Clinical trial NCT05788289
Conditions: Mantle Cell Lymphoma MCL
Keywords: Mantle Cell Lymphoma MCL R/R MCL Tafasitamab Lenalidomide Memorial Sloan Kettering Cancer Center 22-380
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2023-03-14; Completion date: 2024-08-01
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if the combination of tafasitamab and lenalidomide is an effective treatment for relapsed or refractory Mantle Cell Lymphoma.

Detailed description:

Arms: arm 1: Participants have a diagnosis of Mantle Cell Lymphoma have previously failed or could not tolerate Bruton's tyrosine kinase inhibitors/BTKi
Interventions: intervention 1: Tafasitamab intervention 2: Lenalidomide
Intervention descriptions: intervention 1: Participants will receive treatment with intravenous tafasitamab and oral lenalidomide for up to 12 cycles. Each cycle is 28 days in length. intervention 2: Lenalidomide will be self-administered by patients orally on days 1-21 of each 28-day cycle of induction (cycles 1 through 12).

Protocol documents:
Prot_SAP_000.pdf: 
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MSK PROTOCOL COVER SHEET 
Phase 2 Study of Tafasitamab and Lenalidomide in Relapsed or Refractory Mantle 
Cell Lymphoma 
 
Principal Investigator/Department: Anita Kumar/Medicine 
 
 
 
Glossary of Terms
Term
Definition
ADCC
Antibody-dependent cellular cytotoxicity
AdjBW
Adjusted body weight
AOL
Activities of daily living
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine transaminase
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplantation
AST
Aspartate transaminase
BM
Bone marrow
BSA
Body surface area
BTKi
Bruton's tyrosine kinase inhibitor
CBC
Complete blood count
CMP
Comprehensive metabolic panel
CR
Complete response
CRu
Unconfirmed complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
OCR
Disease Control Rate
DOR
Duration of response
ECG
Electrocardiogram
EOT
End of treatment
FOG
[18F]fluorodeoxyglucose
G-CSF
Granulocyte colony stimulating factor
GVHD
Graft-versus-host disease
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HIV
Human immunodeficiency virus
IBW
Ideal body weight


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IMiD
lmmunomodulatory imide drug
IMPACT
Integrated Mutation Profiling of Actionable Cancer Targets
IND
lnvestigational new drug
IRR
Infusion-related reaction
KPS
Karnofsky performance status
LAR
Legally authorized representative
LOH
Lactate dehydrogenase
MCL
Mantle cell lymphoma
MIPI
Mantle cell lymphoma international prognostic index
NHL
Non-Hodgkin lymphoma
MRD
Minimal residual disease
NGS
Next-generation sequencing
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
Pl
Principal investigator
PR
Partial response
REMS
Risk Evaluation and Mitigation Strategy
R/R
Relapsed or refractory
RSA
Research Study Assistant
SAE
Serious adverse event
SD
Stable disease
soc
Standard of care
TBW
Total body weight
TTP
Time to progression
ULN
Upper limit of normal
V(D)J
Variable, diversity, and joining gene segments


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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 5 
2.1 
Primary objective .................................................................................................................. 5 
2.2 
Secondary objectives ........................................................................................................... 6 
2.3 
Exploratory objectives 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 7 
3.1 Correlative studies 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................... 12 
4.1 
Design ................................................................................................................................ 12 
4.2 
Intervention ......................................................................................................................... 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ............. 13 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY ........................................................................ 15 
6.1 
Participant Inclusion Criteria ............................................................................................... 15 
6.2 
Participant Exclusion Criteria .............................................................................................. 16 
7.0 
RECRUITMENT PLAN .......................................................................................................... 18 
7.1 
Research Participant Registration ....................................................................................... 18 
8.0 
INFORMED CONSENT PROCEDURES ................................................................................. 18 
9.0 
PRE-TREATMENT/INTERVENTION ...................................................................................... 19 
9.1 Pre-treatment/intervention evaluations .................................................................................... 19 
9.2 Concomitant therapy ............................................................................................................... 20 
9.2.1 Permitted concomitant therapies .......................................................................................... 20 
9.2.2 Prohibited concomitant therapies.......................................................................................... 20 
9.2.3 Drug-drug interactions .......................................................................................................... 20 
10.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 21 
10.1 Tafasitamab .......................................................................................................................... 21 
10.2 Lenalidomide ......................................................................................................................... 21 
10.3 Required prophylaxis ............................................................................................................. 22 
10.4 Study duration ....................................................................................................................... 23 
10.5 Dose continuation, modification, and interruption ................................................................... 23 
10.5.1 Parameters for treatment continuation ................................................................................ 23 


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10.5.2 Tafasitamab infusion-related reactions ............................................................................... 23 
10.5.2.1 Monitoring, grading, and acute management of tafasitamab IRR ..................................... 23 
10.5.2.2 Rechallenge after tafasitamab IRR .................................................................................. 24 
10.5.3 Lenalidomide-associated diarrhea ...................................................................................... 24 
10.5.4 Hematologic and other toxicities ......................................................................................... 25 
10.5.5 Lenalidomide-associated tumor flare .................................................................................. 28 
10.5.6 Lenalidomide dose reductions for toxicity ........................................................................... 28 
10.5.7 Maximum duration of treatment interruption ........................................................................ 29 
11.0 EVALUATION DURING TREATMENT/INTERVENTION ....................................................... 30 
11.1 General overview of evaluations ............................................................................................ 30 
11.2 Correlative studies ................................................................................................................ 33 
12.0 CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 33 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY ................... 33 
13.1 Criteria for Therapeutic Response/Outcome Assessment ..................................................... 33 
13.2 Criteria for Study Endpoint Evaluability .................................................................................. 34 
14.0 BIOSTATISTICS .................................................................................................................... 34 
15.0 
TOXICITIES/RISKS/SIDE EFFECTS ..................................................................................... 36 
15.1 Serious Adverse Event (SAE) Reporting ............................................................................... 38 
15.2 External SAE Reporting ......................................................................................................... 39 
15.3 Pregnancy ............................................................................................................................. 40 
16.0 PROTECTION OF HUMAN PARTICIPANTS ......................................................................... 40 
16.1 Privacy ............................................................................................................................... 41 
16.2 Data Management ................................................................................................................ 41 
16.3 Quality Assurance .............................................................................................................. 41 
16.4 Data and Safety Monitoring ................................................................................................ 42 
17.0 
REFERENCES ...................................................................................................................... 42 
18.0 
APPENDICES ....................................................................................................................... 44 
Appendix A: Karnofsky performance status33•34 .......................................................................... 45 
Appendix B: Cockcroft-Gault CrCl35•36 ........................................................................................ 46 
Appendix C: Acute management of infusion-related reactions ....................................................... 47 
Appendix D: Suggested symptom management of lenalidomide-associated diarrhea ................... 48 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a single-center, open-label phase II study of the combination of tafasitamab and 
lenalidomide in relapsed or refractory (R/R) mantle cell lymphoma (MCL) who have received 
previous treatment with a Bruton's tyrosine kinase inhibitor (BTKi). The study aims to 
evaluate the efficacy of the combination therapy. The primary endpoint will be objective 
response rate (ORR) to tafasitamab and lenalidomide, and will be evaluated when all 
patients have completed 12 cycles of treatment or at treatment discontinuation, whichever 
comes first. 
 
Patients will be enrolled to receive tafasitamab via IV infusion and self-administer 
lenalidomide orally according to the treatment schema below. for a maximum of 36 cycles (3 
years) In the first stage of the Simon 2-stage design, a total of 19 patients will accrue. If 6 or 
fewer have objective response, the trial will close due to a lack of efficacy; otherwise, an 
additional 20 patients will accrue. If at the end of the study, 17 or more out of 39 have an 
objective response, the trial will be considered promising for future development. 
 
The anticipated accrual rate for this study is 1 to 2 patients per month, and the trial will 
continue through three years after the last accrued patient. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary objective 
 
The primary objective of this study is to assess the ORR, defined as the percent of patients 
(relative to the total number considered evaluable as in 13.2) who achieve complete response 
(CR) or partial response (PR) according to the 2014 Lugano response criteria for non-Hodgkin 
lymphoma (NHL), to the combination of tafasitamab and lenalidomide in patients with R/R MCL 
who have experienced failure of or intolerance to past treatment with BTKi.1•2 
Figure 1: Treatment schema
 
 


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2.2 
Secondary objectives 
 
2.2.1 To determine disease control rate (DCR), defined as the percent of patients (relative to 
the total number evaluable) who achieve CR, PR, or stable disease (SD) at the time of 
ORR assessment. 
 
2.2.2 To estimate DOR, defined as the time from achievement of PR or CR to progression of 
disease (POD) according to Lugano criteria.1•2 
 
2.2.3 To estimate PFS, defined as the time from initiation of study treatment to the earlier of 
POD or death from any cause. 
 
2.2.4 To estimate OS, defined as the time from initiation of study treatment to death from any 
cause. 
 
2.2.5 To estimate TTP, defined as the time from initiation of study treatment to POD or death 
from MCL. 
 
2.2.6 To describe the safety of the combination of tafasitamab and lenalidomide in patients 
with R/R MCL, defined as the incidence and severity (according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0). 
 
2.3 Exploratory objectives 
 
2.3.1 To assess the rate of conversion to undetectable minimal residual disease (MRD) by 
immunoglobulin gene next-generation sequencing (NGS) relative to baseline at 3, 6, 
and 12 months post initiation of study treatment; MRD will also be assessed at POD. 
 
2.3.2 To characterize clonal evolution using circulating tumor DNA (ctDNA) in peripheral 
blood via high-depth targeted genomic sequencing at baseline, at 3, 6, and 12 months 
post initiation of study treatment, and at POD. 
 
2.3.3 To evaluate effects of study treatment on: 
- Antitumor immune response (via surface protein expression, RNA expression, and 
variable, diversity, and joining (V(D)J) gene segment recombination of peripheral 
mononuclear cells (PBMCs)) relative to baseline at 3, 6, and 12 months post 
initiation of study treatment, and at POD. 
MCL-driven immunosuppression in the tumor microenvironment (via flow cytometry 
enumeration of lymphocyte subsets in tumor biopsy samples) relative to baseline 
between days 21-28 of cycle 1, and at POD. 


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3.0 
BACKGROUND AND RATIONALE 
R/R MCL 
 
MCL is an uncommon B-cell NHL comprising approximately 6-8% of all NHL diagnoses.3.4 
MCL is more common in men than women, presents at a median age of 68 years, and is 
usually in an advanced stage at diagnosis, with bone marrow and the gastrointestinal tract 
being common extranodal sties of involvement. 5 Despite improvement in overall survival of 
MCL with intensive frontline chemotherapy, it remains an incurable disease and most 
patients are destined to relapse after initial therapy.6 After relapse, MCL is more challenging 
to treat and is associated with progressively shorter remission durations after each 
subsequent line of therapy, resistance to traditional cytotoxic chemotherapy, and limited 
survival.7 The therapeutic landscape in MCL is rapidly evolving, and a number of biologically 
targeted therapies, such as lenalidomide, the Bruton's tyrosine kinase inhibitors (BTKis; 
ibrutinib, acalabrutinib, and zanubrutinib), and venetoclax, have demonstrated promising 
efficacy in the R/R setting.8•12 However, after failure of BTKi therapy, outcomes are generally 
poor for patients with R/R MCL, with median OS of 5.8 months.13 
Recently, there was a promising therapeutic advance for R/R MCL with the FDA approval of 
brexucabtagene autoleucel, an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy 
with an associated 93% ORR, including 67% with CR.14 Unfortunately, some patients may be 
ineligible for CAR-T, and others may face access constraints and logistical challenges given 
the need for referral to a specialized treatment center and the complexities associated with 
leukapheresis and manufacturing of the CAR-T product. In addition, this approach is 
associated with a high rate of adverse events (AEs), including grade 3 or higher cytokine 
release syndrome and neurologic events in 15% and 31% of patients, respectively. There 
remains a need for additional therapeutic options after BTKi failure, particularly in patients 
with R/R MCL with advanced age and multiple comorbidities. 
Lenalidomide in MCL 
 
Lenalidomide is an oral immunomodulatory imide drug (IMiD) with multiple immune-mediated 
and anti-angiogenic antitumor effects. Lenalidomide has been demonstrated to impede 
angiogenesis through inhibition of bFGF, VEGF, and TNF-a-induced endothelial cell 
migration, due at least in part to inhibition of Akt phosphorylation response to bFGF.15 Its 
myriad immunomodulatory effects include stimulation of T-cell proliferation, production of IL- 
2, IL-10, and IFNy, inhibition of IL-1 and IL6, and modulation of IL-12 production.16 
Lenalidomide produces direct cytotoxicity in some hematologic malignancies through binding 
of cereblon, a component of the E3 ubiquitin ligase complex and thereby modulating protein 
ubiquitination and degradation.17•18 In MCL, lenalidomide's activity appears to be primarily 
mediated through expansion of CD56+ CD15+ NK cells and increased immune synapse 
formation, promoting NK cell-mediated cytotoxicity in the tumor microenvironment.19 
Several studies demonstrated promising activity of single-agent lenalidomide as well as the 
combination of lenalidomide and the CD20 monoclonal antibody rituximab for treatment of 


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R/R MCL. In a subset of 57 patients with R/R MCL in the phase II NHL-003 study, 
lenalidomide 25mg daily was associated with an ORR of 35% with a median duration of 
response of 16.3 months after median follow-up of approximately 20 months.20 In the larger 
international, multicenter phase II EMERGE study in patients with R/R MCL following 
bortezomib, single-agent lenalidomide produced an ORR of 28% (7.5% CR/unconfirmed CR 
(CRu)), with a similar median duration of response of 16.6 months.9 This study led to FDA 
approval of lenalidomide in patients with R/R MCL after at least two prior therapies, one of 
which included bortezomib. In a phase 1/11 trial of lenalidomide with rituximab, the 
combination was well-tolerated and produced an improved ORR of 57% (36% CR/CRu).21 
The maximum tolerated dose of lenalidomide identified in the phase I portion of this trial was 
20mg daily. One patient who received lenalidomide 25mg daily developed a grade 4 non- 
neutropenic infection and died. 
After BTKis were established as a standard second-line treatment option for R/R MCL, there 
was interest in defining outcomes associated with lenalidomide-based therapy after BTKi 
failure or intolerance. This was evaluated in the retrospective MCL-004 study of a cohort of 
58 patients with R/R MCL (13 treated with lenalidomide monotherapy, 11 with lenalidomide 
and rituximab, and 34 with other lenalidomide combinations).22 Patients had received median 
four prior lines of therapy (range 1-13), with an ORR of 29% (14% CR) and median duration 
of treatment of 8.4 weeks. The median DOR for responders was 20 weeks. 
Tafasitamab in B-ce/1 NHL 
 
Tafasitamab (MOR00208, previously XmAb5574) is an Fe-engineered, humanized 
monoclonal antibody that binds to the human B-cell surface antigen CD19.23 CD19 is broadly 
expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by 
hematological stem cells. Tafasitamab produces significantly higher tumor cytotoxicity 
compared to the parental, non-engineered, murine 4G7 CD19 antibody. Tafasitamab has 
increased affinity for Fey receptors through the introduction of two amino acid modifications 
within the Fe region. Tafasitamab is associated with antibody-dependent cellular cytotoxicity 
(ADCC), antibody-dependent cellular phagocytosis, and exerts direct cytotoxicity. Preclinial 
studies indicate potent in vitro and in vivo activity of tafasitamab in lymphoma and leukemia 
models.23,24 
Tafasitamab was tested in a phase Ila study in B-cell NHL, including diffuse large B-cell 
lymphoma (DLBCL, follicular lymphoma (FL), other indolent NHL, and MCL.25 Patients 
received tafasitamab 12mg/kg IV once weekly for 8 weeks, with those achieving at least SD 
eligible to continue treatment for an additional 4 weeks. Patients who achieved PR or CR 
after 12 weeks could receive further extended treatment every 2 or 4 weeks until POD. The 
primary endpoint of this study was ORR. Ninety-two patients were enrolled: 35 patients with 
DLBCL, 34 with FL, 11 with other indolent NHL, and 12 with MCL. Responses were observed 
among patients with DLBCL, FL, and other indolent NHL (ORR 26%, 29%, and 27%, 
respectively), including several durable responses. Among patients with MCL, there were no 
responders; however, six patients (50%) achieved SD, while five (42%) progressed and one 


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was not evaluable. This experience is in keeping with the poor activity rituximab 
monotherapy, which functions via similar mechanisms, in patients with untreated or R/R 
MCL.26 
 
Tafasitamab and lenalidomide 
 
It was hypothesized that modulation of immune effector cells by lenalidomide would enhance 
NK cell-mediated ADCC exerted by tafasitamab, thereby resulting in therapeutic synergy 
when used in combination. Furthermore, given that prior rituximab exposure in patients with 
R/R DLBCL may result in down-regulated expression and/or internalization of CD20, it was 
postulated that targeting the conserved surface antigen CD19 with tafasitamab may 
overcome rituximab-related resistance and improve outcomes in the R/R setting.27•28 The 
combination of tafasitamab and lenalidomide was evaluated in 80 patients with R/R DLBCL 
in the single-arm phase II L-MIND study.29 Patients received treatment for up to 12 cycles of 
28 days each. In cycles 1 through 3, patients received tafasitamab intravenously on days 1, 
8, 15, and 22, with an additional loading dose administered on day 4 of cycle 1. From cycle 4 
onward, patients received tafasitamab on days 1 and 15. Patients self-administered 
lenalidomide 25mg orally once daily on days 1 through 21 of each cycle, with stepwise dose 
reduction if not tolerated. At median follow-up of 13.2 months, 48 patients (60%) achieved 
response (43% CR, 18% PR). The most common treatment-related AEs were hematologic, 
including neutropenia and thrombocytopenia. Given the promising efficacy and tolerability of 
this novel combination, tafasitamab and lenalidomide received accelerated FDA approval for 
use in transplant-ineligible patients with R/R DLBCL in August 2020. 
Given the strong biologic and clinical rationale for therapeutic synergy of tafasitamab and 
lenalidomide in B-cell NHL, we hypothesize that this combination will improve upon 
outcomes associated with lenalidomide-based therapy for MCL in the post-BTKi R/R setting. 
Patients with R/R MCL typically receive rituximab and may develop resistance to it. Targeting 
CD19 is a clearly efficacious strategy in MCL given the high response rates associated with 
CD19-directed CAR-T therapy. However, this approach can be associated with significant 
toxicity and challenging to access, particularly in elderly patients who often present with 
comorbidities. Combination therapy with tafasitamab and lenalidomide may offer improved 
outcomes with minimal toxicity, potentially fulfilling an unmet need in a population with few 
acceptable treatment options. 
3.1 Correlative Studies 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational "next-generation" profiling in a research (non-CUA) environment will 
be found to have somatic or germline mutations in genes that are known to be associated 
with an increased risk of cancer or other diseases. It will be stated in the consent that the 
participants will not receive any specific results from research tests. The consent will tell 
participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSK Clinical Genetics Service. 


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If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the IRB Genomic Advisory Panel (GAP). The 
finding will be reviewed by the GAP to determine whether the incidental finding should be 
discussed with the participant. For MSK, in the event that the GAP determines that the 
finding should be discussed with the participant, and the participant has consented to be re- 
contacted, then the treating/consenting physician shall be contacted by the panel and asked 
to refer the participant to the Clinical Genetics Service for further discussion of the reearch 
finding. 
 
The following information must be provided to GAP for review: 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, saliva) 
• 
Incidental Finding 
• 
Collection Protocol # 
• 
Contact: rtmgapirb@mskcc.org 
 
1. Effects of lenalidomide and tafasitamab on the peripheral immune system 
 
Lenalidomide has been shown to enhance the anti-tumor immune function of both T-cells 
and NK cells. The reinvigoration of dysfunctional immune cells can be monitored in the blood 
using multiparametric flow cytometry, including assessment of activation state, proliferative 
capacity, and expression of exhaustion markers. We hypothesize that patients responding to 
tafasitamab and lenalidomide will exhibit an increase in both the activation state and 
proliferative capacity of CDS+ T-cells and NK cells, while non-responding or progressing 
patients will exhibit an increase in exhaustion markers. To test these hypotheses, 
multiparametic flow cytometry will be performed in the laboratory of Dr. Vardhana. The 
Vardhana laboratory has already published several papers in using deep immune profiling 
and high-dimensional flow cytometry analysis of peripheral blood mononuclear cells in 
hematologic malignancy patients with COVID-19 infection (Bange, Han et al, Nat Med 2021, 
Lyudovyk, Han, Qualls et al Cancer Cell, in press). 
 
These analyses will include: 
 
o 
Assessment of CD4+ and CD8+ T-cell differentiation state (CD45RA, CD27, 
CCR?, TCF-1, T-bet, Eames, FoxP3) 
o 
Activation state of T-cells and NK cells (CD38hi/HLA-DRhi) 
o 
Proliferative capacity of T-cells and NK cells (Ki-67hi) 
o 
Exhaustion state of T-cells and NK cells (expression of PD-1, LAG-3, Tim-3, 
and CTLA-4) 


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We have hypothesized that the combination of tafasitamab and lenalidomide will facilitate 
antigen spreading leading to a polyclonal, polyfunctional T and NK cell anti-tumor immune 
response. To determine whether tafasitamab and lenalidomide promote a diversified 
immune response, we will perform unbiased profiling of both PBMCs and, when possible, 
single-cell suspensions from primary tumor samples using CITE-Seq technology, in which 
surface protein and RNA expression are interrogated in single-cells. This will allow for clone- 
specific tracking of T and NK cell evolution in response to therapy. We plan to collect 
peripheral blood mononuclear cells (PBMCs) at day 1 of cycles 1, 2, and 3, and at 
progression. In addition, when possible, we will perform parallel studies on CD45+ cells from 
primary tumor biopsies (either lymph node, tumor, or bone marrow, if known involvement), 
which will be performed pre-treatment and at disease progression. There will also be an 
optional tumor biopsy performed between C1D22 and C1D28 of treatment. These studies will 
be performed in collaboration with MSKCC's Single Cell Research Institute (SCRI). 
 
2. Effect of lenalidomide and tafasitamab on the tumor microenvironment. 
The tumor microenvironment is known to suppress the effector function of tumor-infiltrating 
T- and NK-cells across multiple cancer subtypes. We therefore hypothesize that the 
composition of the local MCL microenvironment will be a key determinant of response to 
tafasitamab and lenalidomide. We will use two parallel strategies to test this hypothesis. 
First, single-cell suspensions will be generated from core biopsies and analyzed for 
intratumoral immune cell composition (including but not limited to T, B, NK cell, 
macrophages, and dendritic cells) via multi-parametric flow cytometry performed on fresh 
biopsy samples by MSKCC's Hematopathology service. Should additional tumor biopsy 
samples be available, we will analyze the composition of the tumor microenvironment both at 
baseline and in response to therapy using CITE-Seq technology identical to that described 
above. If we see evidence of increased immune cell recruitment, will pursue additional 
downstream assays such as multiplexed ion beam imaging (MIBI) in collaboration with the 
Immune Monitoring Facility. We will collect biopsy (either fine needle aspiration or core 
needle biopsy of lymph node or bone marrow) at baseline and at time of progression. There 
will also be an optional biopsy (either fine needle aspiration or core needle biopsy of lymph 
node or bone marrow) performed between C1D22 and C1D28 of treatment. 
 
3. Mechanism of synergy between lenalidomide and tafasitamab and mechanisms of 
resistance to combination therapy 
The mechanism by which lenalidomide alters immune function was recently described; 
lenalidomide binds and redirects cereblon, resulting in E3-dependent ubiquitylation and 
degradation of several proteins including the lkaros family of transcription factors (including 
lkaros and Aiolos). These transcription factors are expressed in most lymphocyte subsets, 
and therefore the mechanism by which lenalidomide alters both lymphoma cell and infiltrating 
immune cell function remains poorly characterized, particularly in mantle cell lymphoma. To 
interrogate the epigenetic effects of lenalidomide, we will perform single-cell ATAC- 
sequencing and paired CITE-sequencing of bone marrow samples isolated from patients 
both prior to initiation of therapy and at disease progression. The goal of this analysis will be 


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to determine whether progression of disease in patients occurs because a) activity of lkaros 
family transcription factors is restored, orb) immune suppression persists in the absence of 
recurrent lkaros-dependent transcriptional activation. 
 
4. Minimal residual disease (MRD) 
MRD assessment can further refine response assessment in MCL and provides prognostic 
information in MCL [33558202]. In this study, we will perform MRD assessment using a next 
generation immunosequencing (IS) MRD assay (Adaptive Biotechnologies, Seattle, WA). 
This IS MRD assay leverages multiplex PCR followed by NGS to identify and track 
rearrangements of lgH, V-J, D-J and lgK/L loci and translocations in Bcl1/2-lgH. Peripheral 
blood will be collected at screening, day 1 of cycles 3, 7, and 13, and at end of treatment for 
MRD analysis, and evaluated for association with progression-free survival. 
 
5. Clonal evolution in MCL. 
Dynamic molecular monitoring in MCL patients treated with biologically targeted agents, such 
as ibrutinib and venetoclax, have revealed mutations that mediate therapeutic resistance 
[30455436]. In this study, we aim to characterize the clonal evolution of MCL in serial patient 
samples on treatment with tafasitamab and lenalidomide. Patients will have ctDNA in 
peripheral blood collected and banked for genomic testing by high-depth targeted 
sequencing pretreatment and serially during therapy, in order to study the effect of protocol 
therapy on clonal composition of MCL and assess whether genetic alterations arise that are 
associated with resistance. An MSK platform for assessment of circulating tumor DNA in 
peripheral blood specimens will be utilized. 
 
6. Tumor molecular profiling and prognosis 
Molecular analysis of diagnostic tumor samples obtained during screening with paired normal 
tissue (saliva or nails) will be analyzed using the MSK IMPACT platform under IRB protocol 
12-245. Genomic alterations in MCL will be analyzed for associations with key clinical 
outcomes including PFS, ORR, and OS. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
A single-center, single-arm, open-label phase II study evaluating the combination of 
tafasitamab and lenalidomide for treatment of adults with R/R MCL who have previously 
failed or could not tolerate BTKi therapy. Patients will be eligible if they have received one or 
more prior lines of therapy, one of which must have been a BTKi. Patients will be enrolled 
according to a Simon two-stage design, described in 14.0, with early stop criteria for lack of 
efficacy. 
Tafasitamab will be administered intravenously and lenalidomide will be self-administered 
orally according to the treatment schema in 4.2. The primary endpoint is ORR (CR plus PR) 


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evaluated by PET/CT according to Lugano criteria at the end of cycle 12 or treatment 
discontinuation, whichever is earlier.1•2 
4.2 
Intervention 
Patients will receive treatment with intravenous tafasitamab and oral lenalidomide for up to 
12 cycles. Each cycle is 28 days in length. Lenalidomide will be self-administered at a dose 
of 20mg daily days 1-21 of cycles 1 through 12. During the first cycle, tafasitamab will be 
administered on days 1, 4, 8, 15, and 22. During cycles 2 and 3, tafasitamab will be 
administered weekly on days 1, 8, 15, and 22. During cycles 4 through 12, tafasitamab will 
be administered every other week on days 1 and 15. Upon earliest of completion of cycle 12 
or EOT, patients will undergo radiologic evaluation of response. Patients who achieve SD, 
PR, or CR at completion of cycle 12 will continue tafasitamab maintenance therapy on day 1 
of each cycle until the earliest of POD or 36 cycles (inclusive of the first 12 cycles). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
5.1 Tafasitamab 
Tafasitamab, also known as MOR00208, is an intravenously-administered CD19 monoclonal 
antibody manufactured by Morphosys. The Morphosys tafasitamab investigational new drug 
(IND) application will be cross-referenced by MSKCC. 
Dose Formulation: Tafasitamab-cxix will be supplied as 200mg lyophilized powder in single- 
use vials by Morphosys 
• 
Preparation: 
Figure 1: Treatment schema


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o Lyophilized powder should be reconstituted with 5ml sterile water for injection 
to a concentration of 40mg/ml 
o Sterile water for injection should be directed toward the vial wall, then gently 
swirled until powder is completely dissolved (-5 minutes) 
o The total volume of 40mg/ml reconstituted solution required should be 
calculated; equivalent volume should be removed from a 250ml bag of 0.9% 
sodium chloride 
o The total volume of 40mg/ml reconstituted solution should be withdrawn and 
slowly injected into the bag of 0.9% sodium chloride, producing a diluted 
tafasitamab concentration of 2mg/ml to 8mg/ml in a total volume of 250ml 
o Gently invert the bag (to not shake) to mix 
o Unused reconstituted solution should be discarded 
• 
Handling and storage 
o Unreconstituted vials should be protected from light, stored in refrigeration 
(2°C to 8°C; 36°F to 46°F), and must not be frozen 
o Reconstituted solution should be protected from light and used immediately; if 
not used immediately: 
■ 
Do not freeze 
■ 
Store in refrigeration (2°C to 8°C; 36°F to 46°F) for up to 18 hours, or 
■ 
Store at room temperature (20°C to 25°C; 68°F to 77°F) for up to 12 
hours, inclusive of time for infusion 
• 
Source of Supply: investigational supply of tafasitamab will be supplied by Morphosys 
5.2 Lenalidomide 
Lenalidomide is an orally-administered IMiD manufactured by Celgene. Generic formulations 
of lenalidomide were approved by FDA in May 2021 and are anticipated to become available 
in March 2022. Information below is for lenalidomide manufactured under brand name by 
Celgene; details of generic manufacturers' formulations are not yet available. Lenalidomide 
will be obtained commercially based on an approved FDA indication in MCL. 
• 
Dose formulation: Lenalidomide is available as capsules ranging in strength from 
2.5mg to 25mg 
o 2.5mg (bottles of 28 or 100): white and blue-green opaque hard capsules, 
imprinted "REV" on one half and "2.5 mg" on the other half in black ink 
o 5mg (bottles of 28 or 100): white opaque capsules imprinted "REV" on one 
half and "5 mg" on the other half in black ink 
o 10mg (bottles of 28 or 100): blue/green and pale yellow opaque capsules 
imprinted "REV" on one half and "10 mg" on the other half in black ink 
o 15mg (bottles of 21 or 100): powder blue and white opaque capsules 
imprinted "REV" on one half and "15 mg" on the other half in black ink 
o 
20mg (bottles of 21 or 100): powder blue and blue-green opaque hard 
capsules imprinted "REV" on one half and "20 mg" on the other half in black 
ink 


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o 
25mg (bottles of 21 or 100): white opaque capsules imprinted "REV" on one 
half and "25 mg" on the other half in black ink 
• 
Packaging and labeling of lenalidomide will be determined by the external commercial 
specialty pharmacy filling the prescription, in accordance with governing regulatory 
agencies 
• 
Handling and storage: 
o 
Lenalidomide should be stored at room temperature (20°C to 25°C; 68°F to 
77°F) in the original packaging dispensed to the patient; excursions to 15°C to 
30°C (59°F to 86°F) are permissible 
o 
Care should be taken in handling lenalidomide; capsules sould never be 
opened or broken 
o If a patient's skin comes into contact with powder from a lenalidomide capsule, 
the skin should be immediately and thoroughly washed with soap and water; if 
a patient's mucous membranes come into contact with powder from a 
lenalidomide capsule, immediately and thoroughly flush with water 
• 
Source of supply: 
o 
Commercial supply of lenalidomide (branded or generic product as available 
and accessible for the patient) will be prescribed by the investigator to a 
commercial specialty pharmacy according to patient's and/or patient's 
prescription drug insurance's preference 
o 
For patients without prescription drug insurance, whose prescription drug 
insurance does not cover lenalidomide, or whose copay for lenalidomide is 
financially burdensome, enrollment in the BMS Access Support program will 
be sought prior to study initiation (see Section 9.0 Pre-Treatment) 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
Patients will be relapsed or refractory MCL patients who have previously failed or did not 
tolerate BTKi therapy. 
6.1 
Participant Inclusion Criteria 
Patients must meet fill of the following criteria to be eligible for inclusion in this study: 
• 
Age ;:: 18 years at the time of signing Informed Consent 
• 
Karnofsky performance status (KPS) ;:: 70% (see Appendix A) 
• 
Pathologically confirmed diagnosis of R/R MCL 
• 
Previously treated with at least one prior line of systemic therapy for MCL, at least 
one of which must have been a BTKi 
• 
If patient previously received CD19-directed therapy (such as CAR-T therapy), then 
there must be evidence of CD19 expression confirmed by immunohistochemistry or 
flow cytometry per institutional guidelines. This must be confirmed on a biopsy 
performed after receipt of CD19-directed therapy. 


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• 
Previous systemic chemotherapy must have been discontinued at least 2 weeks prior 
to C1D1 and previous anti-cancer radiation therapy or targeted therapy must be 
discontinued prior to initiation of treatment on study 
o 
All adverse effects should resolve to grade 1 or baseline (excluding alopecia) 
• 
Presence of evaluable disease 
• 
Adequate bone marrow and organ function: 
o 
Absolute neutrophil count (ANC) 2: 1,500 cells/mcL, unless felt to be 
secondary to underlying MCL 
o Platelet count 2: 90,000 cells/mcL, unless felt to be secondary to underlying 
MCL 
o 
Renal function assessed by calculated Cockcroft-Gault creatinine clearance 
(CrCI; see Appendix B) 2: 30ml/min. See 10.0 Treatment Plan, Table 10-1, for 
lenalidomide dose adjustment for CrCI 2: 30ml/min and < 60ml/min. 
o 
Hepatic function: 
■ 
Total bilirubin < 2.5x upper limit of normal (ULN), unless secondary to 
Gilbert's syndrome or documented liver involvement by lymphoma. 
Patients with Gilbert's syndrome or documented liver involvement by 
lymphoma may be included if total bilirubin is s; 5x ULN. 
■ 
Aspartate transaminase (AST) and alanine transaminase (ALT) s; 3x 
ULN, unless secondary to documented liver involvement by 
lymphoma. Patients with documented liver involvement by lymphoma 
may be included if AST and ALT ares; 5x ULN. 
• 
Willingness to receive adequate prophylaxis and/or therapy for thromboembolic 
events, unless contraindicated in the opinion of the investigator 
• 
Willingness to undergo confirmatory procedures for assessment of disease status and 
experimental studies as required by protocol, including bone marrow (BM) 
aspiration/biopsy, gastrointestinal endoscopy/colonoscopy with biopsy, and/or biopsy 
of other tissue when appropriate and medically feasible 
• 
Each patient must sign Informed Consent form indicating that he or she understands 
the purpose of and procedures required for the study and are willing to participate 
• 
Short course systemic corticosteroids (total daily dose equivalent of prednisone 
100mg or less) are permissible for disease control, improvement of performance 
status, or non-cancer indication if administered for s; 10 days and discontinued prior to 
initiation of study treatment 
• 
Willingness of patients who are able to become pregnant according to 
Revlimid/lenalidomide Risk Evaluation and Mitigation Strategy (REMS) criteria to 
undergo pregnancy testing in accordance with REMS requirements 
• 
Willingness of all patients to adhere to contraception requirements mandated by the 
Revlimid/lenalidomide REMS 
6.2 
Participant Exclusion Criteria 
Patients must not meet any if the following criteria to be eligible for inclusion in this study: 


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• 
Any life-threatening illness, medical condition, or organ system dysfunction that, in 
the opinion of the investigator, could compromise the patient's safety or put the study 
outcomes at undue risk 
• 
History of human immunodeficiency virus (HIV) unless fill of the following criteria are 
met:31 
o 
CD4+ T-cell count 250 cells/mcl 
o 
No acquired immunodeficiency syndrome (AIDS)-defining opportunistic 
infections within 1 year prior to signing Informed Consent form 
o Stable (no change in regimen for 4 weeks) and effective antiretroviral 
regimen, and HIV viral load < 400 copies/ml within 4 weeks prior to signing 
Informed Consent form 
• 
Hepatitis B or C with detectable viral load requiring antiviral therapy 
• 
Pregnant or lactating 
• 
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection 
(excluding fungal infections of nail beds) at study enrollment, or any major episode of 
infection requiring treatment with IV antibiotics or hospitalization (relating to the 
completion of the course of antibiotics) within 2 weeks prior to cycle 1 day 1 
• 
Clinical significant history of liver disease, including viral or other hepatitis, current 
alcohol abuse, or cirrhosis 
• 
Active central nervous system lymphoma 
• 
Patients who, in the opinion of the investigator, have not recovered sufficiently from 
adverse effects of prior therapies 
• 
Documented refractoriness to lenalidomide, defined as no response (PR or CR) 
within 6 months of therapy 
• 
Lenalidomide exposure within 12 months prior to Day 1 of Cycle 1 
• 
History of hypersensitivity to compounds of similar biological or chemical composition 
to tafasitamab, lenalidomide, and/or excipients contained in the study drug 
formulations 
• 
Autologous stem cell transplantation (ASCT) within 3 months prior to signing the 
Informed Consent form. Patients with more distant history of ASCT must exhibit full 
hematologic recovery before enrollment into this study. 
• 
Allogeneic stem cell transplantation within 3 months prior to signing the Informed 
Consent form, with evidence of graft-versus-host disease (GVHD), or receiving 
immunosuppressive therapy for GVHD. 
• 
Concurrent use of other anticancer or experimental treatments 
• 
No concurrent malignancy requiring active therapy within the last 3 years with the 
exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited 
to the skin, carcinoma in situ of the cervix or breast, adequately treated lentigo 
maligna melanoma, or localized prostate cancer. Adjuvant or maintenance therapy to 
reduce the risk of recurrence of other malignancy previously treated for curative intent 
is permitted. 
• 
Administration of a live vaccine within 28 days prior to the start of study treatment 
(Cycle 1 Day 1). 


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7.0 
RECRUITMENT PLAN 
The study will be conducted at MSKCC. Patients will be treated by members of the 
lymphoma service at MSKCC. Every effort will be made to include women and minorities in 
this study. Patients will be recruited by the treating team of physicians and medical 
professionals. The consenting attending physician will inform patients of their diagnosis, 
current treatment options including standard treatment, and the risks, benefits, and 
experimental nature of this treatment program. All patients will be required to sign an 
Informed Consent form that conforms to FDA and MSKCC IRB guidelines. 
7.1 
Research Participant Registration 
 
Eligibility will be confirmed as defined in section 6.0 Criteria for Participant Eligibility. 
Informed consent will be obtained by following procedures defined in section 8.0 Informed 
Consent Procedures. During the registration process registering individuals will be required 
to complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
 
8.0 
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 or their legally authorized representatives 
(LARs) will also be informed that they are free to withdraw from the study at any time. All 
participants/LARs must sign an IRS/PB-approved consent form indicating their consent to 
participate. 
The consent form/research authorization 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, objectives, potential risks, and benefits of the intended study. 
2. The length of study, what it entails, 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. 


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6. How the participants' data will be protected, who will have access to their PHI, 
and what data will be disclosed for research purposes 
Prior to inclusion in the study and before protocol-specified procedures are carried out, the 
consenting professionals will explain the details of the protocol as outlined in the consent and 
research authorization to the participants/LARs. The participant/LAR will also be informed 
that they are free to withdraw from the study at any time. The consent discussion may occur 
in person or remotely via teleconference, telephone, or videoconference. 
All participants/LARs must sign an IRB/PB-approved consent form/research authorization 
indicating their consent to participate. Each participant/LAR and consenting professional will 
sign and date the consent form. The participant/LAR must receive a copy of the signed 
informed consent form. 
9.0 
PRE-TREATMENT/INTERVENTION 
9.1 Pre-treatment/intervention evaluations 
All study-related evaluations and interventions are summarized in Section 11.0, Table 11-1. 
Within 6 weeks prior to initiating study treatment: 
• 
Pathologic confirmation of R/R MCL, with repeat biopsy prior to initiation of study 
treatment preferred 
• 
Tumor genomic profiling on MSKCC protocol 12-245 (Integrated Mutation Profiling of 
Actionable Cancer Targets (IMPACT)) within 6 months prior to signing Informed 
Consent form, and preferably repeated for patients who did not have IMPACT 
performed after discontinuing their last line of treatment 
Within 4 weeks prior to initiating study treatment (SOC, unless indicated otherwise): 
 
• 
Physical exam, vital sign measurements, height and weight measurements, and 
assessment of KPS 
• 
CT scans of chest, abdomen, and pelvis and FOG-PET scan for pretreatment staging 
(can include CT neck if appropriate per physician discretion) 
• 
BM aspiration/biopsy 
• 
Documentation of concomitant medications, including prescription drugs, over-the- 
counter drugs, herbal products, and supplements/medical foods 
• 
Allergies 
• 
Laboratory testing: 
o 
Hepatitis B virus (HBV) surface antigen (HbsAg) and core antibody (HbcAb); if 
either is positive, HBV viral load 
o 
Hepatitis C virus antibody 
o 
HIV 1/2 antibodies 
• 
Enrollment in the Revlimid/lenalidomide REMS program 


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• 
Pregnancy testing according to Revlimid/lenalidomide REMS requirements if 
applicable 
• 
OPTIONAL: fine needle aspirate or other biopsy of involved peripheral nodal tissue 
(paired with cycle 1 day 22 follow-up biopsy- see Table 11-1) 
Within 1 week prior to initiating study treatment (SOC, unless indicated otherwise): 
• 
Laboratory testing: 
o Complete blood count (CBC) with differential 
o Comprehensive metabolic panel (CMP) 
o Phosphorus 
o Uric acid 
o Lactate dehydrogenase (LOH) 
9.2 Concomitant therapy 
 
9.2.1 Permitted concomitant therapies 
• 
Standard therapies for concurrent medical conditions 
• 
Inactivated vaccines (eg, injectable influenza vaccine) 
• 
Herbal product and supplement use is discouraged (with the exception of medicinal 
cannabis administered under the direction and monitoring of an appropriately 
credentialed health care provider) but not prohibited, provided the given product(s) do 
not, in the opinion of the investigator, place the patient's safety and/or study outcomes at 
undue risk 
• 
Antimicrobial prophylaxis 
• 
Palliative and supportive therapies, including but not limited to: 
o 
Prophylactic and as-needed use of antiemetics 
o 
Use of granulocyte colony stimulating factor (G-CSF) for prophylaxis or treatment 
of neutropenia 
o 
Short-term systemic corticosteroid use, including as antiemetic prophylaxis or 
management of acute conditions 
9.2.2 Prohibited concomitant therapies 
• 
Other investigational and antineoplastic therapies 
• 
Live vaccines 
• 
lmmunosuppressive therapies other than corticosteroids as described in 9.2.1 
9.2.3 Drug-drug interactions 
While lenalidomide is a minor substrate of P-glycoprotein (P-gp), it is not anticipated to have 
clinically significant interactions with inhbitors or inducers of P-gp.32 Lenalidomide does not 
undergo phase I or II metabolism, nor is it a known substrate of membrane drug transporters, 
thus there are no anticipated interactions anticipated when co-administered with cytochrome 
P450 isozyme or drug transporter inhibitors, inducers, or substrates. 


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Tafasitamab has not undergone dedicated food-drug or drug-drug interactions. Because its 
mechanism does not include direct inflammation and it is not extensively hepatically 
metabolized, it is not anticipated to affect nor be affected by drugs metabolized by, inhibiting, 
or inducing cytochrome P450 isozymes. 
10.0 TREATMENT/INTERVENTION PLAN 
10.1 Tafasitamab 
Tafasitamab will be administered intravenously according to the MSK tafasitamab infusion 
guideline on the following schedule: 
• 
Induction: 
o 
Cycle 1 (28 days): days 1, 4, 8 , 15, and 22 
o 
Cycles 2 and 3 (28 days each): days 1, 8, 15, and 22 
o 
Cycles 4 through 12 (28 days each): days 1 and 15 
• 
If SD, PR, or CR after cycle 12, maintenance: 
o 
Cycles 13-36 (28 days each): day 1 
 
The dose of each tafasitamab infusion is 12mg/kg according to total (actual) body weight. 
Dose rounding will be performed according to institutional standard. No dose reductions of 
tafasitamab will be permitted. 
10.2 Lenalidomide 
Lenalidomide will be self-administered by patients orally on days 1-21 of each 28-day cycle 
of induction (cycles 1 through 12). Patients will be instructed to take each dose of 
lenalidomide at about the same time each day with approximately 8 ounces (240ml) of 
water, without regard to food. Lenalidomide must be swallowed whole; patients should not 
open or break the capsules. If a dose is missed, the dose may be taken if within 12 hours of 
usual dosing time. If more than 12 hours have elapsed since usual dosing time, the patient 
should skip the missed dose and take the next dose at the usual dosing time. If a patient 
vomits after taking a dose, the dose should not be made up. 
Research personnel will review the dosing instructions with patients. Patients will be provided 
with a medication diary and asked to record the drug administration. Patients will be asked to 
bring any unused drug and empty drug containers to the research personnel at the beginning 
of each cycle. Site staff will count and record the number of used and unused drug at the 
beginning of each cycle and reconcile their findings with the patient diary. 
The daily dose of lenalidomide in patients with normal renal function (CrCI 2: 60ml/min) is 
20mg. Renal adjustments are outlined in Table 10-1. In patients with impaired renal function 
at baseline who qualify for study inclusion (CrCI < 60ml/min but 2: 30ml/min), the daily dose 
of lenalidomide is 10mg daily, with escalation to 15mg daily permitted after 2 cycles if 
tolerating treatment in the opinion of the investigator. Patients who subsequently develop 
severe renal dysfunction (CrCI 
30ml/min) after initiation of study treatment may continue 
treatment with lenalidomide at a reduced dose as noted in Table 10-1. Note that renal 


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dysfunction resulting from toxicity suspected to be related to tafasitamab and/or lenalidomide 
(eg, due to tumor lysis syndrome) may warrant interruption and/or discontinuation of either or 
both drugs, as outlined in Table 10-4. 
 
Table 10-1: Lenalidomide dose adjustment for renal dysfunction prior to or after 
study initiation 
Cockcroft-Gault CrCI (see 
Appendix B) 
Daily lenalidomide dose 
(days 1-21 of cycles 1-12) 
Note 
 
30ml/min and < 60ml/min 
 
10mg 
May increase to 15mg once 
daily after 2 cycles if 
tolerating treatment in the 
opinion of the investigator 
Severe renal dysfunction after study treatment initiation* 
< 30ml/min not requiring 
dialysis 
5mg once daily 
 
< 30ml/min requiring 
dialysis 
5mg once daily; for doses on 
dialysis days, administer 
after dialysis 
 
*CrCI must be 
30ml/min to be eligible for participation in the study; dose adjustments for 
CrCI < 30ml/min apply only to patients who met inclusion criteria, initiated treatment with the 
appropriate initial lenalidomide dose, and subsequently developed severe renal dysfunction 
10.3 Required prophylaxis 
 
The following prophylactic measures are required: 
 
• 
Tafasitamab infusion-related reaction (IRR) prophylaxis (per the  MSK tafasitamab 
infusion guideline) 
• 
Lenalidomide-associated venous thromboembolism (VTE) prophylaxis: Patients must 
receive VTE prophylaxis throughout the induction phase 
• 
HBV reactivation prophylaxis: in patients positive for HBcAb and/or HBsAg without 
detectable viral load, prophylaxis against reactivation (eg, entecavir 0.5mg PO daily; 
consult pharmacist for dosing in patients with renal dysfunction) should be 
administered throughout study treatment and 
6 months after EOT 
• 
Tumor lysis syndrome (TLS) prophylaxis: 
o 
Patients must be screened for risk of TLS prior to study treatment initiation 
according to the MSK guideline for prevention and management of TLS in 
adults 
o 
Patients at risk of TLS should undergo risk-adapted prophylaxis and 
monitoring according to the institutional guideline and investigator's discretion 


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10.4 Study duration 
 
The maximum duration of treatment for this study is planned to be a total of 36 cycles (12 
cycles of tafasitamab plus lenalidomide induction, 24 cycles of tafasitamab maintenance), not 
to exceed 36 months. 
After discontinuation of both study drugs, patients will complete an EOT visit within 7 days 
from the date of official treatment discontinuation. If treatment must be discontinued due to 
prolonged interruption for toxicity (see 10.5.7), the EOT visit will occur within 7 days of the 
decision to permanently discontinue treatment. 
All patients will be followed for adverse events for at least 30 days following the last dose of 
study treatment or until initiation of new therapy, whichever comes first. Patients who 
proceed to tafasitamab maintenance will be followed for disease status updates for up to 
three years. After completing study treatment, survival, relapse, and new anti-lymphoma 
therapy information will be collected via telephone calls, patient medical records, and/or clinic 
visits approximately every 6 months until death, loss to follow up or consent withdrawal, 
whichever comes first. 
10.5 Dose continuation, modification, and interruption 
 
Patients will be evaluated for AEs at each visit and will undergo laboratory evaluations 
according to the schedule in Section 11.0 and Table 11-1. CTCAE version 5.0 will be utilized 
for toxicity grading. 
The course of action for treatment interruption, modification, and/or reinstatement for specific 
toxicities is outlined below. Any other treatment interruption considered medically necessary 
by the investigator is permitted, and the decision and rationale should be documented. 
10.5.1 Parameters for treatment continuation 
 
Patients may initiate treatment on day 1 of each cycle provided that: 
 
• 
ANC 
1,000 cells/mcl (unless felt to be secondary to underlying MCL) 
• 
Platelets 
50,000 cells/mcl (unless felt to be secondary to underlying MCL) 
• 
No serious organ or other toxicity present 
10.5.2 Tafasitamab infusion-related reactions 
 
10.5.2.1 Monitoring, grading, and acute management of tafasitamab IRR 
 
Vital signs will be monitored during tafasitamab infusion as outlined in Section 11.0, Table 
11-1. Body temperature, systolic and diastolic blood pressure (mmHg), heart rate (beats per 
minute), and respiratory rate (respirations per minute) will be measured immediately prior to 
infusion, at 15 ± 5 and 30 ± 10 minutes after initiating infusion, every 60 ± 15 minutes 


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thereafter, and at the end (± 20 minutes) of infusion. If the infusion is interrupted and/or 
subsequently restarted, vital signs should be assessed every 60 ± 15 minutes after the first 
hour. Vital signs may be monitored more frequently if clinically indicated. 
All patients will receive IRR prophylaxis for at least the first 3 doses of tafasitamab as 
described in Section 10.3. IRRs will be assessed according to CTCAE version 5.0 grading: 
 
Table 10-2: Tafasitamab infusion-related reaction grading 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mild, transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated 
but respond 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for :5 24 
hours 
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for clinical 
sequelae 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Precautions for anaphylaxis will be observed during tafasitamab infusion. Emergency 
resuscitation equipment and medications will be readily available, including medications in 
the Hypersensitivity Order Set (Chemo_Adult_Hypersensitivity_Order_Set (Outpatient)). 
Acute management of signs and symptoms of IRR will be according to the MSK institutional 
standard (Appendix C). 
10.5.2.2 Rechallenge after tafasitamab IRR 
 
For grade 2 and 3 IRRs, once symptoms have resolved to grade :5 1 according to 
investigator assessment, the infusion may be resumed according to the MSK tafasitamab 
infusion guideline. 
For grade 4 IRRs, the patient must not receive further treatment with tafasitamab. Treatment 
with lenalidomide alone may continue. 
10.5.3 Lenalidomide-associated diarrhea 
 
Diarrhea suspected to be secondary to lenalidomide will be graded according to CTCAE 
version 5.0. Interruptions of lenalidomide and dose reductions will be based on grade: 


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Table 10-3: Lenalidomide-associated diarrhea grading and dose 
interruption/reduction 
 
 
 
Grade 1-2 
Increase of::;; 4-6 stools per 
day over baseline; mild- 
moderate increase in 
ostomy output compared to 
baseline; limiting 
instrumental activities of 
daily living (AOL) 
No interruption or dose 
reduction required 
Implement supportive care 
measures; see suggested 
symptom management 
measures (Appendix D) 
 
 
 
 
 
Grade 3-4 
Increase of 
7 stools per 
day over baseline; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self care 
AOL; life-threatening 
consequences; urgent 
intervention indicated 
 
Interrupt lenalidomide 
dosing 
Implement supportive care 
measures; see suggested 
symptom management 
measures (Appendix D) 
 
Resolution to grade ::;; 2 
Resume lenalidomide 
dosing at the next lower 
dose level (Table 10-6) 
 
 
10.5.4 Hematologic and other toxicities 
Toxicities suspected to be related to study medications will be graded according to CTCAE 
version 5.0 and managed according to Tables 10-4 and 10-5 below. 
 
Table 10-4: Hematologic and other toxicities suspected to be related to either study 
medication 
 
 
 
 
 
 
Thrombocytopenia 
grade 3-4 
 
 
Platelets < 50,000 cells/mcL 
Cycles 1 through 3: interrupt both 
tafasitamab and lenalidomide 
Cycle 
4: interrupt lenalidomide 
only 
Obtain CBC every 7 days 
 
 
 
Platelets recover to 
50,000 
cells/mcL 
Provided other criteria for dosing 
are met (see 10.5.1), resume 
study treatment. 
If lenalidomide is being continued, 
it should be resumed at the next 
lower dose level. Dose re- 
escalation is permitted in certain 
circumstances (Table 10-6). 


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Neutropenia grade 3-4 
ANC < 1,000 (but 500) 
cells/mcl for 
7 days 
Or 
ANC < 1,000 cells/mcl with 
fever 38.5°C (101°F) 
Or 
ANC < 500 cells/mcl 
Cycles 1 through 3: interrupt both 
tafasitamab and lenalidomide 
Cycle 
4: interrupt lenalidomide 
only 
Obtain CBC every 7 days 
GCSF use is strongly encouraged 
 
 
 
ANC recovers to 
1,000 
cells/mcl 
Provided other criteria for dosing 
are met (see 10.5.1), resume 
lenalidomide. 
If lenalidomide is being continued, 
it should be resumed at the next 
lower dose level. Dose re- 
escalation is permitted in certain 
circumstances (Table 10-6). 
 
 
 
Other clinically 
significant toxicities 
(except those 
attributable to 
lenalidomide below) 
 
Grade 3-4 
Interrupt the study drug(s) to 
which the toxicity is suspected to 
be attributable. 
 
 
 
Resolution to grade :s; 2 
Provided other criteria for dosing 
are met (see 10.5.1), resume 
previous treatment. 
If lenalidomide was interrupted 
and is being continued, it should 
be resumed at the next lower 
dose level (Table 10-6) 
 
 
 
Table 10-5: Other toxicited suspected to be related to lenalidomide 
 
 
 
 
Thromboembolic events 
 
 
Grade 3-4 
Interrupt lenalidomide dosing 
Start anticoagulation as per 
MSK anticoagulation guideline 
and investigator's discretion 
 
Resolution to grade :s; 2 
Resume lenalidomide at 
investigator's discretion 
(maintain dose level) 


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Allergic reaction or hypersensitivity grade 3-4 (including 
but not limited to Stevens-Johnson syndrome, toxic 
epidermal necrolysis, exfoliative or bullous rash, 
angioedema) 
 
 
 
 
Discontinue lenalidomide 
permanently 
 
Desquamating {blistering) rash grade 3-4 
 
Discontinue lenalidomide 
permanently 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nondesquamating rash 
 
 
Grade 1 (< 10% of body 
surface area (BSA)) 
Treat with topical 
corticosteroids and oral 
antihistamines until resolution 
of rash/symptoms; short 
course of low-dose oral 
corticosteroid is permitted 
 
 
 
 
Grade 2 (10-30% of BSA) 
Consider interrupting 
lenalidomide dosing until 
grade :5 1 
Treat with topical 
corticosteroids and oral 
antihistamines until resolution 
of rash/symptoms to grade s; 
1; short course of low-dose 
oral corticosteroid is permitted 
 
 
 
 
Grade 3 (> 30% of BSA) 
Interrupt lenalidomide dosing 
until grade s; 
Treat with topical 
corticosteroids and oral 
antihistamines until resolution 
of rash/symptoms to grade :5 
1; short course of low-dose 
oral corticosteroid is permitted 
 
Grade 4 (life-threatening) 
Discontinue lenalidomide 
permanently 
Tumor flare reaction 
grade 1-2 
Continue lenalidomide at current dose level or interrupt 
lenalidomide at investigator's discretion 


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Tumor flare reaction 
grade 3-4 
Grade 3-4 (see 10.5.5) 
Interrupt lenalidomide dosing 
Resolution to grade 
1 
Resume lenalidomide 
(maintain dose level) 
 
 
10.5.5 Lenalidomide-associated tumor flare 
Patients should be monitored at each visit for tumor flare reactions (TFRs). TFR is defined as 
a sudden and tender increase in the size of the disease bearing sites (such as lymph nodes, 
spleen, and/or liver), often accompanied by low-grade fever, non-pruritic diffuse rash, and in 
some cases, an increase in peripheral blood lymphocyte count. Such reactions are expected 
with lenalidomide, especially in patients with a high burden of disease and may mimic 
disease progression. Therefore, careful monitoring and evaluation is important prior to 
discontinuing a study patient for progressive disease in the initial cycles of lenalidomide 
therapy. There are currently no laboratory oor radiological tests to help distinguish TFR from 
POD. The distinction should be made on clinical grounds, incorporating observations such as 
associated physical findings, laboratory findings, and pace of disease before and after study 
treatment initiation. TFR should be recorded as an AE of special interest, graded using 
CTCAE version 5.0, and not as POD. 
Treatment of TFR is at the discretion of the investigator. 
 
10.5.6 Lenalidomide dose reductions for toxicity 
If lenalidomide dosing was interrupted during the previous cycle, restarted at the next lower 
dose level during the same cycle in which it was interrupted, and did not require interruption 
for the remainder of the cycle, then that reduced dose level will be initiated on day 1 of the 
next cycle. There will be no more than one dose reduction from one cycle to the next. 
A dose reduction of lenalidomide constitutes a 5mg decrease in the daily dose from the 
previous dose, including in patients who initiate treatment at a decreased dose due to renal 
dysfunction. Patients who are unable to tolerate the lowest dose of 5mg once daily should 
discontinue lenalidomide but continue treatment with tafasitamab alone. 
 
 
 
Table 10-6: Lenalidomide dose reductions for toxicity 
Note 
Starting dose 
20mg once daily days 1-21 of 
each 28-day cycle 
In patients who required 
lenalidomide dose reduction 
for hematologic toxicity early 
in the treatment course due, 
in the opinion of the 
investigator, to bone marrow 
and/or splenic disease 
Dose level -1 
15mg once daily days 1-21 of 
each 28-day cycle 
Dose level -2 
10mg once daily days 1-21 of 
each 28-day cycle 


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Dose level -3 
5mg once daily days 1-21 of each 
28-day cycle 
involvement, re-escalation to
the previous dose level is 
permitted 
Further reduction 
indicated 
Discontinue 
10.5.7 Maximum duration of treatment interruption 
If treatment is interrupted for 
28 consecutive days, treatment should continue at the next 
protocol scheduled visit. No missed visits or doses of either drug should be made up. 
If treatment with one study drug is interrupted for more than 28 consecutive days, that drug is 
to be permanently discontinued and the patient will continue treatment with the other study 
drug per protocol. If treatment with both study drugs is interrupted for more than 28 
consecutive days, the EOT visit will be performed as noted in 10.4. 


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11.0 
EVALUATION DURING TREATMENT/INTERVENTION 
11.1 General overview of evaluations 
Evaluations during screening and study treatment are as indicated in Table 11-1. 
 
Table 11-1. Schedule of evaluations (screening through cycle 3).
 
Screening 
Cycle 1 (28 days) 
Cycle 2 (28 days) 
Cycle 3 (28 days) 
Day
S 28 days
S 7 days
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Window
before C1D1
before C1D1 I
I
I
 
 I
±1
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion checklist
X
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy and pathologic
confirmation of MCL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET
X
 
 
 
 
 
 
 
 
 
 
X
 
 
 
CT CAP (+neck if indicated)
X
 
 
 
 
 
 
 
 
 
 
X
 
 
 
KPS
X
 
X
 
 
 
 
X
 
 
 
X
 
 
 
Vital signs1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
CBC with differential 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry2 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Hepatitis B serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if ap
icable)3 
X
 
X
 
 
 
 
X
 
 
 
X
 
 
 
Consent to 12-245 IMPACT
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and sam
e collection4 
BM aspirate and biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research blood tests 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Optional research biopsy5 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
(S)AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tafasitamab administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lenalidomide administration 
Patients will self-administer Days 1-21 of each Cycle 


 
 


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3Patients able to become pregnant must have pregnancy testing performed according to Revlimid/lenalidomide REMS requirements: one test (sensitive 
to at least 50mlU/mL) 10-14 days before writing the initial lenalidomide prescription, and a second test within 24 hours prior to writing the initial 
lenalidomide prescription. Subsequent pregnancy testing should occur every 4 weeks. 
4Unless previously performed within 6 months of study initiation 
 
5Optional biopsy can be a fine needle aspirate or other biopsy of involved peripheral lymph node tissue, and/or bone marrow aspirate (if MCL 
involvement of marrow was demonstrated pre-treatment). Optional biopsy/aspirate occurs at baseline, cycle 1 between day 22-28, and at end of 
treatment/disease progression. Note that the biopsy performed for required confirmation of R/R MCL diagnosis is acceptable for the first research biopsy, 
provided that tissue is available, the biopsy was performed within the screening period, and the site can be re-biopsied at cycle 1 day 22. 
6Prior to study drug administration 
 
7Evaluation by CT CAP with IV contrast (include neck if disease involvement). 
8Evaluation by PET/CT approximately every 6 months from previous scan 
9Only required if not performed in the cycle before the EOT visit 
10Only required for discontinuation for POD 


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11.2 Correlative studies 
Patients will have tumor samples analyzed for genomic alterations via 12-245 IMPACT 
targeted sequencing platform. 
Additionally, ctDNA will be collected serially according to Table 11-1 to evaluate tumor clonal 
evolution. See lab manual for collection instructions. 
MRD assessment via IS MRD assay will be performed using serial peripheral blood draws 
according to the schedule in Table 11-1. See lab manual for collection and shipping 
instructions. 
Serial peripheral blood samples for PBMCs according to schedule in Table 11-1 will be 
obtained for 1) T-cell and NK-cell profiling and 2) CITE-Seq. See lab manual for collection 
instructions. 
An optional pair of biopsies of involved peripheral nodal tissue at baseline and during cycle 1 
between days 22-28 will be obtained to assess effect of therapy on the tumor 
microenvironment. See lab manual for collection instructions. 
12.0 
CRITERIA FOR REMOVAL FROM STUDY 
Patients may voluntarily withdraw from the study or be removed from the study at the 
discretion of the investigator at any time. Patients may be withdrawn from the study if any of 
the following occur: 
• 
Disease progression 
• 
Ineligibility (at the cycle 1 day 1 evaluation or earlier) as defined in the 
inclusion/exclusion criteria 
• 
Treatment will be discontinued at the request of the patient, refusal of therapy, non- 
compliance, or upon development of an intercurrent significant medical illness 
• 
Significant protocol violation 
• 
Unacceptable toxicity necessitating drug discontinuation as outlined in 10.5 
• 
Decision by the investigator that termination is in the patient's best medical interest 
• 
Loss to follow-up 
• 
Development of active HBV, HCV, or HIV infection 
• 
Pregnancy or positive pregnancy test 
• 
Death of the patient 
• 
Start of any other antineoplastic therapy 
13.0 
CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
13.1 Criteria for Therapeutic Response/Outcome Assessment 
Response and progression of disease will be evaluated using the Lugano criteria (Figure 
3).1•2 Clinical evaluation and tumor assessments will be performed periodically as indicated in 
Table 11-1. Clinical suspicion of disease progression at any time will require physical 


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examination and radiological confirmation to be performed promptly, rather than waiting for 
the next scheduled tumor assessment. In case of an unscheduled or delayed tumor 
assessment for any reason, subsequent tumor assessments must be performed according to 
the originally planned schedule. 
13.2 Criteria for Study Endpoint Evaluability 
All patients who received at least one dose of tafasitamab and one dose of lenalidomide will 
be considered evaluable for the primary endpoint of ORR and all secondary endpoints. This 
will be the primary analysis. Safety endpoints will be evaluated in all patients who received at 
least one dose of tafasitamab or one dose of lenalidomide. Any patient that is removed from 
the study for reasons other than progression will be counted as a failure for ORR analysis and 
as an event for PFS analysis (as long as they have received at least 1 dose of tafasitamab and 
1 dose of lenalidomide). For OS analysis, patients who are removed from the study for any 
reason other than death will be censored at the time of study removal. The study will continue 
enrollment until the required number of evaluable patients (those that receive at least one dose 
of both study drugs) is reached in each stage of the study. 
 
The primary and secondary endpoints will also be evaluated in the per-protocol cohort (patients 
who did not have any major protocol violations) as a supportive, secondary analysis. 
 
14.0 
BIOSTATISTICS 
Objectives: 
 
The primary objective is to estimate the ORR, defined as the percent of patients (relative to 
the total number considered evaluable as in 13.2) who achieve CR or PR. The primary 
endpoint will be analysed when all patients have completed 12 cycles of treatment or at 
treatment discontinuation, whichever comes first. 
Secondary objectives are estimates of OCR, DOR, PFS, OS, and TTP, and descriptions of 
incidence and severity of AEs. Exploratory objectives include rate of conversion to 
undetectable MRD, ctDNA/clonal evolution, antitumor immune response, and effects on 
tumor microenvironment immunosuppression. 
Exploratory objectives are described in Section 3.1 Correlative studies. 
Study design: 
The primary endpoint is ORR and the study is designed to determine preliminary clinical 
effectiveness of tafasitamab and lenalidomide. Based upon limited data available for 
lenalidomide and associated combinations in the post-BTKi setting, the combination of 
tafasitamab and lenalidomide will be considered worthy of further evaluation if the ORR is 
greater than 30%. This combination will be considered promising in the R/R setting if the 
ORR is greater than 50% given multiple evolving treatment options for patients post-BTKi 
failure or intolerance. To this end, , a single-arm Simon's two-stage minimax design will 


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utilize a null (non-promising) ORR of 30% and an alternative (promising) ORR of 50%. In the 
first stage, a total of 19 patients will accrue. If 6 or fewer have objective response, the trial 
will close due to a lack of efficacy; otherwise, an additional 20 patients will accrue. If at the 
end of the study, 17 or more out of 39 have an objective response, the trial will be considered 
promising for future development. This design will give 80% power with a type I error rate of 
5%. Patients will continue to enroll without holding enrollment while the interim analysis is 
evaluated in the first 19 patients. 
The anticipated accrual rate for this study is 1 to 2 patients per month. We anticipate total 
accrual will be completed in 2-3 years. The study will continue enrollment until the required 
number of evaluable patients (those that receive at least one dose of both study drugs) is 
reached in each stage of the study. 
 
Methods: 
Primary objectives: ORR will be calculated as a proportion and summarized along with 95% 
confidence intervals. Patients who withdraw prior to response evaluation will be classified as 
nonresponders for the primary objective. 
Secondary objectives: OCR will be defined as the percent of patients who achieve CR, PR or 
stable disease (SD) at the time of ORR assessment. Patients who withdraw prior to response 
evaluation will be classified as failures. The OCR will be estimated by proportion along with 
95% confidence intervals. DOR will be defined as the time from achievement of PR or CR to 
progression of disease (POD) according to Lugano criteria or death. PFS will be defined as 
the time from initiation of study treatment to the earlier of POD or death from any cause. OS 
will be defined as the time from initiation of treatment to death from any cause. Kaplan-Meier 
estimates of DOR, PFS, and OS will be calculated and presented with 95% confidence 
intervals. TTP will be defined as the time from start of treatment to POD or death specially 
from MCL, and will be estimated with 95% confidence intervals by cumulative incidence 
function. Death from other causes will be treated as a competing risk. Frequency and 
severity of adverse events will be summarized descriptively. 
Exploratory objectives will be performed in conjunction with collaborating laboratories at 
MSK. Study designs and analytic approaches are detailed in Section 3.1. Most objectives will 
be summarized descriptively. For assessing association between minimal MRD and PFS, the 
log rank test will be used and Kaplan-Meier curves will be presented. For assessing 
association between genomic alterations discovered through MSK-IMPACT sequencing and 
time-to-event outcomes PFS and OS, Cox regression will be used and hazard ratios with 
95% confidence intervals will be presented. For assessing association between genomic 
alterations and ORR, Fisher's exact test will be used, and p-values will be adjusted for 
multiple testing with the false discovery rate (FDR). 
14.1 Populations for analysis include the following: 


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• 
Primary analysis (primary endpoint and all secondary endpoints): All patients who 
received at least one dose of tafasitamab and one dose of lenalidomide 
• 
Safety analysis: All patients who received at least one dose of tafasitamab or one dose of 
lenalidomide 
• 
Secondary per-protocol analysis (primary endpoint and all secondary endpoints): All 
patients who did not have any major protocol violations, identified for each patient with a 
protocol violation before database closure 
 
15.0 TOXICITIES/RISKS/SIDE EFFECTS 
An AE is defined as the appearance of (or worsening of any pre-exisintg) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient's signed Informed Consent form 
has been obtained. Abnormal laboratory values or test results occurring after informed 
consent constitute AEs only if they induce clinical signs or symptoms, are considered 
clinically significant, require treatment (eg, hematologic abnormality that requires transfusion 
or hematologic stem cell support), or require changes in study medication(s). 
 
AEs that begin or worsen after informed consent should be recorded in Medidata. Conditions 
that were already present at the time of informed consent should be recorded in the Medical 
History in Medidata. AE monitoring should be continued for at least 30 days following the last 
dose of study treatment or until initiation of new therapy, whichever comes first. AEs 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
 
CTCAE Version 5 will be utilized for toxicity evaluation. If CTCAE grading does not exist for 
an AE, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 
1-4, will be used. CTCAE grade 5 (death) will not be used - rather, information about deaths 
will be collected through a Death form. 
The occurring of AEs should be sought by non-directive questioning of the patient during the 
screening process after signing Informed Consent form and at each visit during the study. 
AEs also may be detected when they are volunteered by the patient during the screening 
process or between visits, or through physical examination, laboratory test, orother 
assessments. As far as possible, each AE should be evaluated to determine: 
• 
The severity grade (CTCAE grade 1-4) 
• 
Its duration (start and end dates) 
• 
Its relationship to the study treatment (reasonable possibility that AE is related: yes or 
no) 
• 
Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, or not applicable) 
• 
Whether medication or therapy taken (no concomitant medication/non-drug therapy 
or concomitant medication/non-drug therapy) 


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• 
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, or unknown) 
• 
Whether it is serious, as defined below 
• 
All AEs should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded in Medidata. 
• 
Once an AE is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study 
treatment, the interventions required to treat it, and the outcome 
• 
Progression of malignancy (including fatal outcomes), if documented by use of 
appropriate method (Lugano criteria), should not be reported as an SAE 
• 
AEs separate from POD (eg, deep vein thrombosis at time of progression or 
hemoptysis concurrent with finding of POD) will be reported as per usual guideline for 
such events with proper attribution regarding relatedness to the drug 
Adverse events of special interest (AESls) are a subset of events of scientific and medical 
concern specific to this study. Such an event may require further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication 
by the trial Sponsor to other parties (eg, regulatory authorities) may also be warranted. 
AESls include IRRs, overdoses (defined as exceeding the planned dose by more than 20%), 
second primary malignancies, TFR, thromboembolic events, and TLS. 
The 5 most common adverse events associated with tafasitamab/lenalidomide in the L-MIND 
study were neutropenia (51%), fatigue (38%), anemia (36%), diarrhea (36%), and 
thrombocytopenia (31%). Details on adverse events are described in Table 15-1. 
 
Table 15-1: Adverse reactions in patients with relapsed or refractory diffuse large B-
cell lymphoma who received tafasitamab in L-MIND (n = 81) 
Adverse reactions occurring in
10%
All-grade%
Grade 3-4 %
Dermatologic
Pruritus
10
1.2
Rash
15
2.5
Gastrointestinal
Abdominal pain
15
1.2
Constipation
17
0
Decreased appetite
22
0
Diarrhea
36
1.2
Nausea
15
0 
Vomiting 
15 
0 
Hematologic
Anemia
 
36 
7
Febrile neutropenia 
 
I
12 
12 


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Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
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Neutropenia
51
49
Thrombocytopenia
31
17
Musculoskeletal
Back pain
I
19
2.5
Muscle spasms
I
15
0
Other
Fatigue
38
3.7
Hypokalemia
19
6
Peripheral edema
24
0
Pyrexia
24
1.2
Respiratory
Bronchitis
16
1.2
Cough
26
1.2
Dyspnea
12
1.2
Respiratory tract infection
24
4.9
Urologic
Urinary tract infection
17
4.9
 
 
15.1 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 participant 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 starts investigational 
treatment/intervention. SAE reporting is required for 30 days after the participant's last 
investigational treatmenUintervention. Any event that occurs after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 


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IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
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Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (e.g., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP Office per 
IRB SOP RR-408 'Reporting of Serious Adverse Events,' the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o 
A description of the participant's condition 
o Indication if the participant 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 
15.2 External SAE Reporting 
 
SAE Reporting to lncyte 
The Principal Investigator (Pl) must report all SAEs to lncyte within 24 hours of learning of an 
event, regardless of the Pl's causality assessment. This notification should be provided on a 
completed SAE form. SAE reporting for each subject begins the day the informed consent is 
signed by the patient and within 30 days after subject has completed or discontinued from 
the study or has taken last dose of the study drug, or as described in the protocol. 
 
SAEs, occurring using lncyte study drug, are reported in accordance with the effective 
protocol. SAEs occurring with any other commercial drug are reported to the manufacturer 
of that drug in accordance with regulations and protocol. 
 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@lncyte.com or fax(+) 1-866-981-2057. SAE reports should be for a single 
subject. SAE forms should be sent with a cover sheet and any additional attachments. 
 
All SAEs incurred while a patient is on study will be reported to the IRB at MSKCC and 
lncyte. All SAEs and relevant laboratory findings will be reported to the principal investigator 
immediately. All information regarding SAEs must be recorded on the form provided. Patient 
ssuffering SAEs must be carefully followed and all follow-up information also recorded. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 40 of 49
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All life-threatening and lethal known, unknown, or suspected reactions must be reported to 
the principal investigator. It is the treating physician's responsibility to investigate and report 
the date and cause of death of any patient entered on this trial. 
 
Reporting of Pregnancy to lncyte 
An "Initial Pregnancy Report" or equivalent must be completed in full and emailed to 
SafetyReporting@lncyte.com or faxed to(+) 1-866-981-2057 within 24 hours of discovery of 
a pregnancy of a subject who has taken the lncyte product. The "Follow-up Pregnancy 
Report Form" or equivalent must be completed and emailed to SafetyReporting@lncyte.com 
or faxed to(+) 1-866-981-2057 within 30 days after delivery, so that lncyte is provided with 
information regarding the outcome of the pregnancy. If the pregnancy results in any events 
which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting process 
needs to be followed and the timelines associated with a SAE should be followed. 
 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office. 
15.3 Pregnancy 
 
Lenalidomide is related to thalidomide. Thalidomide is known to cause severe, life- 
threatening human birth defects. Lenalidomide is known to cause birth defects in animals. If 
lenalidomide is taken during pregnancy, it may cause birth defects or death to any unborn 
baby. Females must not become pregnant or breastfeed while taking lenalidomide. Because 
lenalidomide carries a risk of causing thromboembolism, it is recommended that patients 
avoid taking oral contraceptives or hormone replacement therapy before discussing with the 
investigator and considering risks and benefits of these choices. In men taking lenalidomide, 
the drug is present in the semen at very low levels for three days after discontinuing, and 
may be present longer in those with impaired drug elimination (eg, renal dysfunction). All 
patients must adhere to the contraception requirements of the Revlimid REMS program. 
Patients should not donate blood during treatment or for 28 days following discontinuation of 
lenalidomide. 
If a patient inadvertently becomes or is suspected to have become pregnant while receiving 
study treatment, the patient will immediately be removed from the study. The investigator will 
follow the reporting and monitoring requirements of the Revlimid REMS program. 
 
16.0 
PROTECTION OF HUMAN PARTICIPANTS 
Potential risks to human subjects include drug-related toxicity; pain and discomfort 
associated with therapy; treatment side effects; phlebotomy; and possible psychologic 
discomfort from the stresses associated with obtaining imaging studies. 
 
The side effects and potential toxicities of all agents are listed in section 15.0. All efforts will 
be made to avoid any complication by completely reviewing patients' symptoms, providing 
appropriate management, and monitoring blood tests. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
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If an AE occurs, the patient will first contact the primary oncologist or the principal 
investigator. At nights and weekends, there is an oncology physician on call at all times. 
Patients may either call or come directly to the Urgent Care Center at Memorial Hospital (or 
to their local emergency room) to be seen. 
 
Costs to the patient (third party insurer) will include the cost of blood tests and diagnostic 
studies, office visits, those admissions which may be required as a consequence of 
treatment-related complications, and the costs of obtaining lenalidomide. 
 
16.1 
Privacy 
MSK'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/entities described in the 
Research Authorization form. A Research Authorization form must be approved by the IRB 
and Privacy Board (IRB/PB). 
The consent indicates that individualized, de-identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information, which will not include 
protected health information such as the participant's name, except for dates. It is also stated 
in the Research Authorization that their research data may be shared with others at the time 
of study publication. 
 
16.2 
Data Management 
A Clinical Research Associate (CRA) will be assigned to the study. The responsibilities of the 
CRA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database (Medidata) at 
MSKCC. Source documentation will be available to support the computerized patient record. 
Final data sets for publication are required to be locked and stored centrally for potential 
future access requests from outside entities. 
16.3 
Quality Assurance 
Registration reports will be generated on an ongoing basis to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations and 
follow-up will be monitored periodically throughout the study 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 and more frequently if indicated. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
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16.4 
Data and Safety Monitoring 
The Data and Safety Monitoring Plan utilized for this study must align with the  MSK DSM 
Plan where applicable. 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. 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." 
There are several different mechanisms by which clinical studies are monitored for data 
safety and quality. At a departmental/Pl level, there exist procedures for quality control by the 
research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA, 
and 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 Deputy Physician-in-Chief of Clinical Research. 
The degree of monitoring required will be determined based on level of risk and documented. 
The MSK DSMB monitors phase Ill trials and the DSMC monitors non-phase Ill trials. The 
DSMB/C have oversight over the following trials: 
• 
MSK Investigator-Initiated Trials (IITs; MSK as sponsor) 
• 
External studies where MSK is the data coordinating center 
• 
Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant, or by the end of 
the year one if no accruals, and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 
17.0 
REFERENCES 
1. 
Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and 
response assessment of lymphoma: consensus of the International Conference on Malignant 
Lymphomas Imaging Working Group. J Clin Oneal. 2014;32(27):3048-3058. 
2. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oneal. 2014;32(27):3059-3068. 
3. 
A clinical evaluation of the International Lymphoma Study Group classification of non- 
Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 
1997;89(11):3909-3918. 
4. 
Zhou Y, Wang H, Fang W, et al. Incidence trends of mantle cell lymphoma in the United 
States between 1992 and 2004. Cancer. 2008;113(4):791-798. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
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New York, New York 10065 
Page 43 of 49
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5. 
Fu S, Wang M, Lairson DR, Li R, Zhao B, Du XL. Trends and variations in mantle cell 
lymphoma incidence from 1995 to 2013: A comparative study between Texas and National 
SEER areas. Oncotarget. 2017;8(68):112516-112529. 
6. 
Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage 
mantle cell lymphoma. J Clin Oneal. 2009;27(4):511-518. 
7. 
Kumar A, Sha F, Toure A, et al. Patterns of survival in patients with recurrent mantle cell 
lymphoma in the modern era: progressive shortening in response duration and survival after 
each relapse. Blood Cancer J. 2019;9(6):50. 
8. 
Davids MS, Roberts AW, Seymour JF, et al. Phase I First-in-Human Study of Venetoclax in 
Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oneal. 
2017;35(8):826-833. 
9. 
Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell 
lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL- 
001 (EMERGE) study. J Clin Oneal. 2013;31(29):3688-3695. 
10. 
Song Y, Zhou K, Zou D, et al. Treatment of Patients with Relapsed or Refractory Mantle-Cell 
Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase. Clin Cancer 
Res. 2020;26(16):4216-4224. 
11. 
Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell 
lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 
2018;391(10121):659-667. 
12. 
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory 
mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. 
13. 
Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell 
lymphoma. Blood. 2016;127(12):1559-1563. 
14. 
Wang M, Munoz J, Goy A, et al. KTE-X19 CART-Cell Therapy in Relapsed or Refractory 
Mantle-Cell Lymphoma. N Engl J Med. 2020;382(14):1331-1342. 
15. 
Dredge K, Horsfall R, Robinson SP, et al. Orally administered lenalidomide (CC-5013) is 
anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. 
Microvasc Res. 2005;69(1-2):56-63. 
16. 
Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation 
by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J 
lmmunol. 1999;163(1):380-386. 
17. 
Gandhi AK, Kang J, Havens CG, et al. lmmunomodulatory agents lenalidomide and 
pomalidomide co-stimulate T cells by inducing degradation of T cell repressors lkaros and 
Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 
2014;164(6):811-821. 
18. 
Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R. Lenalidomide efficacy in 
activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and 
cereblon expression. Br J Haematol. 2013;160(4):487-502. 
19. 
Hagner PR, Chiu H, Ortiz M, et al. Activity of lenalidomide in mantle cell lymphoma can be 
explained by NK cell-mediated cytotoxicity. Br J Haematol. 2017;179(3):399-409. 
20. 
Zinzani PL, Vose JM, Czuczman MS, et al. Long-term follow-up of lenalidomide in 
relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann Oneal. 
2013;24(11):2892-2897. 
21. 
Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for 
patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet 
Oneal. 2012;13(7):716-723. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 44 of 49
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22. 
Wang M, Schuster SJ, Phillips T, et al. Observational study of lenalidomide in patients with 
mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib 
(MCL-004). J Hematol Oneal. 2017;10(1):171. 
23. 
Horton HM, Bernett MJ, Pong E, et al. Potent in vitro and in vivo activity of an Fe-engineered 
anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res. 
2008;68(19):8049-8057. 
24. 
Awan FT, Lapalombella R, Trotta R, et al. CD19 targeting of chronic lymphocytic leukemia 
with a novel Fe-domain-engineered monoclonal antibody. Blood. 2010;115(6):1204-1213. 
25. 
Jurczak W, Zinzani PL, Gaidano G, et al. Phase Ila study of the CD19 antibody MOR208 in 
patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Ann Oneal. 
2018;29(5): 1266-1272. 
26. 
Grillo-Lopez AJ. Is rituximab effective as a single agent in mantle-cell lymphoma? Nat Clin 
Pract Oneal. 2005;2(10):500-501. 
27. 
Hiraga J, Tomita A, Sugimoto T, et al. Down-regulation of CD20 expression in B-cell 
lymphoma cells after treatment with rituximab-containing combination chemotherapies: its 
prevalence and clinical significance. Blood. 2009;113(20):4885-4893. 
28. 
Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and 
therapy. Exp Hematol Oneal. 2012;1(1):36. 
29. 
Salles G, Duell J, Gonzalez Barca E, et al. Tafasitamab plus lenalidomide in relapsed or 
refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, 
phase 2 study. Lancet Oneal. 2020;21(7):978-988. 
30. 
Ladetto M, Tavarozzi R, Pott C. Minimal Residual Disease in Mantle Cell Lymphoma: 
Methods and Clinical Significance. Hematology/Oncology Clinics of North America. 
2020;34(5):887-901. 
31. 
Uldrick TS, Ison G, Rudek MA, et al. Modernizing Clinical Trial Eligibility Criteria: 
Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research 
HIV Working Group. J Clin Oneal. 2017;35(33):3774-3780. 
32. 
Chen N, Zhou S, Palmisano M. Clinical Pharmacokinetics and Pharmacodynamics of 
Lenalidomide. Clin Pharmacokinet. 2017;56(2): 139-152. 
33. 
Karnofsky DA, Burchenal JH. (1949). 'The Clinical Evaluation of Chemotherapeutic Agents in 
Cancer.' In: Macleod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ 
Press. Page 196. 
34. 
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, 
and guidelines. J Clin Oneal. 1984;2(3):187-193. 
35. 
Cockcroft OW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
36. 
Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine 
concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy. 
2012;32(7):604-612. 
37. 
Pawlyn C, Khan MS, Muls A, et al. Lenalidomide-induced diarrhea in patients with myeloma 
is caused by bile acid malabsorption that responds to treatment. Blood. 2014;124(15):2467- 
2468. 
 
 
18.0 
APPENDICES 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
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Appendix A: Karnofsky performance status33•34 
 
% 
Performance status description 
100 
Normal. No complaints. No evidence of disease. 
90 
Able to carry on normal activity. Minor signs or symptoms of disease. 
80 
Normal activity with effort. Some signs or symptoms of disease. 
70 
Cares for self. Unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of their personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled. Requires special care and assistance. 
30 
Severely disabled. Hospitalization is indicated although death is not imminent. 
20 
Hospitalization necessary, very sick, active supportive treatment necessary. 
10 
Moribund. Fatal processes progressing rapidly. 
0 
Dead. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
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New York, New York 10065 
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Appendix B: Cockcroft-Gault CrCl35•36 
1. Determine weight to be used: 
a. Calculate ideal body weight (IBW) in kilograms: 
i. Female: 45.5 + (2.3 x ([height, inches] - 60)) 
ii. Male: 50 + (2.3 x ([height, inches] - 60)) 
b. If IBW > total (actual) body weight (TBW), use TBW in kilograms 
c. If IBW :s; TBW: 
i. If rnw < 1.3, use IBW in kilograms 
IBW 
ii. If rnw 
1.3, use adjusted body weight (AdjBW) in  kilograms: 
IBW 
[IBW, kilograms]+ (0.4 x ([TEW, kilograms] - [IBW, kilograms]) 
2. Calculate CrCI using weight determined in step 1: 
ml) 
(140 - [age,years]) x [weight, kilograms] 
CrCl ( -. 
=  
[ 
mg] 
 x (0.85 only if female) 
mm 
72 x serum creatinine, dL 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
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Memor:ial Sloan Kettering Cancer Center 
MANAGEMENT OF INFUSION or HYPERSENSITIVITY REACTION 
 
 
YES
PHYSICAl M EASUIRES 
Ensure patent IV access of NS at KVO 
 
 
 
 
 
 
 
 
 
 
SUPPORTIVE TREATMENT
 
 
CHILLS/FEVER: 
Acetaminophen 6,50mg PO 
8.-.c</ABO PAIN: 
 Analgesic< 
 
 
 
 ------------- 
ASSESS AJRWAY
 
AIRWAY0B5TRUCTlON - RESPIRATORYFAI.WRE- ARREST  Manual Resuscitative Mask 
AIRWAY OBSTRUCTION FROM ANGI0EDEMA Activate RRT/EMS - Intubate 
 
 
 
 
CONSIDER OTHER MEDICATIONS 
 
 
URTICARIA: - Dlphenhydramlne 50mg IVP 
 
 
ON BETA BlOCKER w/NO RESPONSE TO EPI: - Glucagon 1mg kit IM - If available 
H'l'POTENStON: Vasopre.ssor lnfusfon per UP -if available 
 
 
 
 
PRESCRIPTIONS: Consider for delayed recurrent reaction after discharge 
Ep1nephrine auto-injector 0.3mg
 
SIGNS of ANAPHVLAXIS 
 
 
 
Respiratory- SOB, wheeze, strldor 
 
Persistent GI symptoms 
 
 
SIGNS of INFUSION/ALLERGIC REACTION 
 
 
 
 
 
 
Rashes or hives 
 
& 
Assess Patient 
Appendix C: Acute management of infusion-related reactions 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
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Appendix D: Suggested symptom management of lenalidomide-associated diarrhea 
 
Lenalidomide-associated diarrhea is caused by bile acid malabsorption, and can be 
managed using bile acid sequestrants.37 Tafasitamab is not expected to contribute to 
diarrhea incidence.25 Gastrointestinal opioid agonists (eg, loperamide, diphenoxylate) are 
frequently ineffective against lenalidomide-induced diarrhea and may produce constipation 
and other untoward effects. Use of bile acid sequestrants as first-line management of non- 
infectious diarrhea according to the decision tree below is suggested, but is left to the 
investigator's discretion. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 22-380 A(4) 
Approval date: 26-Mar-2024 
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Patient reports grade 
1 diarrhea after 
initiation of study 
treatment 
 
 
 
 
 
 
Fasting serum 
triglycerides 
300mg/dl? 
No 
Clinical assessment: 
suspected infectious 
diarrhea? 
Yes 
 Gastrointestinal 
pathogen testing 
before initiating 
antidiarrheals 
 
 
 
 
 
 
Initiate bile acid 
sequestrant: 
• Colesevalam 
1875mg twice daily 
or 3750mg once 
daily 
• Lower doses may 
be used at 
investigator's 
discretion 
• Administer at least 
4 hours after 
lenalidomide 
• Alternative bile acid 
sequestrants may 
be used at 
investigator's 
discretion 
Initiate standard 
antidiarrheal at 
investigator's 
discretion 
 
 
 
Improvement of 
No 
diarrhea to grade :s; 1 
after 48-72 hours? 
 
 
 
 
Continue current 
antidiarrheal regimen 
through completion of 
lenalidomide or 
discontinuation at 
investigator's 
discretion 
 
 
 
 
• If receiving bile acid 
sequestrant, add 
standard 
antidiarrheal 
• Add antidiarrheal(s) 
and/or escalate 
dose(s) if safe and 
feasible - consult 
pharmacist 
• Consider supportive 
care consult