Clinical trial NCT02880228
Conditions: Plasma Cell Myeloma
Sponsor: Mayo Clinic
Start date: 2016-09-16; Completion date: 2018-07-29
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pembrolizumab, lenalidomide, and dexamethasone work in treating patients with newly diagnosed multiple myeloma that are eligible for stem cell transplant. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab, lenalidomide, and dexamethasone may work better in treating patients with multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the very good partial response (VGPR) or better response rate (\>= VGPR) after 4 cycles of pembrolizumab added to standard doses of lenalidomide and dexamethasone, when used as initial therapy in patients with previously untreated symptomatic multiple myeloma (MM) in patients, who are considered eligible for stem cell transplantation.

SECONDARY OBJECTIVES:

I. To determine the \>= partial response (PR) rate after 4 cycles of treatment with pembrolizumab added to standard doses of lenalidomide and dexamethasone.

II. To determine the \>= VGPR response rate at any time during treatment with pembrolizumab added to standard doses of lenalidomide and dexamethasone.

III. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with the combination of pembrolizumab, lenalidomide and dexamethasone.

IV. To determine the toxicities associated with pembrolizumab added to standard doses of lenalidomide and dexamethasone in patients with previously untreated symptomatic MM.

V. To determine the success rate of stem cell collection following initial therapy with the combination of pembrolizumab, lenalidomide and dexamethasone in patients with newly diagnosed MM.

TERTIARY OBJECTIVES:

I. PDL-1 expression on myeloma cells and non-tumor cell compartments from the bone marrow will be assessed at baseline.

II. Measures of T-cell activation / exhaustion will be assessed at baseline and after cycle 1, cycle 2, cycle 3, and cycle 4.

III. Natural killer (NK) cell function and numbers will be evaluated at baseline and after cycle 1, cycle 2, cycle 3, and cycle 4.

OUTLINE:

Patients receive lenalidomide orally (PO) daily on days 1-21 and dexamethasone PO daily on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on days 1 and 22 of course 1, day 15 of course 2, and day 8 of course 3. Courses 1-3 repeat beyond 3 courses in the absence of disease progression or unacceptable toxicity. Patients may undergo stem cell transplantation after 4 courses of treatment.

After completion of study treatment, patients are followed up every 3 months or 6 months for up to 3 years.

Arms: arm 1: Patients receive lenalidomide PO daily on days 1-21 and dexamethasone PO daily on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on days 1 and 22 of course 1, day 15 of course 2, and day 8 of course 3. Courses 1-3 repeat beyond 3 courses in the absence of disease progression or unacceptable toxicity. Patients may undergo stem cell transplantation after 4 courses of treatment.
Interventions: intervention 1: Dexamethasone intervention 2: Laboratory Biomarker Analysis intervention 3: Lenalidomide intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
 
Phase 2 Trial of Pembrolizumab, Lenalidomide and Dexamethasone for Initial Therapy of Newly 
Diagnosed Multiple Myeloma Eligible for Stem Cell Transplantation .......................................... 1 
Table of Contents ............................................................................................................................ 3 
Schema ............................................................................................................................................ 4 
1.0 
Background ...................................................................................................................... 5 
2.0 
Goals............................................................................................................................... 10 
3.0 
Patient Eligibility............................................................................................................ 11 
4.0 
Test Schedule ................................................................................................................. 14 
5.0 
Grouping Factor: None................................................................................................... 16 
6.0  
Registration Procedures.................................................................................................. 16 
7.0 
Protocol Treatment ......................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 19 
9.0 
Ancillary Treatment/Supportive Care ............................................................................ 28 
10.0 
Adverse Event (AE) Reporting and Monitoring......................................................... 32 
11.0 
Treatment Evaluation ................................................................................................. 41 
12.0 
Descriptive Factors ..................................................................................................... 45 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................... 46 
14.0 
Body Fluid Biospecimens ........................................................................................... 48 
15.0 
Drug Information ........................................................................................................ 50 
16.0  
Statistical Considerations and Methodology .............................................................. 58 
17.0 
Pathology Considerations/Tissue Biospecimens: None ............................................. 63 
18.0 
Records and Data Collection Procedures ................................................................... 63 
19.0  
Budget ......................................................................................................................... 64 
20.0 
References .................................................................................................................. 65 
Appendix I ECOG Performance Status ..................................................................................... 66 
Appendix II 
Patient Medication Diary .................................................................................... 67 
 
 


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
1Cycle length during Induction = 28 days  
2Confirmation of MR or PR is not required. 
3Progressive disease should be confirmed. However, treatment may be discontinued for progressive 
disease that is unconfirmed per physician discretion. In this case, an objective status of PD should be 
entered on the measurement form and progressive disease should be reported on the event monitoring 
form. 
4Patients may receive stem cell transplant (SCT) at physician discretion at any time after 4 cycles. If 
patient goes to SCT, they will go to Survival and Disease Status Follow-Up/ Event Monitoring per 
Section 4.2 and the transplant should be recorded on the event monitoring form. 
 
Generic name: Pembrolizumab 
Brand name(s): Keytruda® 
Mayo Abbreviation: MK-3475 
Availability: Provided by Merck 
Generic name: Lenalidomide 
Brand name(s): Revlimid® 
Mayo Abbreviation: LEN 
Availability: Revlimid REMS™ 
program 
Generic name: Dexamethasone 
Brand name(s): Decadron® 
Mayo Abbreviation: DXM 
Availability: Commercial 
Registration 
Induction  
Lenalidomide + Pembrolizumab + 
Dexamethasone 1, 4 
Patients who are unable to 
proceed directly to 
transplant may interrupt 
therapy for stem cell 
collection any time after 
4 cycles 
PD at any time 3 
Unacceptable adverse events 
Event Monitoring (per Section 4.2) 
Patient refusal 
Patient will go off 
treatment to event 
monitoring if an MR 
is not seen after 
2 cycles and a PR is 
not seen after 
4 cycles2 
Event Monitoring (per Section 4.2) 


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1.0 
Background 
1.1 Multiple Myeloma:  
Multiple myeloma is a malignancy of the differentiated plasma cells, that affect the older patient 
with a median age at onset of 65-70 years and a slight male predominance. Nearly 20,000 patients 
with myeloma are diagnosed in the United States each year, and despite considerable 
improvements in therapy, the disease remains incurable and uniformly fatal with a median overall 
survival of around 8 years. Recent improvements in therapies have significantly improved the 
survival outcomes, but given the inevitable relapses seen in these patients, new approaches to 
therapy are clearly needed. The highly effective drug combinations currently used are beset with 
a degree of toxicity that precludes long-term therapy and also can affect quality of life metrics. 
Finally, some of these regimens require IV or subcutaneous administration, which can require 
frequent clinic visits for patients. The highly effective multi-drug regimens currently in use 
typically include a proteasome inhibitor, either bortezomib given IV or SQ or carfilzomib given 
IV. 
1.2 Lenalidomide:  
Lenalidomide has significant activity in the setting of multiple myeloma; both in relapsed and in 
newly diagnosed disease. Initial phase I/II study of lenalidomide in relapsed myeloma determined 
the ideal dose to be 25 mg once daily given for 3 of 4 weeks.1 The initial trial in the relapsed 
disease also demonstrated increased activity in combination with pulsed doses of dexamethasone. 
These findings led to the initial trials of the combination in newly diagnosed disease as well as 
randomized trials of the combination in relapsed myeloma.2 In the phase III trials of lenalidomide 
and dexamethasone, the combination was demonstrated to be superior to dexamethasone in terms 
of response rates and progression free and overall survival.3 The initial phase II study of 
lenalidomide and dexamethasone in newly diagnosed myeloma, conducted at the Mayo Clinic, 
also employed the combination of lenalidomide and pulsed dose dexamethasone (40 mg daily on 
four days on four days off schedule) for the first four cycles followed by 40 mg weekly for the 
subsequent cycles. The phase II study demonstrated significant response rates and long term 
follow up demonstrated sustained responses and 1-year survival rates of over 90%. The 
subsequent phase III trial in the ECOG (E4A03) compared the same dosing strategy to one that 
employed a lower dose of dexamethasone (40 mg weekly) right from the start of therapy.3 The 
results of the trial demonstrated a superior overall survival for the lower dose dexamethasone 
arm. 
Two large, multicenter, randomized, placebo-controlled phase III pivotal trials MM-009 (n = 353) 
conducted in North America, and MM-010 (n = 351) in Europe, Australia and Israel; which 
collectively included 704 patients assessed the efficacy and safety of lenalidomide plus 
dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple 
myeloma (RRMM).4,5 Patients were randomized to receive either oral lenalidomide 25 mg per 
day or placebo for three weeks along with 40 mg oral dexamethasone for four days starting 1, 9 
and 17 day of each 28-day cycle (for 4 cycles) until disease progression. After four cycles, 
dexamethasone (40 mg/day) was limited to days 1-4 only. The results of both studies were similar 
and the pooled analysis showed that treatment with lenalidomide plus dexamethasone 
significantly improved overall response (OR: 60.6 vs 21.9%, P<0.001), complete response rate 
(CR: 15.0 vs 2.0%, P<0.001), time to progression (TTP: median of 13.4 vs 4.6 months, P<0.001) 
and duration of response (DOR: median of 15.8 months vs 7 months, P<0.001) compared with 
dexamethasone-placebo. Even at a median follow-up of 48 months for surviving patients, a 
significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained. 
Thus the data confirmed the significant response and survival benefit with lenalidomide and 
dexamethasone and this led to approval of lenalidomide in combination with dexamethasone for 


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the treatment of MM in patients who have received at least one earlier therapy by the US FDA in 
June 2006 followed by European Medicines Agency in June 2007.  
Sub-analysis of MM-09 and MM-10 by Harousseau et al revealed that half of the patients who 
initially had a partial response achieved a complete or very good partial response with further 
treatment. (Harousseau, Dimopoulos et al. 2010) The probability of achieving a complete or very 
good partial response with continued lenalidomide treatment decreased with delayed achievement 
of a partial response (by cycle 4 versus later); however, it still remained clinically significant. The 
quality of response also showed a positive prognostic impact with an extended follow-up of 
48 months, as patients who achieved a CR/VGPR as their best response had significantly longer 
median response duration, time-to-progression, and overall survival than in those with a partial 
response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached 
versus 44.2 months, P=0.021, respectively) and this was regardless of when the CR/VGPR was 
achieved. Another sub-analysis of the same studies determined that continued lenalidomide 
treatment until disease progression after achievement of ≥PR is associated with a significant 
survival advantage when controlling for patient characteristics. A Dutch study showed that 
treatment with Len-Dex is highly effective and feasible in heavily pretreated multiple myeloma 
patients by analyzing the clinical data of more than 100 patients who had been on a median of 
3 previous lines of therapy, including thalidomide in most. With a median of 7 cycles of 
treatment, an overall response rate of 69%, including complete response in 6% was achieved and 
this was not influenced by previous thalidomide and/or bortezomib treatment. Using the 
recommended prophylaxis, incidence of venous thrombotic events was low (5%) but grade ≥3 
myelosuppression occurred in more than a third (37%). 
Lenalidomide has significant activity in the setting of multiple myeloma; both in relapsed and in 
newly diagnosed disease. Initial phase 1/2 study of lenalidomide in relapsed myeloma determined 
the ideal dose to be 25 mg once daily given for 3 of 4 weeks. The initial trial in the relapsed 
disease also demonstrated increased activity in combination with pulsed doses of dexamethasone. 
These findings led to the initial trials of the combination in newly diagnosed disease as well as 
randomized trials of the combination in relapsed myeloma. In the phase III trials of lenalidomide 
and dexamethasone, the combination was demonstrated to be superior to dexamethasone in terms 
of response rates and progression free and overall survival. The initial phase II study of 
lenalidomide and dexamethasone in newly diagnosed myeloma, conducted at the Mayo Clinic, 
also employed the combination of lenalidomide and pulsed dose dexamethasone (40 mg daily on 
four days on four days off schedule) for the first four cycles followed by 40 mg weekly for the 
subsequent cycles. The phase II study demonstrated significant response rates and long term 
follow up demonstrated sustained responses and 1-year survival rates of over 90%. The 
subsequent phase III trial in the ECOG (E4A03) compared the same dosing strategy to one that 
employed a lower dose of dexamethasone (40 mg weekly) right from the start of therapy. The 
overall (complete plus partial) response to therapy after four cycles was higher with high-dose 
dexamethasone than with low-dose, 169 (79%) of 214 patients on high-dose dexamethasone had 
an overall response (complete or partial) compared with 142 (68·3%) of 208 on low-dose 
(p=0.008). Despite this, the trial demonstrated a superior overall survival for the lower dose 
dexamethasone arm. 90 (42%) patients achieved complete response or very good partial response 
in the high-dose dexamethasone group in the first four cycles of therapy compared with 49 (24%) 
patients in the low-dose treatment group (p<0.0001). Long term follow up of patients receiving 
lenalidomide and dexamethasone induction followed by autologous stem cell transplantation 
demonstrated 86% overall survival at 4 years, in a single institution study, underscoring the utility 
of this regimen as a well-tolerated and effective initial therapy.  
Lenalidomide and dexamethasone was studied in a large phase 3 trial, where 1623 patients were 
randomized to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 


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patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 
72 weeks (547 patients). Response rates were higher with continuous lenalidomide–
dexamethasone (75%) and with 18 cycles of lenalidomide–dexamethasone (73%) than with MPT 
(62%; P<0.001 for both comparisons). Rates of very good partial response or better were also 
higher with continuous lenalidomide–dexamethasone (44%) or 18 cycles of lenalidomide–
dexamethasone (43%) than with MPT (28%), as were rates of complete response (15%, 14%, and 
9%, respectively). The median progression-free survival was 25.5 months with continuous 
lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 
21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous 
lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 
18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Overall survival at 
4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of 
lenalidomide-dexamethasone, and 51% with MPT. As compared with MPT, continuous 
lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, 
a moderate increase in infections, and fewer second primary hematologic cancers.  
1.3 Pembrolizumab 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4, which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD-1 has been 
resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells. Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors . Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed 
at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-


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cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This suggests that 
the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered 
as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United States for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475. The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities 
were observed. This first in human study of MK-3475 showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the highest dose tested in PN001, 
will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumor activity. Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.  
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights. MK-3475 has been found to have a wide therapeutic range based on the melanoma 
indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 


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The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 
3) will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
1.4 Rationale for the current trial:  
Currently, there is considerable amount of work being done to enhance this regimen. Combining 
a proteasome inhibitor with lenalidomide clearly enhances the efficacy, but also increases the 
toxicity and can be an issue in the older patient. Recent trials are evaluating monoclonal 
antibodies in combination with lenalidomide, to capitalize on the immunomodulatory effects of 
lenalidomide, specifically the NK cell and T-cell enhancing activity. Binding of the PD-1 ligands, 
PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and 
cytokine production. Upregulation of PD-1 ligands occur in some tumors and signaling through 
this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. 
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its 
interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune 
response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking 
PD-1 activity resulted in decreased tumor growth. In the setting of myeloma, B-cell responses are 
altered to a state of functional hypogammaglobulinemia, leading to an increased risk for 
infections. T-cell-mediated immunity is also severely impaired in MM with T-helper (Th)1/Th2 
imbalance leading to immune dysfunction. Several studies have shown that PD-L1 is absent from 
normal plasma cells, whereas it is expressed on myeloma cell lines and primary myeloma tumor 
cells from patients with MM. It has been demonstrated that PD-1 expression is upregulated on T 
cells isolated from patients with MM, suggesting that this pathway is of importance in mediating 
the immunosuppressive state in this patient population. Benson et al. have shown that NK cells 
from MM patients express PD-1 and suggested that PD-1/PD-L1 interactions undermine the 
immunological control of MM by NK cells. They have also demonstrated that the application of 
an anti-PD-1 monoclonal antibody enhances the cytolytic activity of NK cells against autologous, 
primary MM cells. It was observed that lenalidomide was capable of downregulating the 
expression of PD-L1 on the malignant plasma cells from MM patients and that its in vitro 
application resulted in an enhancement of the myeloma-targeting activity of the anti-PD-1 
antibody. Preliminary results from an ongoing phase 1 trial of lenalidomide, dexamethasone, and 
pembrolizumab have demonstrated evidence of activity with one complete response and two 
VGPR in patients with relapsed disease. Given these findings, it is rational to evaluate the 
combination of pembrolizumab in combination with lenalidomide and dexamethasone in newly 
diagnosed myeloma, which allows for early intervention and maximal benefit from such an 
immunological approach. 


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2.0 
Goals 
2.1 
Primary 
To determine the VGPR or better response rate (≥VGPR) after 4 cycles of 
Pembrolizumab added to standard doses of lenalidomide and dexamethasone, when used 
as initial therapy in patients with previously untreated symptomatic MM in patients, who 
are considered eligible for stem cell transplantation. 
 
2.2 
Secondary 
2.21. 
To determine the ≥ partial response (PR) rate after 4 cycles of treatment with 
Pembrolizumab added to standard doses of lenalidomide and dexamethasone. 
2.22 
To determine the ≥ VGPR response rate at any time during treatment with 
Pembrolizumab added to standard doses of lenalidomide and dexamethasone. 
2.23 
To determine the progression free survival and overall survival among patients 
with previously untreated symptomatic MM following treatment with the 
combination of pembrolizumab, lenalidomide and dexamethasone. 
2.24 
To determine the toxicities associated with pembrolizumab added to standard 
doses of lenalidomide and dexamethasone in patients with previously untreated 
symptomatic MM. 
2.25 
To determine the success rate of stem cell collection following initial therapy 
with the combination of pembrolizumab, lenalidomide and dexamethasone in 
patients with newly diagnosed MM. 
 
2.3 
Correlative Research (IRB#521-93) 
2.31 
PDL-1 expression on myeloma cells and non-tumor cell compartments from the 
bone marrow will be assessed at baseline  
2.32 
Measures of T-cell activation / exhaustion will be assessed at baseline and after 
Cycle 1, Cycle 2, Cycle 3, and Cycle 4. 
2.33 
NK cell function and numbers will be evaluated at baseline and after Cycle 1, 
Cycle 2, Cycle 3, and Cycle 4. 
 
 
 


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3.0 
Patient Eligibility 
3.1 
Inclusion Criteria  
3.11 
Diagnosis and previously untreated active multiple myeloma by IMWG 
diagnostic criteria for multiple myeloma 
3.12  
Age ≥18 years. 
3.13 
The following laboratory values obtained ≤14 days prior to registration.  
• 
Calculated creatinine clearance (using Cockcroft-Gault equation below)* 
≥30 mL/min 
• 
Absolute neutrophil count (ANC) ≥1000/mm3 
• 
Platelet count ≥75000/mm3 
• 
Hemoglobin ≥8.0 g/dL 
• 
Total bilirubin ≤1.5 x ULN 
• 
ALT and AST ≤3 x ULN 
 
*Cockcroft-Gault Equation: 
Creatinine clearance for males = (140 - age)(actual body weight in kg)  
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
 
3.14 
Prior therapy for the treatment of solitary plasmacytoma is permitted, but >7 days 
should have elapsed from the last day of radiation.  
NOTE: Prior therapy with clarithromycin, DHEA, anakinra, pamidronate or 
zoledronic acid is permitted. Any additional agents not listed must be approved 
by the Principal Investigator. 
3.15 
Measurable disease of multiple myeloma as defined by at least ONE of the 
following: 
• 
Serum monoclonal protein ≥1.0 g/dL (see Section 11.1 for definition) 
• 
>200 mg of monoclonal protein in the urine on 24 hour electrophoresis  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum 
immunoglobulin kappa to lambda free light chain ratio. 
3.16 
ECOG performance status (PS) 0 or 1 (See Appendix I) 
3.17 
Provide written informed consent. 
3.18 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
3.19a 
Willing to follow strict birth control measures as suggested by the study. 
3.19a1 
Female patients: If they are of childbearing potential, must agree to one 
of the following: 
• 
Practice 2 effective methods of contraception, at the same time, 
from the time of signing the informed consent form through 90 
days after the last dose of study drug, AND must also adhere to the 
guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR  


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• 
Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
[eg, calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable methods of contraception.) 
3.19a2 
Male patients: even if surgically sterilized (i.e., status post-vasectomy), 
must agree to one of the following: 
• 
Agree to practice effective barrier contraception during the entire 
study treatment period and through 120 days after the last dose of 
study drug, OR 
• 
Must also adhere to the guidelines of any treatment-specific 
pregnancy prevention program, if applicable, OR 
• 
Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable methods of contraception.) 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19c 
Willing to provide consent to IRB#521-93 and provide research tissue and blood 
specimens. 
3.2 
Exclusion Criteria 
3.21  
MGUS or smoldering myeloma. 
3.22  
Prior cytotoxic chemotherapy or corticosteroids for the treatment of multiple 
myeloma.  
NOTE: Prior corticosteroid use for the treatment of non-malignant disorders is 
permitted  
3.23 
Diagnosed or treated for another malignancy ≤2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  
NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type 
are not excluded if they have undergone complete resection.  
3.24 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women  
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
3.25 
Other co-morbidity which would interfere with patient's ability to participate in 
trial, e.g. uncontrolled infection, uncompensated heart or lung disease. 
3.26 
Other concurrent chemotherapy or any ancillary therapy considered 
investigational.  
NOTE: Bisphosphonates are considered to be supportive care rather than therapy, 
and are thus allowed while on protocol treatment. 
3.27 
Peripheral neuropathy ≥Grade 3 on clinical examination or Grade 2 with pain 
during the screening period. 


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Protocol version date: 22Jun2017 
3.28 
Major surgery ≤14 days prior to study registration. 
3.29a 
Radiotherapy ≤14 days prior to registration.  
NOTE: If the involved field is small, 7 days will be considered a sufficient 
interval between treatment and administration of study drugs 
3.29b Participation in any other clinical trials with other investigational agents not 
included in this trial, ≤21 days prior to registration  
3.29c 
Active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  
NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is 
not considered a form of systemic treatment.  
3.29d Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
3.29e 
Active infection requiring systemic therapy. 
3.29f 
History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
3.29g Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.29h Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening 
visit through 120 days after the last dose of trial treatment. 
3.29i 
Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
3.29j 
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
3.29k Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
3.29l 
Received a live vaccine ≤30 days of planned start of study therapy. 
 
 


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4.0 
Test Schedule 
4.1 
Schedule of assessments 
Tests and Procedures 
Screening 
Active Treatment 1 
≤30 days ≤14 days 
 
Cycles 1-3 to be repeated beyond 3 cycles 
 
Cycle 1 
Cycle 2 
Cycle 3 
 
Weekly 
(For first 
2 cycles) 
Cycle 1, 
Day 1,  
Pre-
treatment10 
Pembrolizumab 
infusion  
Cycle 1,  
Day 22, 
Pre-treatment11 
Cycle 2, 
Day 1,  
Pre-
treatment 
Pembrolizumab 
infusion 
Cycle 2,  
Day 15,  
Pre-treatment11 
Cycle 3, 
Day 1,  
Pre-
treatment 
Pembrolizumab 
infusion  
Cycle 3, Day 8,  
Pre-treatment11 
End of 
Induction 
treatment 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
Adverse Event monitoring 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical exam, including weight, vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
Performance status (ECOG scale) 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC with diff (includes hemoglobin, ANC, 
WBC with complete differential, platelets) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time (PT) 
X 
 
 
 
 
 
 
 
 
 
Chemistry group to include sodium, 
potassium, glucose, alkaline phosphatase; 
Total and Direct bilirubin; SGOT (AST); 
SGPT (ALT); serum creatinine, calcium 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH, Beta2-microglobulin, Plasma cell 
assessment 
X 
 
 
 
 
 
 
 
 
 
sTSH 
X 
 
 
Every 6 months while on treatment 
Electrophoresis of serum and urine 
(SPEP/UPEP) 
 
X 
 
X9 
 
X9 
 
X9 
 
X9 
Affected Immunoglobulin2 
 
X 
 
X 
 
X 
 
X 
 
X 
Immunofixation serum and urine 
X 
 
 
X3 
 
X3 
 
X3 
 
X3 
Immunoglobulin free light chain 
 
X 
 
X4 
 
X4 
 
X4 
 
X4 
X-ray skeletal survey or  
low dose whole body CT 
X 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate and biopsy, myeloma 
FISH, plasma cell proliferation, and flow 
cytometry 
X 
 
 
X5 
 
X5 
 
X5 
 
X5 


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Protocol version date: 22Jun2017 
Tests and Procedures 
Screening 
Active Treatment 1 
≤30 days ≤14 days 
 
Cycles 1-3 to be repeated beyond 3 cycles 
 
Cycle 1 
Cycle 2 
Cycle 3 
 
Weekly 
(For first 
2 cycles) 
Cycle 1, 
Day 1,  
Pre-
treatment10 
Pembrolizumab 
infusion  
Cycle 1,  
Day 22, 
Pre-treatment11 
Cycle 2, 
Day 1,  
Pre-
treatment 
Pembrolizumab 
infusion 
Cycle 2,  
Day 15,  
Pre-treatment11 
Cycle 3, 
Day 1,  
Pre-
treatment 
Pembrolizumab 
infusion  
Cycle 3, Day 8,  
Pre-treatment11 
End of 
Induction 
treatment 
Research bone marrow R (IRB 521-93)  
X 
 
 
X5 
 
X5 
 
X5 
 
X5 
Research blood sample R(IRB 521-93)  
X 
 
 
X6 
 
X6 
 
X6 
 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
 
X7 
 
 
 
 
 
 
 
 
Patient Medication Diary (Appendix II)8. 
 
 
 
X 
 
X 
 
X 
 
X 
Cycle length during induction = 28 days 
1) All scheduled visits will have a window of ± 4 days, except pembrolizumab infusion days which will have a window of ± 1 day  
2) Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, or IgD. Not applicable if patient “non-secretory” or if patient 
has no heavy chain, i.e. light chain myeloma. 
3) Immunofixation (IF) needed only in the absence of M-spike to document CR or sCR. 
4) FLC is required only if used to assess disease response during active phase 
5) At the end of 4 cycles and to document CR at any time point.  
6)  End of each cycle for first 4 cycles, and then at time of disease progression. 
  
7) For women of childbearing potential only. Must be done ≤7 days prior to registration  
8) The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution. 
9) Urine Electrophoresis required after baseline only if used to assess disease response 
10) Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for Cycle 1. 
11)  If pembrolizumab is discontinued, the patient may continue treatment with the remaining drugs and these visits do not apply. 
R) Research funded (see Section 19.0). Will be charged to study and not to patient’s account. 
 
 
 


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4.2 
Event Monitoring/Survival Follow-up  
 
 
 
Event Monitoring Phase1  
q. 3 months 
until PD 
At PD 
After PD 
q. 6 months 
Death 
New Primary 
Event Monitoring  
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required.  
 
5.0 
Grouping Factor: None 
 
6.0  
Registration Procedures 
6.1 
Registration Procedures 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the remote registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 5:00 p.m. Central Time (Monday through 
Friday).  
The instructions for the registration/randomization application are available on 
the MCCC web page 
 detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office
. If the patient 
was fully registered, the MCCC Registration Office staff can access 
the information from the centralized database and confirm the 
registration. 
• 
Refer to “Instructions for Remote Registration” in Section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.12 
Correlative Research:  
A mandatory correlative research component is part of this study (under 
IRB#521-93), the patient will be automatically registered onto this component 
(see Sections 3.19c and 14.0). 
 
6.13 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 


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Protocol version date: 22Jun2017 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.14 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved.  
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.15 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of Multiple Myeloma at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.16 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a medical oncologist/hematologist. 
 
6.17 
Treatment cannot begin prior to registration and must begin ≤ 14 days after 
registration. 
 
6.18 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.19 
All required baseline symptoms (see Section 10.8) must be documented and 
graded.  
 
6.2 
Trial rules: 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 21 
CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
 
 
 


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Protocol version date: 22Jun2017 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule  
Cycle length: 28 days.  
Agent 
Route 
Dose 
Day 
Retreatment 
Lenalidomide 
PO 
25 mg* 
1-21 
Every 28 days 
Pembrolizumab 
IV 
200mg  
Every 21 days 
Every 21 days 
Dexamethasone 
PO 
40 mg 
1, 8, 15, 22 
Every 28 days 
 
* If the patient has renal insufficiency, lenalidomide dose modifications should be made 
according to the following criteria: 
CrCl >50 mL/min: No adjustment 
CrCl 30-50 mL/min: 10 mg/day 
CrCl <30 mL/min (no dialysis): 15 mg every 48 hours 
CrCl <30 mL/min (dialysis): 5 mg daily (after HD (hemodialysis) on HD days) 
 
7.2 
Lack of Response 
Patients will go off treatment to event monitoring if an MR is not seen after 2 cycles and 
a PR is not seen after 4 cycles. Confirmation of MR or PR is not required. 
 
7.3 
Patient return to Mayo Clinic 
For this protocol, the patient must return to the consenting institution (Mayo Clinic) for 
evaluation every 21 days on the days of infusion while receiving pembrolizumab. (If 
pembrolizumab has been discontinued these visits are not required.) In addition, the 
patient must return every 28 days on Day 1 of each cycle while receiving any study 
treatment. Treatment by a local medical doctor (LMD) is not allowed. 
 
7.4 
Stem cell collection and transplant 
Patients are allowed to collect stem cells and proceed to transplant any time after 4 cycles 
of initial therapy. If patient goes to transplant, they will go directly to event monitoring 
per Section 4.2 and the transplant should be reported on the event monitoring form. In the 
case that patients are unable to go to transplant due to other reasons, they can continue on 
study. In those cases, therapy may be interrupted for up to 4 weeks for the purpose of 
stem cell collection. Stem cells can be collected using standard institutional protocols. 
Any delay beyond 4 weeks should be discussed with the study PI prior to reinitiating 
protocol therapy.  
 
 
 


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Protocol version date: 22Jun2017 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Individual drugs can be dose reduced as per the table below 
depending on the adverse event attribution. Thereafter, these modifications should be regarded as 
guidelines to produce mild-to-moderate, but not debilitating, side effects. If multiple adverse 
events are seen, administer dose based on greatest reduction required for any single adverse event 
observed. Reductions apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1  
Dose Levels for each drug in the combination 
 
Pembrolizumab 
(Every 21 days) 
Lenalidomide 
(Days 1-21) 
Dexamethasone (Days 
1, 8, 15, 22) 
Starting 
dose 
200 mg  
25 mg 
40 mg 
-1 
 
15 mg 
20 mg 
-2 
 
10 mg 
12 mg 
-3 
 
5 mg 
4 mg 
-4 
 
Discontinue 
Discontinue 
 
Note: If pembrolizumab is discontinued, the patient may continue treatment with 
the remaining drugs. If lenalidomide is discontinued, patient will go to event 
monitoring. 
 
8.11 
Instruction for initiation of a new cycle of therapy  
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥1000/μL 
• 
The platelet count is ≥50,000/μL 
• 
Any other non-hematologic drug-related adverse event that may have 
occurred has resolved to ≤Grade 1 or baseline severity. 
If these conditions are not met on Day 1 of a new cycle, dosing should be 
delayed for 1 week. At the end of that time, the patient should be re-evaluated to 
determine whether the criteria have been met. If the patient continues to fail to 
meet the above-cited criteria, delay therapy and continue to re-evaluate. 
If any drug dosing was halted during the previous cycle and was restarted with a 
one-level dose reduction without requiring an interruption for the remainder of 
the cycle, then that reduced dose level will be initiated on Day 1 of the new 
cycle.  
If any drug dosing was omitted for the remainder of the previous cycle or if the 
new cycle is held due to known hematologic toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose 
reduction. If a new cycle of therapy cannot be restarted within 4 weeks of the 
scheduled Day 1 due to non-resolution of drug related toxicities, the patient will 
be removed from protocol therapy and will go to event monitoring. 
 
 
 


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Protocol version date: 22Jun2017 
8.2  
Dose modifications for pembrolizumab based on adverse events during a cycle 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Omit  
Pembrolizumab 
for Grade 
Timing for 
Restarting 
Pembrolizumab 
Pembrolizumab 
Discontinuation 
Gastrointestinal 
disorders 
Diarrhea or Colitis 
2-3 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
 
 
4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
Investigations 
AST, or ALT, or 
Blood bilirubin 
2 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose. 
 
 
3-4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes mellitus 
[if new onset]) or 
Hyperglycemia 
T1DM or 
3-4 
Omit pembrolizumab 
for new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with 
evidence of beta cell 
failure 
Resume pembrolizumab 
when patients are 
clinically and 
metabolically stable. 
Endocrine disorders 
Endocrine 
disorders – Other, 
specify: 
Hypophysitis 
2-4 
AE resolves to Grade 
0-1. Therapy with 
pembrolizumab can 
be continued while 
endocrine 
replacement therapy 
is instituted 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
Endocrine disorders 
Hyperthyroidism 
3 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
 
 
4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 


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Protocol version date: 22Jun2017 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Omit  
Pembrolizumab 
for Grade 
Timing for 
Restarting 
Pembrolizumab 
Pembrolizumab 
Discontinuation 
Endocrine disorders 
Hypothyroidism 
 
Therapy with 
pembrolizumab can 
be continued while 
thyroid replacement 
therapy is instituted 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
General disorders and 
administration site 
conditions 
Infusion related 
reaction 
2a 
AE resolves to Grade 
0-1 
Permanently discontinue 
pembrolizumab if AE 
develops despite 
adequate premedication  
 
 
3-4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
2 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
 
 
3-4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
Renal and urinary 
disorders 
Acute kidney 
injury or Chronic 
kidney disease  
(e g Renal failure 
or Nephritis) 
2 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
 
 
3-4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
 
All Other Drug-
Related Adverse 
Eventsb 
3 or severe 
AE resolves to Grade 
0-1 
AE does not resolve 
within 12 weeks of last 
dose or inability to 
reduce corticosteroid to 
10 mg or less of 
prednisone or equivalent 
per day within 12 weeks 
 
 
4 
Permanently 
discontinue 
pembrolizumab 
Permanently discontinue 
pembrolizumab 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related 
AE that recurs, or any lifethreatening event. 
a If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the next scheduled dose (Section 9.9f). 


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Protocol version date: 22Jun2017 
b Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs 
 Discontinue = The specified drug(s) are totally stopped 
 
 
 


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Protocol version date: 22Jun2017 
8.3  
Dose modifications for lenalidomide based on adverse events during a cycle 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Blood and 
lymphatic system 
disorders 
Febrile neutropenia 
associated with fever 
(temperature ≥38.5ºC) 
Lenalidomide Omit lenalidomide 
dose. 
Follow CBC weekly. 
If neutropenia has 
resolved to ≤Grade 2 
prior to Day 35, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 35.  
If neutropenia is the 
only toxicity for which 
a dose reduction is 
required, G-CSF may 
be used and the 
lenalidomide dose 
maintained 
Omit lenalidomide for 
remainder of cycle. 
See Section 8.11 for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level. 
If neutropenia is the 
only toxicity for which 
a dose reduction is 
required, G-CSF may be 
used and the 
lenalidomide dose 
maintained for the next 
cycle at the 
investigator’s 
discretion. 
Investigations 
Platelet count 
decreased 
≥Grade 3 (platelet 
count <50,000/mm³) 
Lenalidomide Omit lenalidomide 
dose 
Follow CBC weekly 
Hold anticoagulation 
until platelets >50,000 
If thrombocytopenia 
resolves to ≤Grade 2 
prior to Day 35, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 35 
Omit lenalidomide for 
remainder of cycle 
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo papular  
Grade 2 or 3. 
Lenalidomide Omit lenalidomide 
dose 
Follow weekly 
If the event resolves to 
≤Grade 1 prior to Day 
35, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 35 
Omit lenalidomide for 
remainder of cycle 
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Any rash  
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 


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Protocol version date: 22Jun2017 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Nervous System 
Disorders 
Peripheral sensory 
neuropathy 
Grade 3 
Lenalidomide Omit lenalidomide 
dose 
Follow at least weekly 
If the event resolves to 
≤Grade 1 prior to 
Day 35, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 35 
Omit lenalidomide for 
the remainder of the 
cycle. 
See Section 8.11 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Peripheral sensory 
neuropathy  
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
Lenalidomide Omit dose 
Follow at least weekly 
If the toxicity resolves 
to ≤Grade 1 prior to 
Day 35 restart at next 
lower dose level and 
continue the cycle 
until Day 35 
Omit lenalidomide for 
the remainder of the 
cycle 
If the adverse event 
resolves to ≤Grade 1, 
reduce dose 1 level in 
next cycle 
If adverse event recurs, 
discontinue therapy 
Grade 4 
Lenalidomide Discontinue 
lenalidomide 
Discontinue 
lenalidomide 
Vascular disorders 
Thromboembolic 
event 
≥Grade 3 
Lenalidomide Omit dose and start 
anticoagulation; restart 
at investigator’s 
discretion (maintain 
dose level) 
Omit lenalidomide for 
remainder of cycle and 
start anticoagulation. 
Maintain dose level in 
next cycle 
Kidney and Urinary 
System 
Renal Insufficiency 
Lenalidomide CrCl >50 mL/min: No 
adjustment 
CrCl 30-50 mL/min: 
10 mg/day 
CrCl <30 mL/min (no 
dialysis): 15 mg every 
48 hours 
CrCl <30 mL/min 
(dialysis): 5 mg daily 
(after HD 
(hemodialysis) on HD 
days) 
 


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Protocol version date: 22Jun2017 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION** Days 2-
14 of cycle 
ACTION** 
Day ≥15 of cycle 
Endocrine disorders Hyperthyroidism or 
Hypothyroidism 
≥Grade 2 
Lenalidomide Omit lenalidomide for 
remainder of cycle, 
evaluate etiology, and 
initiate appropriate 
therapy.  
See Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide 
by 1 dose level 
Omit lenalidomide for 
remainder of cycle, 
evaluate etiology, and 
initiate appropriate 
therapy.  
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level 
Other non-
hematologic adverse 
event 
Other non-
hematologic toxicity 
≥Grade 3 
Lenalidomide Omit lenalidomide 
dose 
Follow at least weekly 
If AE resolves to 
≤Grade 2 prior to 
Day 35, restart 
lenalidomide at next 
lower dose level and 
continue the cycle 
through Day 35 
Omit lenalidomide for 
remainder of cycle 
See Section 8.11, 
Instructions for 
Initiation of a New 
Cycle and reduce the 
dose of lenalidomide by 
1 dose level. 
 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs 
 Discontinue = The specified drug(s) are totally stopped 
 
 


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8.4 
Dose modifications for dexamethasone based on adverse events during a cycle 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Gastrointestinal 
disorders 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (Symptomatic; 
altered GI function; 
medical intervention 
indicated; limiting 
instrumental ADL ) 
Dexamethasone Treat with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose level. 
 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
≥Grade 3 (Severely altered 
GI function; TPN 
indicated; elective 
operative or endoscopic 
intervention indicated; 
limiting self care ADL; 
disabling) 
Dexamethasone Omit dexamethasone until symptoms 
adequately controlled. Restart one 
dose level below along with 
concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. If 
symptoms persist despite above 
measures, discontinue 
dexamethasone and do not resume. 
 
Pancreatitis 
≥Grade 3 (Severe pain; 
vomiting; medical 
intervention indicated 
(e.g., analgesia, nutritional 
support)) 
Dexamethasone 
Discontinue dexamethasone and do 
not resume. 
General disorders and 
administration site 
conditions 
Edema 
≥Grade 3 (limiting 
function and unresponsive 
to therapy or anasarca) 
Dexamethasone 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level; 
if edema persists despite above 
measures, decrease dose another dose 
level. Discontinue dexamethasone 
and do not resume if symptoms 
persist despite second reduction. 
Psychiatric disorders 
Confusion or Mood 
alteration 
≥Grade 2 (Severe 
disorientation; limiting 
self-care ADL) 
Dexamethasone Omit dexamethasone until symptoms 
resolve. Restart with one dose level 
reduction. If symptoms persist 
despite above measures, discontinue 
dexamethasone and do not resume. 
Musculoskeletal and 
connective tissue 
disorders 
Muscle weakness 
≥Grade 2 
Weakness limiting self 
care ADL; disabling 
Dexamethasone Decrease dexamethasone dose by one 
dose level; if weakness persists 
despite above measures decrease dose 
by one additional dose level. 
Discontinue dexamethasone and do 
not resume if symptoms continue to 
persist. 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Metabolism and 
nutrition disorders 
Hyperglycemia ≥Grade 3 
(>250 - 500 mg/dL;  
>13.9 - 27.8 mmol/L); 
hospitalization indicated 
Dexamethasone 
Treatment with insulin or oral 
hypoglycemics as needed.  
If uncontrolled despite above 
measures, decrease dose by one dose 
level at a time until levels are 
satisfactory. 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient 
does not make up the omitted dose(s) at a later time 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs 
 Discontinue = The specified drug(s) are totally stopped 
 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the three dose-
reduction steps (levels -1, -2 and -3) will be at the discretion of the Principal Investigator, if the 
decision is made for the patient to be kept on study. These dose reductions must be clearly recorded 
in reported clinical data.  
 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full Supportive Care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records.  
9.2 
Thromboprophylaxis 
All patients should receive aspirin 325 mg daily for thromboprophylaxis. For patients 
considered high risk for thrombosis, therapeutic anticoagulation with warfarin or low 
molecular weight heparin should be used 
9.3 
Steroid use 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
9.4 
Medications not permitted 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy 
• 
Any external beam radiotherapy 
9.5 
Use of growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947. 
9.6 
Bisphosphonates 
Patients may receive concurrent treatment with a bisphosphonate.  
9.7 
Pneumonitis:  
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
9.8 
Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
• 
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 


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Protocol version date: 22Jun2017 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
• 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
• 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
9.9a 
Type 1 diabetes mellitus  
If new onset, including diabetic ketoacidosis [DKA] or ≥ Grade 3 Hyperglycemia, if 
associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
9.9b 
Hypophysitis: 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
• 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
9.9c 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
• 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care 
• 
Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
9.9d 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 


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9.9e 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
9.9f 
Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
Table 9.9e1 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 9.9e1 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject 
should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine) 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic) 


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Protocol version date: 22Jun2017 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
 


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10.0 
Adverse Event (AE) Reporting and Monitoring  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP 
web:(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm) 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.5). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT). Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
10.2  
Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific 
consent form. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15.0 of the protocol and the study specific consent form. 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  


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10.31  AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
Routine Reporting 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent is stated 
in the protocol. See Section 10.6. 
• Routine AE reporting for Phase 3 clinical studies using an investigational 
agent/intervention and a commercial agent in combination must be reported as 
defined by the general guidelines provided by sponsors, Groups, Cancer Centers, 
or Principal Investigators. See Section 10.6. 
Expedited Reporting 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report. Refer to Section 10.4 for specific AE reporting requirements or 
exceptions. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch. 
• An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity, expedited reporting is required. The 
clinical investigator must determine severity. 
 
 
 




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Protocol version date: 22Jun2017 
10.42 Additional instructions: 
Mayo Clinic Cancer Center (MCCC) Institutions: Attach copies of 
MedWatch 3500A to Mayo Clinic Cancer Center SAE Reporting Form:  
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158-
56/Processes/MC4158-56-Process.MC4158-56 which will automatically be 
emailed to the MCCC Regulatory Affairs Unit (RAU) Risk Information 
Specialist at cancercrosafetyin@mayo.edu, who will determine and complete 
IRB reporting. The RAU will submit to the MCCC SAE Coordinator and the 
MCCC IND Coordinator. 
10.5 
Adverse event reporting requirements for Merck 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and at each examination on the Adverse Event case 
report forms/worksheets.  
10.51 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any 
dose of 1,000 mg or greater (≥5 times the indicated dose). No specific 
information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In 
the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported 
within 24 hours to the Sponsor and within 2 working days hours to Merck Global 
Safety. (Attn: Worldwide Product Safety; 
). 
10.52 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 
lactation in a subject (spontaneously reported to them), including the pregnancy 
of a male subject's female partner that occurs during the trial or within 120 days 
of completing the trial completing the trial, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier. All 
subjects and female partners of male subjects who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
 
. 


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Protocol version date: 22Jun2017 
10.53 Immediate Reporting of Adverse Events to Merck 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event  
Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time the consent is signed through 90 days 
following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck. 
10.54 SAE reports and any other relevant safety information are to be forwarded 
to the Merck Global Safety facsimile number: 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA, or other local regulators. Investigators will cross reference this 
submission according to local regulations to the Merck Investigational 
Compound Number (IND, CSA, etc.) at the time of submission. Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety;
) at the time of submission to 
FDA. 
All subjects with serious adverse events must be followed up for outcome. 
10.55 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be recorded as such on the Adverse Event case 
report forms/worksheets and reported within 24 hours to the Sponsor and within 
2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
 
) 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined above - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than 
or equal to 2X the upper limit of normal and, at the same time, an alkaline 


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Protocol version date: 22Jun2017 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology. The trial site 
guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent). 
 
10.56 Additional adverse events: 
A separate guidance document has been provided entitled “Event of Clinical 
Interest Guidance Document” (previously entitled, “Event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document”). This document can be 
found in Appendix 4 and provides guidance regarding identification, evaluation 
and management of ECIs and irAEs.  
ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever 
is earlier, need to be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
 
), regardless of attribution to study treatment, consistent with 
standard SAE reporting guidelines. 
Subjects should be assessed for possible ECIs prior to each dose. Lab results 
should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event. Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic 
causes. If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes. If no 
other cause is found, then it is assumed to be immune-related. 
10.6 
Special Situations for Expedited Reporting  
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events1 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious Adverse 
Events. Any protocol specific reporting procedures MUST BE SPECIFIED BELOW and 
will supercede the standard Expedited Adverse Event Reporting Requirements (see 
footnote 1):  
CTCAE 
System/Organ/Class 
(SOC) 
Adverse event/ 
Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported 
General disorders and 
administrations site 
conditions 
Fatigue 
≤Grade 3 
 
 
Gastrointestinal 
Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
Investigations 
Neutrophil count 
decreased 
≤Grade 4 
White blood cell count 
decreased 
≤Grade 4 


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Protocol version date: 22Jun2017 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse event/ 
Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported 
Lymphocyte count 
decreased 
≤Grade 4 
Platelet count 
decreased 
≤Grade 4 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
10.7 
Other Required Reporting 
10.71 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to as 
disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under an 
IND/IDE since they are considered to be a serious AE and must be reported to 
the sponsor as specified in 21 CFR 312.64(b). 
10.72 Death 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life. Death NOS: A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of 
the onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted. 


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Protocol version date: 22Jun2017 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to the investigational agent/intervention requires expedited 
reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last does of the 
investigational agent/intervention requires expedited reporting within 24 
hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
10.73 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE be reported. Three options are available to describe the 
event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.74 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting. 
 
10.75 Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events 
If a woman becomes pregnant or suspects that she is pregnant while participating 
in this study, she must inform the investigator immediately and permanently 
discontinue study drug. 
Suggested Pregnancy Reporting Form: 
• Pregnancy Report Form  
Use form available from the CTEP protocol development page: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/Pregna
ncyReportFormUpdated.pdf  
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies, along with the 
UPIRTSO cover sheet, by email to the MCCC Regulatory Affairs Unit (RAU) 
Risk Information Specialist at 
, who will 
determine and complete IRB reporting. The RAU will submit to the MCCC SAE 
Coordinator and the MCCC IND Coordinator to determine if FDA submission is 
needed. 
Non Mayo Clinic institutions: Submit forms via email to Mayo Clinic Cancer 
Center CRO 
 The CRO will submit to the MCCC SAE 
Coordinator and to the MCCC IND Coordinator. 


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Protocol version date: 22Jun2017 
10.8 
Required Routine Reporting 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
SYSTEM ORGAN CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
White Blood cell decreased (WBC) 
X 
X 
General disorders and 
administration site conditions 
Fatigue 
X 
X 
Gastrointestinal Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Baseline # of Stools 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 
Infections and infestations 
Sepsis 
X 
X 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
 
Febrile neutropenia 
X 
X 
Skin and subcutaneous tissue 
disorders 
Rash, maculopapular 
X 
X 
 
10.81 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.5: 
10.811 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.812 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.813 Grade 5 AEs (Deaths) 
10.8131  Any death within 30 days of the patient’s last study treatment 
or procedure regardless of attribution to the study treatment or 
procedure. 
10.8132 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with 
a CTCAE type and attribution assigned. 
10.83 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 


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Protocol version date: 22Jun2017 
11.0 
Treatment Evaluation 
The International Myeloma Working Group (IMWG) uniform response criteria (Rajkumar 
et al, 2011) will be used to assess response to therapy.  
11.1 
Terms and definitions 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.  
• M-proteins migrating in the β-region (usually IgA M-proteins)  
• Cases in which the M-spike is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
• Cases in which there are multiple peaks of same monoclonal protein 
(aggregates or dimers) 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted, with the exception that quantitative 
IgG may not be used. However, this must be explicitly reported at baseline, and only 
nephelometry can be used for that patient to assess response. SPEP derived M-spike 
values and quantitative nephelometric immunoglobulin values cannot be used 
interchangeably.  
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK). Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 
monoclonal kappa FLC. The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
• 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), and progressive disease 
(PD).  
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 
the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
• 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
o Serum M-protein ≥1 g/dl 
NOTE: Quantitative IgG may not be used for defining measurable disease 
o Urine M-protein ≥200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥10 mg/dl provided serum FLC ratio is 
abnormal 


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Protocol version date: 22Jun2017 
o Bone marrow plasma cells ≥30% 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is “measurable.” 
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR. Thus, both the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response. Patients included on the study on the basis of FLC alone (i.e., no 
measurable serum/urine m-spike) should be the only ones who are evaluated using 
FLC response criteria. The others should follow usual criteria and ignore FLC results 
with the exception of defining stringent complete response. 
• 
Evaluable disease: Patients who do not have a “measurable” serum M-spike, serum 
free light chain, or urine M-spike. 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-spike or urine M-spike, but has had a detectable monoclonal 
protein in his/her serum and/or urine and/or measurable serum free light chain.  
• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable monoclonal protein in his/her serum and/or urine. 
11.2  
Clarification of test indications 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.  
Table 11.21: Tests Required to Assess Response (Must Be Done at Each Disease 
Measurement Visit Except as Indicated1,2) 
On Study Baseline Value 
SPEP4 
24 hr 
UPEP2 
Ig 
FLC 
BM Bx 
Serum monoclonal protein ≥1 g/dl, and urine M-
spike ≥200 mg/24 hrs 
X 
X 
 
 
Serum monoclonal protein ≥1 g/dl, but urine M-
spike <200 mg/24 hrs 
X 
 
 
 
Serum monoclonal protein <1 g/dl, and urine M-
spike≥ 200 mg/24 hrs 
 
X 
 
 
Serum monoclonal protein <1 g/dl, urine M-spike 
<200 mg/24 hrs, but involved Ig FLC is ≥10 
mg/dL 
 
 
X 
 
Serum monoclonal protein <1 g/dl, urine M-spike 
<200 mg/24 hrs, involved Ig FLC is <10 mg/dL, 
bone marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow 
biopsy are required to document CR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to document 
sCR. SPEP and UPEP are required to document VGPR regardless of registration 
values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category. 


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Protocol version date: 22Jun2017 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response. Bone marrow biopsy results do not need to be repeated after 
documented response. 
4 If serum monoclonal protein is being followed by quantitative immunoglobulin levels 
derived from nephelometry or turbidometry, quantitative immunoglobulins are 
required. SPEP is only required to document CR or VGPR.  
11.3 
Confirmed response  
In order to be classified as a hematologic response, confirmation of serum monoclonal 
protein, serum immunoglobulin free light chain (when primary determinant of response) 
and urine monoclonal protein (when primary determinant of response) results must be 
made by verification on two consecutive determinations.  
• 
Bone marrow aspirate and biopsy are only required to document CR or sCR, 
except for patients with evaluable disease only, where a bone marrow is required 
to document all response categories including progression. However, a second 
confirmatory bone marrow is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements, 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
Appropriate tests required to document and confirm response are listed in Table 11.21. 
11.4 
Bone progression  
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone. Compression fracture does not exclude continued response 
and may not indicate progression. When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
11.5 
Response and Progression 
Criteria for response and progression are listed in Table 11.51. Progressive disease for all 
patients as defined in Table 11.51.  
Table 11.51 
CATEGORY 
RESPONSE CATEGORYa 
Stringent Complete Response 
(sCR) b 
• 
CR as defined plus 
• 
Normal FLC ratio and 
• 
Absence of clonal PCs by immunohistochemistry or 2- to 4- 
color flow cytometry i 
Complete Response (CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• ≤5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d 
Very Good Partial Response 
(VGPR) 
• Serum and urine M-component detectable by immunofixation but 
not on electrophoresis c or 
• ≥90% reduction in serum m-component and urine m-component 
<100 mg/24 h c 
• If the only measurable disease is FLC, a ≥90% reduction in the 
difference between involved and involved FLC levels 


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Protocol version date: 22Jun2017 
CATEGORY 
RESPONSE CATEGORYa 
Partial Response (PR) 
• If present at baseline, ≥50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein or to <200 mg/24hrs 
• If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and involved FLC levels 
• If the only measurable disease is BM, a ≥50% reduction in BM 
PC's (provided the baseline PC's was ≥30%) 
• If present at baseline, ≥50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR) 
• If present at baseline, ≥25% but <49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
• If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
• No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 
Progressive Disease (PD) b, h Increase of 25% from lowest value in any of the following f, g: 
• Serum M-component (absolute increase must be ≥0.5 mg/dL) 
AND/OR 
• Urine M-component (absolute increase must be ≥200 mg/24 hrs) 
AND/OR 
• If the only measurable disease is FLC, the difference between 
involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL)  
AND/OR 
• If the only measurable disease is BM, bone marrow PC percentage 
(absolute increase must be >10%) e 
Or any one or more of the following: 
• Development of new bone lesion or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytoma 
• Development of hypercalcemia (corrected serum calcium 
>11.5mg/dL) that can be attributed solely to the PC proliferative 
disorder 
Stable Disease (SD) 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at 
anytime before the institution of any new therapy; sCR, CR, VGPR, PR, MR and SD categories also 
require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments 
need not be confirmed. Each category, except for stable disease, will have a working subcategory of 
“unconfirmed” [prefix ‘u”] to designate first time point at which response category MAY have been 
achieved if confirmed. 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD. A 
positive immunofixation alone is not sufficient. 
c If more than one M protein spikes meet the criteria for measurable disease at baseline, then both need to 
be followed for response. Otherwise, only follow the measurable M protein spike for response.  
d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a 
normal FLC ratio of 0.26-1.65 in addition to the CR criteria listed above. 


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Protocol version date: 22Jun2017 
e Bone marrow criteria for PD are only to be used in patients without measurable disease by M protein and 
by FLC.  
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, 
soft tissue plasmacytoma or hypercalcemia. The lowest value does not need to be a confirmed value. If 
the lowest serum M-component is ≥5 g/dL, an increase in serum M-component of ≥1 g/dL is sufficient to 
define disease progression. 
g In the case where a value is felt to be a spurious result per physician discretion (for example, a possible 
lab error), that value will not be considered when determining the lowest value. 
h Progressive disease should be confirmed. However, treatment may be discontinued for progressive 
disease that is unconfirmed per physician discretion. In this case, an objective status of PD should be 
entered on the measurement form and progressive disease should be reported on the event monitoring 
form. 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is k/l of 4:1 or 1:2.  
 
12.0 
Descriptive Factors  
12.1 
Parameters followed for hematologic response (pick one): serum monoclonal protein 
≥1 g/dL and urine M-spike ≥200 mg/24 hours vs. serum monoclonal protein ≥1g/dL only 
vs. urine M-spike ≥200 mg/24 hours only vs. serum immunoglobulin free light chain 
≥10 mg/dL.  
NOTE: Distinguish between SPEP measurement versus quantitative IgA measurement 
for serum monoclonal protein. 
 
 


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Protocol version date: 22Jun2017 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Categories of response 
Patients who are sCR, CR, VGPR, PR, MR, or (or usCR, uCR, uVGPR, uPR, uMR) will 
continue treatment per protocol. Patients will go off treatment to event monitoring if an 
MR is not seen after 2 cycles and a PR is not seen after 4 cycles. Confirmation of MR or 
PR is not required. 
13.2 
Patients who receive transplant 
Patients who receive a transplant will go to event monitoring per Section 18.0. The 
transplant should be reported on the event monitoring form. 
13.3 
Progressive disease or alternate therapy 
Patients who develop progressive disease or start alternate therapy will go to the event-
monitoring phase per Section 18.0. 
13.4 
Off protocol for reasons other than PD 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
13.5 
Discontinuation for unacceptable AEs 
Patients who discontinue therapy for an unacceptable adverse event(s) will be followed 
until resolution or stabilization of the AE(s). 
13.6 
Criteria for Patient Withdrawal from Study Treatment 
Patients may be withdrawn from the study for the following reasons: 
• 
Progressive multiple myeloma 
• 
Patient refuses further treatment on the trial 
• 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
• 
The Investigator withdraws the patient in the patient’s best interests 
• 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions) 
• 
Administrative reasons (e.g., the patient is transferred to hospice care) 
• 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early. 
13.7 
Criteria for Study Discontinuation 
The study may be temporarily or permanently discontinued at any site and at any time. 
Reasons for study discontinuation may include, but are not limited to, the following: 
• 
Safety concerns 
• 
Poor enrollment 
• 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 


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Protocol version date: 22Jun2017 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons. In the case of such termination, the 
Investigator will notify the IRB. 
13.8 
Patient Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.9a 
Patient major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
13.9b Patient cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 


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Protocol version date: 22Jun2017 
14.0 
Body Fluid Biospecimens  
 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be collected for IRB #521-93 :  
 
Correlative 
Study 
(Section for 
more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycles ≥5 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
End of 
cycle 
End of 
cycle 
End of 
cycle 
End of 
cycle 
PDL1 
expression 
(14.41) 
Mandatory Marrow 
ACD 
(yellow) 
6 ml per 
tube (3) 
X 
 
 
 
X 
Any 
subsequent 
marrow 
No 
Kool-pak 
Immune 
markers 
(14.42) 
Mandatory 
Blood 
ACD 
(yellow) 
6 mL 
(4) 
X 
X 
X 
X 
X 
At 
progression 
No 
Kool-pak 
 
14.2 
Collection and Processing:  
14.21 Samples are to be shipped the same day as they are collected. No processing is required at the sites. 
14.3 
Shipping and Handling 
14.31 Kits 
14.311 Kits will be used for this study. Kits will contain supplies and instructions for collection, processing and shipping 
specimens 
14.312 Participating sites may obtain kits by emailing: 
 Email requests should include 
address, contact information and number of kits being requested. 
14.313 Kits will be sent via FedEx Ground at no additional cost to participating sites. Allow 3-4 business days to receive 
kits. 
 
 




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Protocol version date: 22Jun2017 
15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background: Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation:  
Pembrolizumab (MK-3475) Solution for Infusion is a sterile, non-pyrogenic 
aqueous solution supplied in single-use Type I glass vial containing 100 mg/4 
mL of pembrolizumab (MK-3475). The product is preservative-free solution 
which is essentially free of extraneous particulates.s available as a liquid 25 
mg/mL, 100 mg/vial.  
15.13 Preparation and storage:  
Vials should be stored in the refrigerator at temperatures between 2-8°C.  
Drug concentrate is further diluted with normal saline (or 5% dextrose) in the 
concentration range of 1 to 10 mg/m)  in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material.  Reconstituted vials should be immediately 
used to prepare the infusion solution in the IV bag and the infusion solution 
should be immediately administered.  Diluted pembrolizumab solutions may be 
stored at room temperature for a cumulative period of up to 4 hours. This 
includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion.  In addition, IV bags can be stored at 2-8 °C for up to a 
cumulative time of 20 hours. 
15.14 Administration: 
Pembrolizumab is administered by intravenous infusion over 30 minutes via a 
0.22 micron in-line filter. The final infusion volume must be between 1 and 10 
mg/mL. Maximum rate of infusion should not exceed 6.7 mL/minute through a 
peripheral or indwelling catheter. Flush the line with 0.9% NaCL following the 
completion of the infusion. 
15.15 Pharmacokinetic information: 
a) Absorption – Steady-state is predicted to be achieved after ~18 weeks of 
repeated dosing, with ~2.2-fold accumulation in exposure during 
administration Q3W relative to exposure observed following single dose 
administration. The majority (~81%) of this accumulation has occurred by 
the fourth dose. In the dose range studied for efficacy (2 to 10 mg/kg), 
pembrolizumab exposure increases in a dose-proportional manner, with 
clearance being independent of time or pembrolizumab concentration. 
b) Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion – The systemic clearance of pembrolizumab is ~0.22 L/day and the 
terminal elimination half-life (t½) is estimated to be ~26 days.  
d)  Metabolism - Pembrolizumab is catabolized by general protein degradation 
processes; typical small molecule metabolic pathways (eg, cytochrome P450 
enzymes, glucuronosyltransferases) do not contribute to its clearance. 
15.16 Potential Drug Interactions: There are no known significant drug interactions.  
15.17 Known potential toxicities:  
Common known potential toxicities, > 10%:   


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Protocol version date: 22Jun2017 
 
Dermatologic: Pruritus, skin rash 
Gastrointestinal: diarrhea  
 
Neuromuscular & skeletal: arthralgia, back pain 
 
Respiratory:  Cough 
 
 
Less common known potential toxicities, 1% - 10%: 
 
Infusion related reactions 
 
Dermatologic:  vitiligo, severe skin reactions 
Endocrine & metabolic: Hypothyroidism, hyperthyroidism, hyponatremia 
 
Gastrointestinal: Colitis, abdominal pain 
 
Respiratory:  Pneumonitis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Secondary adrenocortical insufficiency (immune-mediated), hepatitis (including 
autoimmune hepatitis), hypophysitis, nephritis, Guillain-Barre syndrome 
(immune-mediated), myositis (immune-mediated), pancreatitis (immune-
mediated), uveitis (immune-mediated),  and Type 1 diabetes mellitus. 
Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and   Immune-mediated 
myocarditis 
Two important potential risks have been identified, although the data available 
thus far for these events does not provide sufficient evidence of a causal 
relationship to pembrolizumab. The two important potential risks are: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and venoocclusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors. The Sponsor continues to monitor and collect data 
on these potential risks in order to further characterize their potential relationship 
to Pembrolizumab. 
 
15.18 Drug procurement: Pembrolizumab will be provided free of charge to study 
participants by Merck. 
15.19 Nursing Guidelines:  
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen however is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per Section 9.0 and monitor for effectiveness.  


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Protocol version date: 22Jun2017 
15.194 
Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well” . Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD.  
15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizimab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines. 
15.199b  Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
Pemrbolizumab. 
15.2 
Lenalidomide (Revlimid®, CC-5013, CDC-501)  
15.21 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
15.22 Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 
15-, 20-, and 25-mg capsules for oral administration. Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. The lenalidomide capsules are supplied in push-through 
blister foil or tamper-evident, child-resistant, opaque, high-density polyethylene 
(HDPE) containers with HDPE caps. 
15.23 Preparation and storage: Lenalidomide should be stored at room temperature, 
between 59 and 86ºF (15-30ºC). Store drug away from direct sunlight.  


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15.24 Administration: Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules. 
15.25 Pharmacokinetic information: 
a) Absorption – Lenalidomide is rapidly absorbed following oral administration 
to healthy subjects, with maximum plasma concentrations occurring between 0.5 
and 1.5 hours post-dose. Co administration with a high-fat and high-calorie meal 
in healthy subjects reduced the extent of absorption, resulting in an 
approximately 20% decrease in AUC and 50% decrease in Cmax in plasma.  
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation. In 
plasma, the relative exposures of the S- and R-enantiomers of lenalidomide are 
approximately 55% and 45% respectively. 
b) Distribution – In vitro (14C)-lenalidomide binding to plasma proteins was low, 
with mean plasma protein binding at 22.7% and 29.2% in multiple myeloma 
subjects and healthy volunteers, respectively. In a multiple dose study in healthy 
subjects administered 25 mg/day for 4 days, a small amount of lenalidomide 
(<0.01% of the dose) was detected in semen. Three days after stopping the drug, 
the amount of drug in semen was undetectable. 
c) Metabolism – Results from in vitro metabolism studies showed that 
lenalidomide was neither metabolized by nor inhibited or induced the CYP 
pathway. In healthy subjects, lenalidomide undergoes limited metabolism and the 
parent compound is the predominant circulating component. 
d) Excretion – Approximately 65% to 85% of lenalidomide is eliminated 
unchanged through urinary excretion in subjects with normal renal function. The 
half-life of elimination is approximately 3 to 4 hours at the clinically relevant 
doses (5 to 50 mg/day). Steady-state levels are achieved within 4 days. 
Analyses in subjects with impaired renal function indicate that as renal function 
decreases, the total drug clearance decreases proportionally resulting in an 
increase in AUC. The t½ of lenalidomide of lenalidomide was longer by 
approximately 6 to 12 hours in subjects with moderate or worse RI. 
15.26 Potential Drug Interactions: 
Results from human in vitro metabolism studies indicated that lenalidomide is 
not metabolized by CYP enzymes, suggesting that administration of lenalidomide 
with drugs that inhibit CYP enzymes is not likely to result in metabolic drug 
interactions. Lenalidomide did not inhibit or induce marker enzyme activities for 
human CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro. In cultured human 
hepatocytes, lenalidomide did not induce the catalytic activities of CYP1A2, 
2B6, 2C9, 2C19, or 3A4/5. Results from in vitro studies showed that 
lenalidomide is not a substrate of human MRP1, MRP2, or MRP3 efflux 
transporters. Results from in vitro studies also demonstrated that lenalidomide is 
not a substrate of human OAT1, OAT3, OATP1B1 (OATP2), nor OCT1. 
Lenalidomide is a weak substrate of P-glycoprotein, but does not inhibit P-
glycoprotein. Therefore, clinically relevant drug-drug interactions are unlikely 
between lenalidomide and P-glycoprotein substrates or inhibitors. 
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on 
the single dose pharmacokinetics of R- and S-warfarin. Co-administration of 


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single 25-mg dose warfarin had no effect on the pharmacokinetics of 
lenalidomide. However, it is not known whether there is an interaction during 
clinical use.  
Concomitant administration with lenalidomide 10 mg/day increased the plasma 
exposure of digoxin (0.5 mg, single dose) by 14%. It is not known whether the 
effect will be different in the therapeutic situation (higher lenalidomide doses and 
concomitant treatment with dexamethasone).  
15.27 Known potential toxicities: 
Pregnancy Warning: Lenalidomide is structurally related to thalidomide, a known 
human teratogen. Therefore, in an effort to prevent to the greatest extent possible 
any chance of fetal exposure, lenalidomide is available through a controlled 
distribution program, specifically a pregnancy prevention program called 
Revlimid REMS. It is contraindicated in women who are or may become 
pregnant. Female subjects of childbearing potential are required to submit to 
regular pregnancy testing, and to agree to use effective forms of birth control as 
outlined in study protocols. Male subjects, even those who have had a 
vasectomy, must agree to use a condom during sexual contact with a pregnant 
woman or a woman who can become pregnant. 
Very Common AEs (≥10%): anemia, febrile neutropenia, leukopenia, 
neutropenia, thrombocytopenia, cataracts, blurred vision, abdominal pain, 
constipation, diarrhea, dyspepsia, nausea, vomiting, asthenia, chills, edema 
including peripheral, fatigue, pyrexia, abnormal liver function tests, bacterial, 
viral and fungal infections (including opportunistic infections), bronchitis, 
nasopharyngitis, sinusitis, pneumonia, rhinitis, upper respiratory tract infection, 
urinary tract infection weight decreased, decreased appetite, hyperglycemia, 
hypocalcemia, hypokalemia, arthralgia, back pain, bone pain, muscle spasms, 
musculoskeletal pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, 
hypoesthesia, neuropathy peripheral, neuropathy, tremor, depression, insomnia, 
renal failure, cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry 
skin, pruritus, rash, and deep vein thrombosis.  
Common (≥1% and <10%):  granulocytopenia, hemolytic anemia, 
lymphopenia, pancytopenia, acute myocardial infarction, atrial fibrillation, 
cardiac failure, congestive heart failure, myocardial ischemia,   tachycardia, 
vertigo, upper abdominal pain, dry mouth,   toothache, chest pain, fall, 
cholestasis, bacteremia, cellulitis, erysipelas, gastroenteritis, herpes simplex, 
herpes zoster, influenza, lower respiratory infection, respiratory infection, sepsis, 
contusion, alanine aminotransferase increased, c-reactive protein increased, 
gamma-glutamyltransferase increased, dehydration, diabetes mellitus, gout, 
hypercalcemia, hyperuricemia, hypophosphatemia, hypomagnesemia, 
hyponatremia, iron overload, muscular weakness, acute myeloid leukemia,    
basal cell carcinoma, Myelodysplastic syndrome, squamous cell carcinoma of 
skin, T-cell type acute leukemia, tumor flare, tumor lysis syndrome, 
cerebrovascular accident, lethargy, paresthesia, peripheral sensory neuropathy, 
syncope, mood altered, renal failure, respiratory distress, erythema, 
hyperhidrosis, night sweats, hematoma, hypertension, hypotension, peripheral 
ischemia, thrombosis, and vasculitis. 
Uncommon, limited to important or life-threatening (<1%): hypersensitivity, 
Graft vs. Host Disease, viral reactivation (such as hepatitis B virus or herpes 
zoster), DRESS.  


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The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be possibly 
related to the administration of lenalidomide: granulocytopenia, cataract, vision 
blurred, abdominal pain upper, dry mouth, gastrointestinal motility disorder, 
toothache, fall, herpes simplex, influenza, rhinitis, hyperuricemia, 
hypophosphatemia, iron overload, musculoskeletal pain, dysgeusia, headache, 
paresthesia, dry skin, hyperhidrosis, and pruritus. 
Please refer to the Investigator Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
15.28 Drug procurement and accountability: 
As a requirement of the REMS program, access to Lenalidomide is restricted. 
Lenalidomide is approved for marketing only under a FDA approved, restricted 
distribution program called REVLIMID REMS (www.REVLIMIDREMS.com) 
formerly known as the RevAssist program. Physicians, pharmacies, and patients 
must be registered; a maximum 28-day supply may be dispensed; a new 
prescription is required each time it is filled; pregnancy testing is required for 
females of childbearing potential. 
Drug will be shipped directly to the patient through Revlimid REMS Program. 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS™  program. 
15.29  Nursing Guidelines 
15.291 The most common side effects are neutropenia and thrombocytopenia.  
15.292 Due to the highly teratogenic potential of the closely related thalidomide, 
it is highly recommended that all women of childbearing age group and 
all men use effective contraception during therapy. All staff who are 
pregnant or who can become pregnant should not handle this drug 
outside of its original packaging. 
15.293 Instruct patient to report any rash immediately to the study team.  
15.294 Lenalidomide capsules should be swallowed whole, and should not be 
broken, chewed or opened.   
15.295 If a dose of lenalidomide is missed, it should be taken as soon as possible 
on the same day. If it is missed for the entire day, it should not be made 
up. 
15.296 Patients who take more than the prescribed dose of lenalidomide should 
be instructed to seek emergency medical care if needed and contact study 
staff immediately. 
15.3 
Dexamethasone for Oral Administration (DXM) 
15.31 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
15.32 Formulation: Commercially available for oral administration as:  
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg. 


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Solution, oral: 0.5 mg/mL (500 mL). 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL). 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
15.34 Administration: Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
15.35 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw (Uncaria tomentosa), echinacea 
(have immunostimulant properties) 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, frequency not defined:  
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 


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convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.39 Nursing Guidelines: 
15.391 Monitor patient regularly for hypertension, CHF and other evidence of 
fluid retention. 
15.392 Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis. Instruct patient to report any 
suspected changes to healthcare team. 
15.393 Assess for symptoms of gastric ulcer, heartburn, or gastritis. Suggest 
antacids. Instruct patient to report symptoms to healthcare team if unable 
to control. 
15.394 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
15.395 Monitor blood glucose frequently. 
15.396 Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
15.397 Advise patient that easy bruising is a side effect. 
 
 


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16.0  
Statistical Considerations and Methodology  
16.1 
Overview 
This is a phase II study of a novel regimen of pembrolizumab with lenalidomide and 
dexamethasone for initial treatment of newly diagnosed multiple myeloma patients 
requiring therapy. This study is designed to assess the VGPR or better response rate 
associated with therapy with pembrolizumab added to standard doses of lenalidomide and 
dexamethasone, in patients with previously untreated multiple myeloma using a single 
stage phase II study design with an interim analysis. 
16.11 
Endpoint: The primary endpoint of the trial is the rate of complete or very good 
partial response after 4 cycles of induction treatment. A success will be defined 
as an sCR, CR, or VGPR noted as the objective status on two consecutive 
evaluations. Response will be evaluated using the first 4 cycles of induction 
therapy. Throughout Section 16.0, sCR, CR, or VGPR will be considered 
synonymous with “success” in the phase II portion, unless specified otherwise.  
16.12 
Sample Size: The single-stage study design with an interim analysis to be used is 
fully described below. A minimum of 13 and a maximum of 37 evaluable 
patients will be accrued in the phase II study unless undue toxicity is 
encountered. We anticipate accruing an additional 4 patients to account for 
ineligibility, cancellation, major treatment violation, or other reasons for a 
maximum of 41 patients. 
16.13 
Accrual Rate and Study Duration: The anticipated accrual rate is 2-3 evaluable 
multiple myeloma patients per month. At this rate, it will likely take about 1.5 
years to enroll the patients. The maximum total study duration is expected to be 
approximately 2 years, or until the last patient accrued has been observed for at 
least 6 months. 
16.2  
Statistical Design: 
16.21 Decision Rule:  
A combination of lenalidomide plus dexamethasone, an oral regimen, is the 
mainstay therapy for newly diagnosed multiple myeloma. In a large multi-center 
study, 208 patients were evaluated for response to treatment with lenalidomide 
plus low dose dexamethasone.6 Forty-nine patients (24%) achieved a complete or 
very good partial response. An increase in the rate of complete plus very good 
partial response with the addition of pembrolizumab to lenalidomide plus 
dexamethasone would be of interest. 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 25%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 45%. The following one-stage design with an interim 
analysis is based on a Simon optimum design13 and requires 37 evaluable patients 
to test the null hypothesis that the true success proportion in this patient 
population is at most 25%.  
16.211 
Interim Analysis: Enter 13 evaluable patients into the study. If 3 or 
fewer successes are observed in the first 13 evaluable patients, we will 
consider this regimen ineffective in this patient population and 
terminate this study. Otherwise, if the number of successes is at least 4, 
we will continue accrual. 


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16.212 
Final Decision Rule: Enter an additional 24 evaluable patients into the 
study. If 12 or fewer successes are observed in the first 37 evaluable 
patients, we will consider this regimen ineffective in this patient 
population. Otherwise, if the number of successes is at least 13, this 
will be considered evidence of promising activity and the treatment 
may be recommended for further testing in subsequent studies. 
16.213 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process. Analyses involving over accrued 
patients are discussed in Section 16.34. 
16.214  
NOTE: We will not suspend accrual at the interim analysis to allow the 
first 13 patients to become evaluable, unless undue toxicity is 
observed. Given the limited overall sample size and the inclusion of an 
adverse events stopping rule, we feel it is ethical to not halt accrual for 
the interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients 
16.22 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping after the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
If the true success proportion is.. 
0.25 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring that 
the regimen warrants further study is… 
0.092 
0.256 
0.485 
0.703 
0.856 
And the probability of stopping after 
the interim analysis is … 
0.584 
0.421 
0.278 
0.169 
0.093 
16.23 Other considerations: Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
16.3 
Analysis Plan 
16.31 Primary Outcome Analyses: 
16.311 Definition: The primary endpoint in the phase II portion of this trial is 
the proportion of complete plus very good partial responses after 4 cycles 
of induction treatment. A success is defined as an sCR, CR, or VGPR 
noted as the objective status on two consecutive evaluations. Response 
will be evaluated using the first 4 cycles of induction therapy. All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response, with the 
exception of patients who are determined to be a major violation. 
16.312 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. 


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Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner (Duffy D 1987). 
16.32 Secondary Outcome Analyses 
16.321 The ≥PR response rate after 4 cycles of induction treatment with 
pembrolizumab added to lenalidomide and dexamethasone will be 
estimated by the number of patients who achieve a PR, VGPR, CR, or 
sCR after 4 cycles divided by the total number of evaluable patients. 
Exact binomial 95% confidence intervals for the true success rate will 
be calculated. 
16.322 The ≥VGPR response rate at any time during treatment with 
pembrolizumab added to lenalidomide and dexamethasone will be 
estimated by the number of patients who achieve a VGPR, CR, or sCR 
at any time divided by the total number of evaluable patients. Exact 
binomial 95% confidence intervals for the true success rate will be 
calculated. 
16.323 Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier7.  
16.324 Progression-free survival is defined as the time from registration to the 
earliest date of documentation of disease progression or death due to 
any cause. Patients who receive subsequent treatment for myeloma 
before disease progression will be censored on the date of their last 
disease assessment prior to initiation of the subsequent treatment. 
Transplant will not be considered subsequent treatment. The distribution 
of progression-free survival will be estimated using the method of 
Kaplan-Meier 
16.325 Adverse Events: All eligible patients that have initiated treatment will be 
considered evaluable for assessing adverse event rate(s). The maximum 
grade for each type of adverse event will be recorded for each patient, 
and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
16.326 The success rate of stem cell collection following initial therapy with the 
combination of pembrolizumab, lenalidomide and dexamethasone in 
patients with newly diagnosed MM will be estimated by the number of 
patients with a successful stem cell collection divided by the total 
number of evaluable patients. Exact binomial 95% confidence intervals 
for the true success rate will be calculated. 
16.33  Correlative Analyses (IRB#521-93) 
16.331 PDL-1 expression on myeloma cells and non-tumor cell compartments 
from the bone marrow will be assessed at baseline. Each measure will be 
summarized descriptively by median, min, max and interquartile range.  
16.332 Markers of T-cell activation and exhaustion will be summarized 
descriptively by median, min, max, and interquartile range at each time 
point. Patterns over time will be summarized by absolute difference or 
relative change. Changes across time will be assessed using paired 


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analyses, including Wilcoxon signed rank tests. Jitplots will be used to 
visually examine differences between groups for continuous factors. 
16.333 NK cell function and numbers will be summarized descriptively by 
median, min, max, and interquartile range at each time point. Patterns 
over time will be summarized by absolute difference or relative change. 
Changes across time will be assessed using paired analyses, including 
Wilcoxon signed rank tests. Jitplots will be used to visually examine 
differences between groups for continuous factors. 
16.34 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final endpoint 
estimates and confidence intervals. 
16.4 
Data & Safety Monitoring: 
16.41 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.42 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy 
one of the following: 
• 
if 5 or more patients in the first 15 treated patients experience a Grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
• 
if after the first 15 patients have been treated, 40% of all patients experience 
a Grade 4 or higher non-hematologic adverse event at least possibly related 
to treatment. 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.5 
Results Reporting on ClinicalTrials.gov: 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 2 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 


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16.6 
Inclusion of Women and Minorities 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.63 The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
Accrual Estimates by Gender/Ethnicity/Race  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
14 
26 
0 
40 
Ethnic Category: Total of all subjects* 
14 
27 
0 
41 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
13 
26 
0 
39 
Racial Category: Total of all subjects* 
14 
27 
0 
41 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino. 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands have been recorded as 
Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 




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18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be 
considered “not received” and will not be edited or otherwise processed until the 
missing information is received. A list of the missing documents will be made 
available to the appropriate site coordinator. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated 
monthly. The listings will be sorted by location and will include the patient study 
registration number. The appropriate site coordinator will be responsible to 
obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to 
the appropriate site coordinator who will make the correction and return the 
query and documentation of correction back to the QAS.  
 
19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care, study drugs lenalidomide and 
dexamethasone 
 
19.2 
Tests to be research funded: study drug pembrolizumab 
 
19.3 
Other budget concerns: None 
 
 
 


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20.0 
References 
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to Evaluate the Efficacy and Safety of 2 CDC-5013 Dose Regimens When Used Alone or in 
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Multiple Myeloma (MM). Blood. 2003;102:235a. 
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3. Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of lenalidomide plus high-dose 
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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html