least a total of 4 cycles if adequate response ( PR) 
has been achieved, or will continue therapy until 8 cycles on study. If stem cells are collected, patients 
will resume treatment on study after stem cell collection for additional cycles (not to exceed a total of 8 
cycles on study). All patients, whether completing the 8-cycles, or are removed from treatment for 
reasons other than POD, will return for follow-up once every 2 months until progression of disease 
(POD). 
► Patients who have progression of disease (POD) after 2 cycles of RVD will be taken off study 
 
► Patients who have stable disease (SD) after 2 cycles of RVD may be taken off study at the discretion of the 
treating physician 
 
► Beyond 8 cycles, the treatment will be left to the discretion of the treating physician. The following 
maintenance treatment is recommended: Lenalidomide maintenance at the last tolerated dose for patients 
who received lenalidomide during the first 8 cycles (21 days out of 28 day-cycle), and bortezomib on a 
maintenance schedule (every other week or 4 weeks ON followed by 4 weeks OFF) if lenalidomide was not 
added during the first 8 cycles. 
9.1.3 
Stem cell collection 
After at least 4 cycles of treatment, patients who have achieved at least a PR may proceed with stem cell 
mobilization and collection as per institutional guidelines. A leukapheresis catheter may be placed if deemed 
necessary for stem cell collection. Leukapheresis will begin as per SOP of the Blood Donor Room. Once stem 
cell collection begins, a target of 10 x 106 CD34+ cells per kg will be sought, allowing the collection of adequate 
stem cells for at least 2 stem cell transplantations in a patient's lifetime. We will seek a minimal acceptable 
collection of 2 x 106 CD34+ cells per kg, allowing at least one ASCT procedure. Patients failing to collect the 
minimum dose may be mobilized a second time as per MSKCC guidelines, at the discretion of the treating 
physician. Patients who are mobilized twice and have less than 2 x 106 CD34+ cells per kg will continue on 
study without plan for transplantation. Peripheral blood stem cells will be cryopreserved according to standard 
operating procedures of the Cytotherapy Laboratory. 
9.2 
Pre-Treatment Criteria 

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9.2.1 
Criteria for initiation of New Cycle of BD or RVD Therapy (Day 1): 
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle of BO or RVD if the following 
criteria are met: 
■ 
ANC.:::. 1,000/ mm3 (growth factor support is permitted during cycles of BO or RVD, with the 
exception of Cycle 1 Day 1; it is allowed on the same day as treatment administration) 
■ 
Platelet count.:::_ 50,000/ mm3 (platelet support is permitted during cycles of BO or RVD; it is 
allowed on the same day as treatment administration) 
■ 
Any lenalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/other 
cardiac arrhythmia adverse event that may have occurred has resolved to grade 1 
severity. 
■ 
Any other lenalidomide or bortezomib-related adverse event that may have occurred has 
resolved to 
grade 2 severity. 
■ 
 Grade 1 peripheral neuropathy with pain or grade 2 peripheral neuropathy without pain 
requires dose modification, and grade 2 peripheral neuropathy with pain requires that 
bortezomib be held. 
■ 
Herpes Zoster lesions are dry 
 
If these conditions are not met on Day 1 of a new cycle, the participant will be evaluated weekly and a new 
cycle of therapy will not be initiated until the toxicity has resolved as described above. The maximum 
amount of time for which a drug may be held due to toxicity is 6 weeks. If drug is held for more than 6 
weeks due to toxicity, the participant will be removed from study treatment. 
9.2.2 
Criteria for intra-cycle Therapy (Days 8, 15 and 22): 
Treatment on Days 8, 15 and 22 during a cycle may be administered if the following criteria are met: 
■ 
ANC .:::_ 750/mm3 (growth factor support is permitted) 
■ 
 Platelet count.:::. 30,000/mm3 (Transfusion to support platelet count is permitted at 
investigator discretion) 
9.3 
Dose Modifications/Delays 
Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), Version 4.0 http://ctep.cancer.gov/reporting/ctc.html). Dose modifications or delays will be 
done based on the toxicity experienced during a cycle of therapy or newly encountered on day 1 of each 
cycle. The participant may continue on therapy if the toxicity can be managed according to the dose 
modification guidelines as outlined below. 
Dose delays beyond what is specified in section 10.0 or for reason(s) other than toxicity may be allowed with 
Principal Investigator approval. 
9.3.1 
General Guidelines 
If there were dose modifications or delays in the previous cycle, use the following guidelines: 
■ 
 Once one of the treatment doses (lenalidomide, bortezomib, or dexamethasone) is reduced for 
toxicity, no re-escalation will be allowed with the exception of lenalidomide in case of renal 
insufficiency during RVD therapy. 
• 
Reduction and/or temporary suspension of one agent and not the others is appropriate if toxicity is 
related primarily to one of the agents. 

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• 
Drug may be held for no more than 6 weeks due to toxicity. During RVD cycles, if all three concerned 
treatments are held for more than 6 weeks, the patient will be withdrawn from the study treatment 
and will be followed until disease progression. 
9.3.2 
Dose Reduction Steps and Guidelines 
 
Dose Reduction Steps for Lenalidomide during RVD therapy 
 
Starting dose 
of 
lenalidomide 
1st Dose 
Reduction 
2nd Dose 
Reduction 
3rd Dose 
Reduction 
4th Dose 
Reduction 
5th Dose 
Reduction 
15mgPOqd 
10 mg PO qd 
5 mg PO qd x 
2.5 mg PO qd 
2.5 mg PO 
qod 
Discontinue 
lenalidomide 
 
If the dose of lenalidomide was escalated to 20mg or 25mg as per guidelines in paragraph 9.1.2, and dose 
reduction is subsequently mandated, the dose would be de-escalated incrementally by 5mg per cycle to 15mg 
and 20mg respectfully. 
If there were dose modifications or delays in the previous cycle, use the following guidelines: 
• 
If the cycle was completed without requiring further dose modification, then the next cycle will 
start at the same reduced dose of lenalidomide. 
• 
If Lenalidomide was held during the previous cycle and restarted at a reduced dose level, 
without interruption for the remainder of the cycle, then the reduced dose level will be initiated 
on Day 1 of the new cycle. 
• 
If Lenalidomide dosing was omitted for the remainder of the previous cycle or if a new cycle is 
delayed due to lenalidomide-related toxicity newly encountered on the scheduled Day 1, then 
the new cycle will be started with a one-level dose reduction. 
 
Dose Reduction Steps for Bortezomib 
 
Starting dose of 
bortezomib 
1st Dose 
Reduction 
2nd Dose 
Reduction 
3rd Dose 
Reduction 
4th Dose 
Reduction 
1.5 mg/m2 
1.3 mg/m2 
1.0 mg/m2 
0.7 mg/m2 
Discontinue 
Bortezomib 
 
See Table in section 9.3.3 for separate dose modification guidelines for peripheral neuropathy. 
If there were dose modifications or delays in the previous cycle, use the following guidelines: 
• 
In case of dose reduction during initial BO or RVD therapy, the participant will receive the 
reduced dose levels (the last level applied during initial therapy) 
• 
If any two or more doses of bortezomib were held during the cycle (either consecutively or two 
or more in one cycle), then the new cycle will be started with one level dose reduction. 
• 
If the new cycle is delayed due to bortezomib-related toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose reduction. 

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IRS Number: 13-064 A(22) 
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Page 32 of 61 
 
 
• 
If after bortezomib has been held, the toxicity does not resolve, then bortezomib must be 
discontinued. 
 
Dose Reductions Steps for Dexamethasone 
 
Starting dose of 
dexamethasone 
1st Dose Reduction 
2nd Dose 
Reduction 
Yd Dose 
Modification 
40 mg/d 
20 mg/d 
10 mg/d 
Discontinue 
dexamethasone 
 
Dexamethasone doses can be split over 2 days. 
9.3.3 Dose Modification Guidelines for Specific Drug-Associated Adverse Events 
Each Adverse Event should be attributed to a specific study drug if possible so that dose modifications can 
be made accordingly. Reduction and/or temporary suspension of one agent and not the others is 
appropriate if toxicity is related primarily to one of the agents. Further clarification can be obtained in 
consultation with the Pl. If multiple toxicities are noted, the dose adjustment should be made according to 
the most severe toxicity guidelines. Drug may be held for no more than 6 weeks to allow resolution of 
toxicity. 
Drug Related Adverse Event Dose Modification Guidelines during RVD therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
CTCAE Category 
AGENTS 
Toxicity During a Cycle 
Grade 3 neutropenia associated 
with fever (temperature 
38.SC) or 
Grade 4 neutropenia 
and/or 
Platelet count < 10,000/mm3 or G3 
thrombocytopenia with bleeding 
Lenalidomide 
Hold therapy (interrupt). Follow CBC on days 8 and 15. 
Use of G-CSF is allowed and recommended. 
If neutropenia resolved to s grade 2, resume lenalidomide 
with one level dose reduction and continue through the 
scheduled end of the cycle. Otherwise, omit for remainder 
of cycle and reduce the dose of lenalidomide by one dose 
level at the start of the next cycle. Omitted doses are not 
made up. 
If thrombocytopenia resolved to S grade 2, resume 
lenalidomide with one dose level reduction and continue 
through the scheduled end of the cycle. Otherwise, omit 
for remainder of cycle and reduce the dose of lenalidomide 
by one dose level at the start of the next cycle. Omitted 
doses are not made up. 
Bortezomib 
Hold therapy 
Use of platelet transfusion is allowed. 
If thrombocytopenia resolved to s grade 2 and neutropenia 
resolves to S grade 2 and if the Day 8, 15 or 22 dose is 
held, that dose should be omitted and treatment should 
continue with next planned dose (i.e., if Day 8 or 15 is 
skipped, the next dosing day is Day 15 or 22, respectively) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
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of bortezomib at same dose. 
If thrombocytopenia resolved to .:=:. grade 2 and neutropenia 
resolves to.:=:. grade 2 and if any 2 or more doses were held 
due to toxicity (either consecutive or two or more in one 
cycle), then reduce the bortezomib dose by one level. 
Non-blistering rash 
Grade 3 
Lenalidomide 
Hold (interrupt dose). Follow weekly. 
If the toxicity resolves to .:=:. grade 1, restart lenalidomide 
with one level dose reduction and continue through the 
scheduled end of the cycle. Otherwise, omit for remainder 
of cycle and reduce the dose of lenalidomide by one dose 
level at the start of the next cycle. Omitted doses are not 
made up. 
Non-blistering rash 
Grade 4 
Discontinue lenalidomide study drug for grade 4 toxicity. 
Desquamating (blistering) rash­ 
any Grade or Erythema multiforme 
Grade 3 
Lenalidomide 
Discontinue lenalidomide study drug. 
Sinus bradycardia/ other cardiac 
arrythmia Grade 2 
Lenalidomide 
Hold (interrupt) dose. Follow at least weekly. 
If the toxicity resolves to .:=:. grade 1 restart at next lower 
dose level. 
Sinus bradycardia/ other cardiac 
arrythmia Grade 
3 
Discontinue lenalidomide study drug for grade 
3 
Allergic reaction or 
hypersensitivity Grade 2-3 
Lenalidomide 
Hold (interrupt) dose. Follow at least weekly. 
If toxicity resolves to .:=:. grade 1 restart at next lower dose 
level 
Allergic reaction or 
hypersensitivity Grade 4 
Discontinue lenalidomide study drug. 
Hyperthyroidism or 
Hypothyroidism 
Lenalidomide 
Omit lenalidomide for remainder of cycle, evaluate etiology, 
and initiate appropriate therapy. Restart lenalidomide at 
investigator's discretion. For toxicity attributable to 
lenalidomide, reduce the dose by one dose level. 
Peripheral Neuropathy 
Bortezomib 
See table 
Neuropathy 
Grade 3 
Lenalidomide 
Hold (interrupt) dose. Follow at least weekly. If the toxicity 
resolves to.:=:. grade 1, restart lenalidomide at next lower 
dose level and continue through the scheduled end of the 
cycle. Otherwise, omit for remainder of cycle and reduce 
the dose of lenalidomide by one dose level at the start of 
the next cycle. Omitted doses are not made up. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
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Grade 4 
Discontinue lenalidomide. 
Herpes Zoster reactivation any 
grade 
Bortezomib 
Hold therapy until lesions are dry. Increase antiviral from 
prophylactic to therapeutic dose for 10 days or until lesions 
are healing and dry. 
Venous Thrombosis/embolism 
Grade 3 
Lenalidomide/ 
Bortezomib 
Hold dose and start anticoagulation; restart at investigator's 
discretion (maintain dose level). 
Moderate renal impairment 
30s Creat Clear<50 ml/min 
Lenalidomide 
10mg once daily. The dose may be escalated to 15mg/d 
after 2 cycles if the patient is tolerating the treatment 
Severe renal impairment 
Creat Clear<30 ml/min 
(not requiring dialysis) 
Lenalidomide 
15mg every other day. The dose may be escalated to 
10mg/d if the patient is tolerating the treatment. 
Severe renal impairment 
Creat Clear<30 ml/min 
(requiring dialysis) 
Lenalidomide 
5mg once daily. On dialysis days, the dose should be 
administered following dialysis. Alternate etiology for 
severe renal impairment should be evaluated. 
Other lenalidomide or bortezomib 
related non-hematologic toxicity 
Grade 3 
Lenalidomide 
Bortezomib 
Determine attribution of toxicity and hold appropriate 
therapy. If toxicity resolves to.:': grade 2, resume therapy 
with one level dose reduction. 
Patients with mild hepatic impairment (bilirubin s 1.5 x ULN) do not require a starting dose adjustment. Please 
note that patients with bilirubin levels > 1.5 ULN are excluded from enrollment in this protocol. If a patient 
develops moderate or severe hepatic impairment with bilirubin 
Grade 2 (> 1.5 X ULN) while on study, the 
investigator should hold Bortezomib until the toxicity returns to < Grade 2. Restarting Bortezomib at the next 
lower dosed level could be considered at the Investigator's discretion and following exclusion of bortezomib­ 
induced liver impairment and careful consideration of liver disease due to other causes, such as, but not limited 
to, active infection and multiple myeloma-related liver disease. 
Dose modifications for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory Neuropathy 
 
Patients who experience bortezomib-related neuropathic pain or peripheral sensory neuropathy are to be 
managed as presented in the following table. Once the dose is reduced for peripheral neuropathy, the dose 
may not be re-escalated. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
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Page 35 of 61 
 
 
Management of Patients With bortezomib-Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
 
 
Severity of Peripheral Neuropathy Signs 
and Symptomsa 
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or parasthesias) without pain or loss 
of function 
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities or 
Daily Living [ADL]b) 
Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self care ADLc) 
Modification of Dose and Regimen 
 
No action 
 
 
Reduce BORTEZOMIB to 1.0 mg/m2 
 
 
Withhold BORTEZOMIB therapy until toxicity 
resolves. When toxicity resolves reinitiate with a 
reduced dose of BORTEZOMIB at 0.7 mg/m2 
once per week. 
Grade 4 (life-threatening consequence; 
Discontinue BORTEZOMIB 
urgent intervention indicated) 
 
Source: VELCADE® USPI issued January 2012. 
Abbreviations: AOL = activities of daily living 
a Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. 
b Instrumental AOL: refers to preparing meals, shopping for groceries or clothes, using 
telephone, managing money, etc 
c Self care AOL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Dose modifications for specific dexamethasone associated adverse events 
I
Dexamethasone dose modifications 
 
 
 
Gastrointestinal 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring medical 
management) 
Treat with H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, decrease 
dexamethasone dose by 1 dose level 
Grade 3 (requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms adequately 
controlled. Restart and decrease one dose level of 
current dose along with concurrent therapy with H2 
blockers, sucralfate, or omeprazole. If symptoms 
persist despite above measures, discontinue 
dexamethasone and do not resume. 
Acute pancreatitis 
Discontinue dexamethasone and do not resume. 
Cardiovascular 
Edema 
Grade 3 (limiting function 
and unresponsive to therapy 
or anasarca) 
Diuretics as needed, and decrease dexamethasone 
dose by 1 dose level; if edema persists despite above 
measures, decrease dose another dose level. 
Discontinue dexamethasone and do not resume if 
symptoms persist despite second reduction. 
Neurology 
Confusion or Mood alteration 
Hold dexamethasone until symptoms resolve. Restart 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
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Grade 2 (interfering with 
function +/- interfering with 
activities of daily living) 
with one dose level reduction. If symptoms persist 
despite above measures, discontinue dexamethasone 
and do not resume. 
Musculoskeletal 
Muscle weakness 
Grade 2 (symptomatic and 
interfering with function +/­ 
interfering with activities of 
daily living 
Decrease dexamethasone by one dose level. If 
weakness persists despite above measures decrease 
dose by one level. Discontinue dexamethasone and do 
not resume if symptoms persist. 
Metabolic 
Hyperglycemia 
Grade 3 or higher 
Treatment with insulin or oral hypoglycemics as 
needed. If uncontrolled despite above measures, 
decrease dose by one dose level until levels are 
satisfactory. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 Evaluation During the Treatment Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I 
Study Procedures 
Screening 
Period 
Treatment Periodk 
End of 8 
cycles of 
treatment and 
At disease 
progressiont 
2-Month 
Follow-upm 
Within 21 
days before 
treatment 
Day1P 
Day 8 
Day 
15 
Day 
22 
Day L 
29 
Informed Consent 
X 
History, System Review, Complete 
Physical 
X 
Xg 
Interval history, System review, 
Complete physical 
Xg 
X 
ECOG Performance Status 
X 
Xg 
X 
Concomitant meds, supportive Rx 
assessment 
X 
Xg 
X 
Adverse event assessment 
Xg 
X 
Quality of life assessment 
X 
xg 
X 
Neurologic Examination 
X 
xg 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel 
X 
Xg 
X 
X 
LOH 
X 
xg 
X 
X 
Mg 
X 
Xg 
X 
X 
Phos 
X 
Xg 
X 
X 
Uric acid 
X 
Xg 
X 
X 
C-reactive protein 
X 
X 
2.microglobulin 
X 
Xg 
X 
PT&APTT 
X 
Xg 
X 
Urinalysis 
X 
xg 
X 
Serum -HCG Pregnancy Test 
xa,b 
xa,b, C 
xa,b,c 
X 
BNP 
X 
X 
Troponin 
X 
X 
HIV 1/2 test 
Xd 
Hepatitis A, B, and C Tests 
Xd 

Memorial Sloan Kettering Cancer Center 
IRS Number: 13-064 A(22) 
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- - 
a Pregnancy tests for women of childbearing potential, defined as 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 not had menses at any time in the preceding 
24 consecutive months); 
b If lenalidomide is added to the regimen of a female that is of childbearing potential, pregnancy tests must occur within 28 days and again within 24 
hours prior to initiation of lenalidomide. A pregnancy test must be done on Day 1 of each consecutive cycle while on therapy, at discontinuation of 
lenalidomide, and at Day 28 post the last dose of lenalidomide. 
c All participants on RVD must be counseled about pregnancy precautions, risks of fetal exposure and other risks. The counseling must be done on 
Day 1 of RVD (or at a minimum of every 28 days) and at drug discontinuation. 
d Must be done within 6 months prior to registration 
• Must be done within 12 weeks prior to registration 
1 Within 4 weeks after com etion of treatment 
9 May be done +/- 3 days of Day 1. Multiple myeloma assessment tests do not need to be repeated on C3D1 and C5D1 since they would have been 
done as per footnote h, on C2D29 and C4D29 
h Mandatory only for Cycles 2 and 4 to assess response and anticipate decision making for Cycles 3 and 5. These labs should be done on Day 29 of 
Cycles 2 and 4 (for cycle 4, only if lenalidomide had not been added to cycle 3) and would not need to be repeated on day 1 of Cycles 3 and 5. A +5 
day window from Day 29 is allowed and Cycles 3 and 5 can be delayed up to one week to allow for these assessments to result 
' To confirm CR (com ete response) or progression of disease 
1 Patients that consent to the correlative research portion of the study will have 20-30 cc of peripheral blood and 10-20 cc of bone marrow aspirate 
collected during screening, on Cycle 5 Day 1 if bone marrow is clinically indicated, and at the End of treatment, when possible. If patient has had a 
bone marrow aspiration within a month prior, the procedure would not be need to be performed again. 
kif treatment is delayed, labs and assessments do not need to be redone if performed within 1 week, including correlative study sam  es. 
LDay 29 is not ap icable for Cycles 1, 3, 5, 6, 7, and 8. It is also not ap  icable to cycle 4 if lenalidomide has been added in cycle 3. 
mpatients that com ete the 8-cycles, and/or are removed from treatment will be followed up once every 2months (+/- 2 weeks) until POD. 
"Beyond 8 cycles, the treatment will be left to the discretion of the treating physician. The following maintenance treatment is recommended: 
Lenalidomide maintenance at the last tolerated dose for patients who received lenalidomide during the first 8 cycles, and bortezomib on a 
maintenance schedule (every other week or 4 weeks ON followed by 4 weeks OFF) if lenalidomide was not added during the first 8 cycles. 
0 A dosing delay with bortezomib on days 8, 15, and 22 is allowed for up to 3 days, provided that safety labs are done within 24 hours of 
administration of bortezomib. Subsequent treatment days with Bortezomib must be adjusted accordingly. 
P Day 1 of any cycle may be delayed for up to 7 days. 
qBortezomib and Dexamethsone will not be administered on day 22 if Lenalidomide has been added. 
'Skeletal Survey is not required for screening if either a PET/CT or MRI have been performed 
 
 
10.1.2 Correlative Studies 
Serum Multiple Myeloma 
Disease Assessment 
• 
Serum protein 
electrophoresis (SPEP) 
• 
Quantitative 
immunoglobulins 
(lgG/lgA/lgM) 
• 
Serum lmmunofixation 
• 
Serum Free Light 
Chains 
X 
Xg 
xh,L 
X 
X 
24 hour Urine Multiple Myeloma 
Disease assessment 
• 
Urine protein 
electrophoresis (UPEP) 
• 
lmmunofixation 
• 
Total protein 
• 
Creatinine clearance 
• 
N-telopeptides 
X 
Xg 
xh,L 
X 
X 
Bone Marrow Aspirate and 
Biopsy for: 
• 
Morphology 
• 
Cytogenetics/FISH 
x• 
X; 
X 
As indicated 
Electrocardiogram 
x• 
As indicated 
As indicated 
Skeletal Survey 
xer 
X 
As indicated 
PET/CT (or MRI of the total spine 
or MRI of the total body could be 
done alternatively) 
x• 
As indicated 
As indicated 
Optional Blood and Bone Marrow 
)(i 
xg,j 
Xi 
Research Sam  es 
Bortezomib Dosing0 
X 
X 
X 
xq 
X" 
Dexamethasone 
X 
X 
X 
xq 
X" 
Lenalidomide 
Daily Days 1-21 
LJ 
X" 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
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Page 38 of 61 
 
 
 
In patients that agree to participate in this portion of the 
study, we propose collection of peripheral blood (20-30 cc 
using CPT or sodium heparin tubes) and bone marrow 
aspirate (5-10 cc in EDTA and 5-10 cc in sodium heparin 
tubes) at the timepoints indicated in the Table above and 
in Figure 1 (right). The bone marrow sample collected in 
EDTA will be sent to the Hematologic Oncology Tissue 
Bank (HOTS) for subsequent studies and eventually 
sequenced in the genomics core facility The peripheral 
blood and bone marrow samples collected in sodium 
heparin will be analyzed under the supervision of 
Alexander M. Lesokhin. 
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 Potential Risks of Bortezomib 
 
To date, more than 300,000 patients have been treated with bortezomib in both clinical trials investigating its 
use in hematological malignancies and solid tumors, and in patients who were treated with commercially 
available bortezomib. 
Prescribing physicians and health care practitioners are referred to their locally approved product label for 
bortezomib regarding Indications and Usage, Contraindications, Warnings, and Precautions. 
The known anticipated risks of bortezomib therapy are presented in Table 0-1 and Table 0-2. These risks are 
grouped according to the combined frequency observed in an integrated analysis of AEs in sponsored clinical 
studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-day schedule, in patients with 
multiple myeloma and mantle cell lymphoma. 
  
 -----------  
 
 
A 
 ------  
 
 
 
 
 
<rYGPRrn 
 
RV0[j:OO!lyclesrn 
 
   
 
Bortezomibrallndrnl 
 
Dexamethasonern 
  

Memorial Sloan Kettering Cancer Center 
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Table 0-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
 
 
System Organ Class 
Observed Incidence 
Blood and Lymphatic System Disorders 
Most common 
Very common 
Common 
 
Cardiac Disorders 
Common 
Uncommon 
 
 
 
Ear and Labyrinth Disorders 
Uncommon 
Eye Disorders 
Common 
Gastrointestinal Disorders 
Most common 
Very common 
Common 
 
 
 
 
Uncommon 
 
Preferred Term 
 
Thrombocytopenia*, anaemia* 
Neutropenia* 
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
 
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Cardiogenic shock*, atrial flutter, cardiac tamponade*±, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest*, cardiac failure, arrhythmia, pericardia! 
effusion, pericarditis, pericardia! disease±, 
cardiopulmonary failure± 
 
Deafness, hearing impaired 
Blurred vision, conjunctivitis, conjunctiva! haemorrhage 
Constipation, diarrhoea*, nausea, vomiting* 
abdominal pain (excluding oral and throat) 
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosa! petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Very common 
Common 
 
Uncommon 
 
 
Hepatobiliary Disorders 
Uncommon 
Immune System Disorders 
Uncommon 
Fatigue, pyrexia 
Chills, oedema peripheral, asthenia 
Neuralgia, lethargy, malaise, chest pain, mucosa! 
inflammation* 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 
 
Hyperbilirubinaemia, hepatitis*± 
Drug hypersensitivity, angioedema 

Memorial Sloan Kettering Cancer Center 
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Page 40 of 61 
 
 
Table 0-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
 
 
System Organ Class 
Observed Incidence 
Infections and Infestations 
Very common 
Common 
 
 
Uncommon 
 
 
 
 
 
 
Injury, Poisoning, and Procedural Complications 
Common 
Uncommon 
Investigations 
Common 
 
 
 
Uncommon 
 
 
Metabolism and Nutritional Disorders 
Very common 
Common 
 
Musculoskeletal and Connective Tissue Disorders 
Very common 
Common 
Uncommon 
 
Preferred Term 
 
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis*, 
bactaeremia*, cellulitis*, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection*, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, empyema±, 
fungal oesophagitis± 
 
Fall 
Subdural haematoma 
 
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
 
Decreased appetite, anorexia, dehydration* 
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
 
Bone pain, myalgia, arthralgia, back pain 
Muscular weakness 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Nervous System Disorders 
Most common 
 
 
Very common 
Common 
 
Uncommon 
Tumour lysis syndrome* 
 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Paresthesia, dizziness excluding vertigo, headache 
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 

Memorial Sloan Kettering Cancer Center 
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Page 41 of 61 
 
 
Table 0-1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
 
System Organ Class 
Observed Incidence 
Preferred Term 
 
reversible posterior leukoencephalopathy syndrome±, 
posterior reversible encephalopathy syndrome <!> 
Psychiatric Disorders 
Very common 
Common 
Uncommon 
Renal and Urinary Disorders 
Common 
Uncommon 
Respiratory, Thoracic, and Mediastinal Disorders 
 
Anxiety, insomnia 
Confusional state 
Delirium 
 
Renal impairment*, renal failure*, haematuria 
Micturition disorder 
Very common 
Cough, dyspnoea 
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema* 
Uncommon 
 Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Common 
Uncommon 
Vascular Disorders 
 
Rash 
Rash pruritic, rash erythematous, urticaria, petechiae 
Cutaneous vasculitis, leukocytoclastic vasculitis± 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
 
Source: VELCADE® (bortezomib) for Injection Investigator's Brochure Edition 15. 
Most common= :2: 30%, Very c01mnon = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
± Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 
<!> Effective MedDRA update to version 14.0, the term 'reversible posterior leukoencephalopathy syndrome' 
updated to 'posterior reversible encephalopathy syndrome (PRES)'. 

Memorial Sloan Kettering Cancer Center 
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Page 42 of 61 
 
 
Table 0-2 
Reports of Adverse Reactions From Postmarketing Experience 
 
 
System Organ Class 
Preferred Term 
Blood and lymphatic system disorders 
Disseminated intravascular coagulation 
Cardiac Disorders 
Atrioventricular block complete 
Cardiac tamponade 
Ear and labyrinth disorders 
Deafness bilateral 
Eye Disorders 
Ophthalmic herpes 
Optic neuropathy 
Blindness 
Gastrointestinal Disorders 
Acute pancreatitis 
lschemic colitis 
Hepatobiliary disorders 
Hepatitis 
Liver failure 
Infections and infestations 
Herpes meningoencephalitis 
Septic shock 
Progressive multifocal leukoencephalopathy 
Immune System Disorders 
Angioedema 
Nervous System Disorders 
Autonomic neuropathy 
Dysautonomia 
Encephalopathy 
Respiratory, thoracic and mediastinal disorders: 
Acute diffuse infiltrative pulmonary diseaseb 
Acute respiratory distress syndrome (ARDS) 
Interstitial pneumonia 
Lung infiltration 
Pneumonitis 
Pulmonary hypertension 
Observed 
Incidence• 
 
 
Rare 
 
 
Rare 
Rare 
 
Rare 
 
 
Rare 
Rare 
Rare 
 
Rare 
Rare 
 
Uncommon 
Unknown 
 
Rare 
Rare 
Very rare 
 
Rare 
 
 
Rare 
Unknown 
Rare 
 
Rare 
Rare 
Rare 
Rare 
Rare 
Rare 

Memorial Sloan Kettering Cancer Center 
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Table 0-2 
Reports of Adverse Reactions From Postmarketing Experience 
 
 
System Organ Class 
Preferred Term 
Observed 
Incidence• 
 
 
 
Skin and subcutaneous system disorders 
Acute febrile neutrophilic dermatosis 
Toxic epidermal necrolysis 
 
Unknown 
Unknown 
Source: VELCADE®(bortezomib) for Injection Investigator's Brochure Edition 15, Addendum 1. 
a Incidence is assigned using the following convention: very common(:?: 1/10); common(:?: 1/100 and 
< 1/10); uncommon(:?: 1/1000 and< 1/100); rare(:?: 1/10,000 and< 1/1000 ); very rare(< 1/10,000, 
including isolated reports). 
b  Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a 
Preferred Term oflnterstitial lung disease. 
 
Other medical events of interest that are considered not causally related to bortezomib include hepatic failure 
and QT prolongation. Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib. 
Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay and in the in vivo 
micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration assay. 
Additional details on the potential risks of bortezomib may be found in the current Investigator's Brochure. 
 
 
SAFETY SUMMARY FOR SUBCUTANEOUS ADMINISTRATION 
 
While the safety profile between the SC and IV treatment groups in general was comparable in most SOCs, a 
difference in incidence in certain safety parameters in favor of the SC treatment group was noted. One 
hundred and forty (95%) subjects in the SC treatment group and 73 (99%) subjects in the IV treatment group 
reported at least 1 treatment-emergent adverse event. In the SC treatment group, there was a lower incidence 
of Grade :2:3 adverse events as compared with the IV treatment group (57% vs. 70%, respectively); a lower 
incidence of adverse events leading to treatment discontinuations (22% in the SC treatment group and 27% in 
the IV treatment group); and a lower incidence of adverse events leading to dose modifications in the SC 
group: dose reduction (33% in the SC treatment group compared with 45% in the IV treatment group); dose 
withholding (30% in the SC treatment group compared with 39% in the IV treatment group); or cycle delay 
(20% in the SC treatment group compared with 34% in the IV treatment group). Serious adverse events were 
similar between the 2 treatment groups (36% in the SC treatment group and 35% in the IV treatment group). 
Deaths during treatment (within 30 days of last dose) were 5% in the SC treatment group and 7% in the IV 
treatment group. 
The SC treatment group reported a lower incidence in several adverse events associated with BORTEZOMIB 
toxicity. The incidence of peripheral neuropathy events (all Grades) was 38% in the SC treatment group and 
53% in the IV treatment group; the incidence of Grade :2:2 peripheral neuropathy events was 24% in the SC 
treatment group and 41% in the IV treatment group; and the incidence of Grade :2:3 peripheral neuropathy 
event was 6% in the SC treatment group and 16% in the IV treatment group. There also appeared to be a 
trend towards lower incidence in gastrointestinal adverse events (37% for SC and 58% for IV, predominantly 

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due to differences in Grade 1-2 abdominal pain, diarrhea, and dyspepsia); as well as a 25% difference in 
incidence of Grade 3 and 4 hematology laboratory results in the SC treatment group compared with the IV 
treatment group for WBC (8% in the SC treatment group compared with 18% in the IV treatment group), 
neutrophil count (22% in the SC treatment group compared with 28% in the IV treatment group) and platelets 
(18% in the SC treatment group compared with 23% in the IV treatment group). 
Local tolerability of SC administration was acceptable. Nine (6%) subjects reported a local reaction to SC 
administration as an adverse event. Eighty-five (58%) subjects in the SC treatment group reported at least 1 
local injection site reaction. The most common local injection site reaction was redness which was reported in 
84 (57%) subjects. The majority of subjects with worst injection site reactions were assessed as mild (38%) or 
moderate (18%). Only 2 (1%) subjects were reported as having severe injection site reactions. All local site 
reactions resolved completely and rarely led to treatment modifications. 
In conclusion, the SC administration of BORTEZOMIB has good local tolerance. The systemic safety profile for 
the SC administration of BORTEZOMIB was associated with a lower incidence of Grade 23 adverse events, 
and treatment modifications (discontinuations and dose reductions). In particular, there was a lower incidence 
of peripheral neuropathy NEC reported. 
 
 
RISKS DURING PREGNANCY 
It is not known what effects bortezomib has on human pregnancy or development of the embryo or fetus. 
Therefore, female patients participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner. Non-sterilized female patients of reproductive age and male 
patients should use effective methods of contraception through defined periods during and after study 
treatment as specified below. 
 
Female patients must meet 1 of the following: 
• 
Postmenopausal for at least 1 year before the screening visit, or 
• 
Surgically sterile, or 
• 
If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time 
of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to 
completely abstain from heterosexual intercourse. 
 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples below). 
 
 
 
Highly effective methods 
Intra-uterine devices (IUD) 
Hormonal contraceptives (birth control pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive 
implants) 
Other effective methods (barrier methods) 
Latex condom 
Diaphragm with spermicide 
Cervical cap 
Sponge 
 
 
If one of the highly effective methods cannot be used, using 2 effective methods at the same time 
is recommended. 
 
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following: 
• 
Practice effective barrier contraception during the entire study treatment period and through a minimum 
of 30 days after the last dose of study drug,_Q[ completely abstain from heterosexual intercourse. 

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11.2 Potential Risks of Lenalidomide 
 
The following is a list of adverse events that are associated with the use of lenalidomide: 
Likely 
Events that have occurred in >20% of individuals treated with lenalidomide include constipation, neutropenia, 
anemia, thrombocytopenia, fatigue, diarrhea, and constipation. 
Less likely 
Events that have occurred in ::; 20% of individuals treated with lenalidomide include hypothyroidism, nausea, 
vomiting, chills, edema of the limbs, fever, infection, decreased lymphocyte count, weight loss, leukocytopenia, 
anorexia, arthralgia, back pain, muscle cramps, myalgia, dizziness, headache, insomnia, cough, dyspnea, 
hyperhidrosis, pruritis, rash, pyroderma gangrenosum, and stroke. 
Rare but serious 
Events that have occurred in 1 % of individuals treated with lenalidomide include risk of DVT, PE, and blood 
clots that could lead to stroke, heart attack, or organ failure, febrile neutropenia, atrial fibrillation, pneumonia or 
lung infections, sepsis, dehydration and renal failure. 
Events that have occurred in <3% of individuals treated with lenalidomide include rare treatment-emergent 
adverse events of angioedema, serious skin reactions including Stevens-Johnson syndrome (SJS), toxic 
epidermal necrolysis (TEN), erythema multiforme, or an allergic skin reaction similar to that seen with 
thalidomide, tumor lysis syndrome (TLS), tumor flare reaction (TFR), rhabdomyolysis, leukemia secondary to 
oncology chemotherapy, myelodysplastic syndrome, leukoencephalopathy, pancreatitis, anaphylaxis, 
increased lipase and acute kidney injury. In addition, lenalidomide has been shown to increase the level of 
digoxin in the blood in some patients. Patients will be instructed to inform their doctor if taking digoxin. 
There may be an increased risk of second cancers in patients who are on lenalidomide maintenance therapy 
after a bone marrow transplant. 
 
 
11.3 Potential Risks of Dexamethasone 
 
Events that have occurred in 10-15% of individuals treated with dexamethasone include increased appetite, 
weight gain, sleep disturbance, hypertension, fluid retention, ankle swelling, bruising, infection, mood changes, 
slow wound healing, depression, and hyperglycemia, which may lead to fatigue, weight loss, excessive thirst 
and frequent urination. 
Events that have occurred in 1-9% of individuals treated with dexamethasone include loss of appetite, muscle 
twitching, increased thirst, frequent urination, increased perspiration, diarrhea, nausea, headache, bone 
thinning, spinal fracture or fracture of bones, tachycardia, fungal infections. 

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Events that have occurred in <1% of individuals treated with dexamethasone include blurred vision, personality 
changes, stomach ulcers with bleeding that may cause hematemesis, blood in the stool and abdominal pain. 
Other, less frequent, events may include bowel perforation, irritation and bleeding of the esophagus, heart 
failure, allergic reaction that may lead to facial redness, shortness of breath, abdominal cramps and 
hypotension, convulsions, brain swelling, dizziness, cataracts, glaucoma and increased pressure in the eye, 
development of diabetes, pancreatic inflammation, abdominal swelling, hypokalemia, DVT or PE, malaise, 
swelling and/or redness of skin, allergic skin reactions, itching, hirsutism, muscle weakness or loss of muscle 
mass, rupture of tendons, menstrual cycle disturbances, facial puffiness leading to the appearance of a "moon 
face", hormonal disturbances, and hiccups. 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 Definition of Measurable Disease 
 
Measurable disease is disease that can be measured either by serum or urinary evaluation of the monoclonal 
component or by serum assay of FLC and is defined by at least one of the following three measurements. 
■ 
Serum M-protein 
1 g/dl 
■ 
Urine M-protein 
200 mg/24 h 
■ 
Serum FLC assay: Involved FLC level 
10 mg/di provided serum FLC ratio is abnormal. 
 
 
 
12.2 Methods for Evaluation of Measurable Disease 
 
Response will be assessed by M-protein quantification using protein electrophoresis and immunofixation from 
serum or 24-hour urine collection, or serum Freelite™ testing. In addition, bone marrow aspiration and biopsy, 
as well as skeletal survey will be performed to determine overall response or confirm response, if deemed 
necessary. 
The same method of assessment and technique should be used for disease measurement at baseline and 
during follow-up. 
 
 
12.3 International Myeloma Working Group Response Criteria 
 
Response criteria for all categories and subcategories of response except CR are applicable only to patients 
who have 'measurable' disease, as defined in Section 12.1. 
Stringent CR: CR as defined below plus normal free light chain ratio and absence of clonal cells in bone 
marrow· by immunohistochemistry or immunofluorescence•. 

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*Presence/absence of clonal cells is based upon the k/A. ratio. An abnormal k/1 ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/A. of> 4:1 or < 1:2. 
CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas 
and 5% plasma cells in bone marrow. 
VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater 
reduction in serum M-protein plus urine M-protein level <100mg per 24 hours. 
PR: .:::, 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or to < 200mg per 
24 hours. If the serum and urine M-protein are unmeasurable, a .:::, 50% decrease in the difference between 
involved and uninvolved free light chain levels is required in place of the M-protein criteria (definition of 
measurable disease in Section 10.2.3). If serum and urine M-protein are unmeasurable, and serum free light 
assay is also unmeasurable, .:::, 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was.:::, 30%. In addition to the above listed criteria, if present at 
baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required. 
SD: Not meeting criteria for CR, VGPR, PR or progressive disease. This is not recommended as an indicator 
of response; stability of disease is best described by providing the time to progression estimates. 
PD: > 25% increase of serum M-protein (which must also be an absolute increase of 
0.5 g/dl) and/or urine 
M-protein (which must also be an absolute increase of  200 mg/24hr). If serum and urine M-protein are 
unmeasurable, there must be an absolute increase of 
10 mg/dl between involved and uninvolved FLC 
levels. PD is also measured by an absolute increase in bone marrow plasma cells.:::, 10%. In addition to the 
above listed criteria, progression may also be measured by a definite development of new bone lesions or soft 
tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas or 
development of hypercalcemia (corrected serum calcium.:::, 11.5 mg/dl or 2.65 mmol/L) that can be attributed 
solely to the plasma cell proliferative disorder. 
Freelite TM Disease Response Criteria 
Complete Response: For those patients being followed by serum free light chain (and NO measurable serum 
or urine M-spike), which were immunofixation negative at enrollment, normalization of serum free light chain 
ratio. 
- Normalization is defined as the serum free light chain ratio being within the normal range. If the serum free 
light chain ratio is not within the normal range, but the individual kappa and lambda light chain values are 
within normal range, this may be considered CR. 
Partial Response: If only measurable parameter is serum immunoglobulins free light chain (FLC), EITHER of 
the following changes qualifies as partial response: 
- A 50% decrease in the difference between involved and uninvolved FLC levels; OR 
- A 50% decrease in the level of involved FLC AND a 50% decrease (or normalization) in the ratio of 
involved/uninvolved FLC 
Progressive Disease: If only measurable parameter is serum immunoglobulins free light (FLC), either of the 
following qualify as progression: 

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- 50% increase in the difference between involved and uninvolved FLC levels from the lowest response level, 
which must also be an absolute increase of at least 10 mg/dl; OR 
- 50% increase in the level of involved FLC AND a 50% increase in the ratio of involved/uninvolved FLC from 
the lowest response level. 
 
 
12.4 QOL Questionnaire 
 
Qol will be assessed in this study using the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and its corresponding multiple myeloma module 
(EORTC QLQ-MY20). 
 
The EORTC QLQ-C30 is a valid, reliable and widely used cancer-specific, multi-dimensional core Qol 
instrument that incorporates nine multi-item scales including five functional scales (physical, role, emotional, 
social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain) and a global health and 
quality of life scale. Six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) are included. Response options are a 4-point Likert-type scale from "not at all" to "very much" or a 
?-point Likert-type scale from "very poor" to "excellent." 
 
Designed to be used in conjunction with the EORTC QLQ-C30, the EORTC QLQ-MY20 scale has been well­ 
validated and was designed to evaluate the effect of the disease and drug therapy in patients with multiple 
myeloma. This measure is comprised of four scales (disease symptoms, side effects, body image, and future 
perspective). 
 
The EORTC QLQ-C30 and MY20 collectively take approximately 12 minutes to complete (Aaronson et al., 
1993; Cocks et al., 2007; Hjermstad et al., 1995) and are designed to be self-administered. However, a 
designated person at the study site will be responsible for administering the surveys to participants and 
providing materials to assist in survey completion (i.e., a clipboard, pen, and envelope to enclose the survey in 
when completed). This person will also be responsible for collecting the completed survey, verifying that no 
items have missing responses, and answering any questions that arise from the participant regarding the 
survey. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Patients will be informed that they have the right to withdraw from the study at any time for any reason, without 
prejudice to their medical care. 
The investigator is required to withdraw patients from the study for any of the following reasons: 
 
• 
If after at least one cycle of RVD treatment a patient shows evidence of hematologic disease 
progression 
• 
If at any time a patient develops unacceptable toxicity 
• 
 General or specific changes in the patient's condition unacceptable for further treatment in the 
judgment of the investigator 
 
The investigator may consider withdrawing patients from the study for any of the following reasons: 

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• 
If after at least 2 cycles of RVD the patient is shown to have only stable disease the investigator needs 
to consider withdrawal of the patient 
• 
If there is protocol violation 
• 
Non-compliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 
 
 
14.0 
BIOSTATISTICS 
14.1 Primary Endpoint 
 
The goal of this phase II trial is to investigate the efficacy of a sequential drug regimen in symptomatic multiple 
myeloma patients. The primary endpoint is the overall response rate (PR or better) after four cycles of therapy. 
Patients who withdraw prior to the primary endpoint evaluation for reasons related to progression of disease or 
drug-related toxicity will be considered treatment failures. 
The study will employ a Simon optimal two-stage design. The sequential drug regimen is considered promising 
if the overall response rate after 4 cycles is 90% or higher and unpromising if the overall response rate is 70% 
or lower. These numbers are based on the results achieved in a phase II clinical trial describing the 
effectiveness of the combination of drugs lenalidomide, bortezomib, and dexamethasone (RVD) given 
concomitantly in untreated multiple myeloma patients. The probabilities of a type I error and type II error are 
each set at 0.10. We will enroll 9 patients in the first stage. If 6 or fewer patients respond after 4 cycles, the trial 
will be terminated. If not, then an additional 19 patients will be enrolled to a total of 28. Upon completion of the 
trial, if there are 23 or more patients who have achieved a PR or better, the drug combination will be 
considered promising for further investigation. 
With an anticipated accrual of 1-2 patients per month, the duration of this trial is approximately 2 years. 
 
14.2 Secondary Endpoints 
There are a number of secondary endpoints in this trial. The proportion of patients in each response category 
(CR, VGPR, PR, SD, and PD) will be tabulated after the completion of cycle four and cycle eight (for those who 
would have completed 8 cycles), and the overall response rate for the entire population after up to eight cycles 
will be estimated and compared to the responses reported in the phase II study by Richardson et al. using the 
3-drug-combination26. For patients going to transplantation prior to completion of 8 cycles, the response prior to 
transplantation will be considered the best response. 
The toxicities of the sequential drug regimen will be investigated. The toxicities outlined in section 11 will be 
tabulated overall for the study population and by whether the two or three drug combination was given at the 
time of the noted toxicity. The toxicities for the entire population will be compared to previously reported and 
tabulated toxicities in the phase II study by Richardson et al. using the 3-drug-combination, focusing on grade 
3 and 4 toxicities26. For toxicity analysis, only toxicity prior to transplantation will be considered. 
QOL will be collected at Screening, on day 1 of each treatment cycle, and at the end of study. The two QOL 
questionnaires for this trial are described in subsection 12.4. Graphical and descriptive measures will used to 
summarize the changes in the nine scales of C30 and four scales of MY20 from baseline to the completion of 
cycles four and eight. Comparison between patients having received 2 versus 3 drugs will be described. QOL 
data will only be collected up to the time of transplantation 

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Lastly, progression-free survival will be estimated for all patients using Kaplan-Meier methodology. This 
analysis will include all patients regardless of their transplantation status. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol specific Eligibility 
Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office at Memorial 
Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am - 5:30pm at 646-735- 
8000. Registrations must be submitted via the PPR Electronic Registration System (http://ppr/). The 
completed signature page of the written consenURA or verbal scripURA, a completed Eligibility Checklist and 
other relevant documents must be uploaded via the PPR Electronic Registration System. 
 
 
15.2 
Randomization 
There is no randomization in this clinical trial 
16.0 
DATA MANAGEMENT ISSUES 
All patients will be enrolled on protocol at Memorial Sloan-Kettering Cancer Center. We expect to be able to 
enroll the necessary 28 patients into this study in 2 years. 
The data manager (Research Study Assistant, RSA) will be responsible for confirming eligibility and assisting 
the MD with the registration process. All study data will be collected by an assigned RSA who will enter this 
information into the Clinical Research Database (CRDB). This database will be utilized for data collection and 
storage and for reporting protocol specific events such as accrual demographics, toxicities and adverse events 
to the IRB, and the sponsor. 
The RSA will collect toxicity and concomitant medication information and patient interviews. Adverse events, 
including all toxic effects of treatment will be tabulated individually according to severity or toxicity grade. The 
data manager will also monitor laboratory testing throughout the study. Laboratory data will be tabulated and 
summarized by descriptive statistics, as well as on the basis of MSKCC specified normal ranges. 
16.1 
Quality Assurance 
Monthly registration reports will be generated to monitor patient accruals and completeness of registration 
data. Routine data quality reports will be generated to assess missing data and inconsistencies. Accrual rates, 
extent and accuracy of evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and action. 
Random sample data quality and protocol compliance audits will be conducted by the study team, at a 
minimum of two times per year, more frequently if indicated. 

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16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center were approved by 
the National Cancer Institute in September 2001. The plans address the new policies set forth by the NCI in 
the document entitled "Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials" 
which can be found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety and quality. There 
are institutional processes in place for quality assurance (e.g., protocol monitoring, compliance and data 
verification audits, therapeutic response, and staff education on clinical research QA) and departmental 
procedures for quality control, plus there are two institutional committees that are responsible for monitoring 
the activities of our clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) 
for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase Ill clinical trials, 
report to the Center's Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its level of risk and 
degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house sponsored, industrial 
sponsored, NCI cooperative group, etc.) will be addressed and the monitoring procedures will be established at 
the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed consent, which 
must conform to MSKCC and collaborating centers IRB guidelines. 
Patients will be eligible for this trial regardless of gender or racial/ethnic background. All patients must follow 
the guidelines for pregnancy testing birth control and counseling related to the risk of fetal exposure to 
lenalidomide and bortezomib as outlined in Appendix F and Table in section 10.1. 
The protocol for this study has been designed in accordance with the general ethical principles outlined in the 
Declaration of Helsinki. The review of this protocol by the IRB and the performance of all aspects of the study, 
including the methods used for obtaining informed consent, must also be in accordance with principles 
enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), 
Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
 
Potential risks and benefits 
The potential risks of this therapy may outweigh the potential benefit in an individual patient. The potential risks 
to patients are related to drug induced adverse effects and are outlined in Section 11.0. Appropriate exclusion 
criteria for patients are listed in Section 6.0: Patient Eligibility. Appropriate exclusion of patients with significant 
organ dysfunction or infection will help avoid treatment-related toxicity. Careful monitoring of laboratory 
parameters and patient symptoms, along with serial assessment for disease recurrence, will be carried out 
routinely in order to minimize the risk of adverse effects during this study. 

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Alternatives/Options for treatment 
Patients with newly diagnosed standard-risk multiple myeloma have many treatment options. Alternative 
therapy for patients who choose not to enroll on this study include standard chemotherapy, including 
thalidomide, steroids, bortezomib, lenalidomide, some combination of the above, autologous or allogeneic stem 
cell transplant, other clinical trials, observation, or supportive care. 
 
Costs 
Patients will be responsible for all costs related to treatment and complications of treatment, including all 
hospitalizations. 
17.1 
Privacy 
MSKCC's Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health information 
will be limited to the individuals described in the Research Authorization form. A Research Authorization form 
must be completed by the Principal Investigator and approved by the IRB and Privacy Board. 
The investigator will grant monitor(s) and auditor(s) from Millennium and regulatory authority(ies) access to the 
patient's original medical records for verification of data gathered on the data capture records and to audit the 
data collection process. The patient's confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
• 
 A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
 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 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 30- 
days after the participant's last investigational treatment or intervention. Any events that occur after the 
30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 'Reporting of Serious Adverse 
Events', the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB requires a 
Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE Office as 
follows: 

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For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
 
• 
Subject's initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The Pl's signature and the date it was signed are required on the completed report. 
17.2.1 Serious Event Reporting to Millennium 
All serious adverse events (SAEs) (regardless of expectedness, causality, and whether commercial or 
investigational bortezomib is used) must be reported to Millennium Pharmacovigilance (or designee). 
The sponsor-investigator is responsible to meet all regulations and requirements applicable to the sponsor­ 
investigator. 
(Millennium will not report SAEs on behalf of the sponsor-investigator to any regulatory agency [eg, US FDA] 
or to the sponsor-investigator's IRB.) 
Definitions 
Adverse Event Definition 
 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with 

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this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product 
whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous 
condition that has increased in severity or frequency since the administration of study drug. 
For this protocol an abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the 
investigator to be a clinically significant change from baseline. 
Serious Adverse Event Definition 
 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see clarification below 
on planned hospitalizations in Section 0). 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a substantial 
disruption of a person's ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. This refers to an AE that may not result in death, be immediately life 
threatening, or require hospitalization, but may be considered serious when, based on appropriate 
medical judgment, may jeopardize the patient, require medical or surgical intervention to prevent one of 
the outcomes listed above, or involves suspected transmission via a medicinal product of an infectious 
agent. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
With respect to the suspected transmission via a medicinal product of an infectious agent; any organism, virus, 
or infectious particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), whether 
pathogenic or non-pathogenic, is considered an infectious agent. 
Clarification should be made between the terms serious and severe because they ARE NOT the same. The 
term severe is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a 
severe headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above and is usually associated with events that pose a threat to a patient's life or 
functioning. A severe AE does not necessarily need to be considered serious. For example, persistent 
nausea of several hours duration may be considered severe nausea but may not be considered an SAE. On 
the other hand, a stroke resulting in only a minor degree of disability may be considered mild but would be 
defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 

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Procedures for Reporting Serious Adverse Events (SAEs) 
 
Adverse events (AEs) may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic procedures. AEs 
which are serious must be reported to Millennium Pharmacovigilance (or designee) from first dose of 
bortezomib up to and including 30 days after administration of the last dose of bortezomib. When possible, 
signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event. 
Any SAE that occurs at any time after completion of bortezomib treatment or after the designated follow-up 
period that the investigator and/or sub-investigator considers to be related to any study drug must be reported 
to the Millennium Pharmacovigilance (or designee). Planned hospital admissions or surgical procedures for an 
illness or disease that existed before the patient was enrolled in the trial are not to be considered AEs unless 
the condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or later 
than planned). All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient's stable or chronic condition or intercurrent illness(es). 
This is an investigator-initiated study. The principal investigator Hani Hassoun is conducting the study and 
acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator include both those of 
a sponsor and those of an investigator. 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with any study drug, to 
Millennium Pharmacovigilance (or designee) as soon as possible, but no later than 5 calendar days of the 
sponsor-investigator's observation or awareness of the event. In the event that this is a multisite study, the 
sponsor-investigator is responsible to ensure that the SAE reports are sent to Millennium Pharmacovigilance 
(or designee) from all sites participating in the study. Sub-investigators must report all SAEs to the sponsor­ 
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations to Millennium 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and sub-investigator(s). 
Millennium Pharmacovigilance (or designee) may request follow-up information to a reported SAE, which the 
sponsor-investigator will be responsible for providing to Millennium Pharmacovigilance (or designee). 
The SAE report must include event term(s), serious criteria, and the investigator's or sub-investigator's 
determination of both the intensity of the event(s) and the relationship of the event(s) to study drug 
administration. 
Intensity for each SAE, including any lab abnormality, will be determined by using the NCI CTCAE, version 
used at your institution, as a guideline, whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
Relationship to all study drugs for each SAE will be determined by the investigator or sub-investigator by 
responding yes or no to the question: Is there a reasonable possibility that the AE is associated with the study 
drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all communications with 
applicable regulatory authorities related to the study or study drug(s), including, but not limited to, telephone 
conversation logs, as soon as possible but no later than 5 calendar days of such communication. 
 
 
Millennium Pharmacovigilance 
 

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Approval date: 11-Apr-2022 
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SAE and Pregnancy Reporting Contact Information: 
North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax: +1 888-488-9697 
Hotline number (available 24/7): 1-800-201-8725 
 
 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she must 
inform the investigator immediately and must permanently discontinue study drug(s). Millennium must be 
contacted immediately by faxing the CRDB report or other approved equivalent form to the Millennium 
Pharmacovigilance or designee (see Section 17.2.1). The pregnancy must be followed for the final pregnancy 
outcome (i.e., delivery, still birth, miscarriage) and Millennium Pharmacovigilance will request this information 
from the investigator. 
If a female partner of a male patient becomes pregnant during the male patient's participation in this study, 
Millennium must also be contacted immediately by the CRDB report. Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of the 
protocol and study procedures as well as the risks involved to participants prior to their inclusion in the study. 
Participants will also be informed that they are free to withdraw from the study at any time. All participants must 
sign an IRB/PB-approved consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review Board/Privacy Board of this 
Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain the 
aspects of patient privacy concerning research specific information. In addition to signing the IRB Informed 
Consent, all patients must agree to the Research Authorization component of the informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
Page 57 of 61 
 
 
Each participant and consenting professional will sign the consent form. The participant must receive a copy of 
the signed informed consent form. 

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IRB Number: 13-064 A(22) 
Approval date: 11-Apr-2022 
Page 58 of 61 
 
 
 
 
19.0 
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IRB Number: 13-064 A(22) 
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20.0 
APPENDICES 
 
Appendix A 
 Cockcroft-Gault estimation of CrCI 
Appendix B 
ECOG Performance Status 
Appendix C 
Performance Status Criteria 
Appendix D 
 Quality of Life Questionnaire 
Appendix E 
Recommendations for Pregnancy 
Appendix F 
 Hartford Alliance Protocol Addendum