Pembrolizumab, Lenalidomide, and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma Eligible for Stem Cell Transplant

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.

Inclusion Criteria:

- Diagnosis and previously untreated active multiple myeloma by International Myeloma
Working Group (IMWG) diagnostic criteria for multiple myeloma

- Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 75000/mm^3

- Hemoglobin >= 8.0 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

- 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, dehydroepiandrosterone (DHEA), anakinra,
pamidronate, or zoledronic acid is permitted; any additional agents not listed
must be approved by the principal investigator

- Measurable disease of multiple myeloma as defined by at least ONE of the following:

- Serum monoclonal protein >= 1.0 g/dL

- > 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

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Provide written informed consent

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Willing to follow strict birth control measures as suggested by the study

- 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

- Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject (periodic abstinence [e.g., calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)

- 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 [e.g., calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Willing to provide consent to Institutional Review Board (IRB) number (#) 521-93 and
provide research tissue and blood specimens

Exclusion Criteria:

- Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma

- Prior cytotoxic chemotherapy or corticosteroids for the treatment of multiple myeloma

- NOTE: Prior corticosteroid use for the treatment of non-malignant disorders is
permitted

- 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

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Other co-morbidity which would interfere with patient's ability to participate in
trial, e.g. uncontrolled infection, uncompensated heart or lung disease

- 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

- Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain during
the screening period

- Major surgery =< 14 days prior to study registration

- 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

- Participation in any other clinical trials with other investigational agents not
included in this trial, =< 21 days prior to registration

- 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 (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.)
is not considered a form of systemic treatment

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Active infection requiring systemic therapy

- 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

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial

- 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

- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Received a live vaccine =< 30 days of planned start of study therapy