Pembrolizumab in Treating Patients With Intermediate or High-Risk Smoldering Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the overall response rate after 8 cycles of treatment according to the
International Myeloma Working Group Criteria (IMWG).

SECONDARY OBJECTIVES:

I. To determine time to progression to multiple myeloma (TTP) at 30 months from study entry.

II. To determine overall survival (OS). III. To determine duration of response (DOR). IV. To
determine the clinical benefit rate (CBR) after 8 cycles of treatment according to the
modified IMWG Criteria for multiple myeloma (MM).

V. To evaluate safety and tolerability of single agent treatment in this population.

TERTIARY OBJECTIVES:

I. Rate of minimal residual disease (MRD) negativity at complete remission (CR).

II. Molecular profiling (including whole exome sequencing and gene expression profiling) and
cellular (including flow cytometry) profiling at baseline and/or at progression using bone
marrow aspirate samples and peripheral blood.

III. Immunophenotypic characterization of dendritic, T-, B-, natural killer (NK)- and natural
killer T (NKT)-cells, and inhibitory/activation markers on tumor cells at baseline and at
completion of 8 cycles of therapy in bone marrow aspirate samples and/or peripheral blood.

IV. Evaluation of changes in PD-L1 and PD-1 expression at baseline/end of 8 cycles of
treatment and correlate with clinical response.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for up to 24 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Inclusion Criteria:

- Adult patients with intermediate or high-risk smoldering multiple myeloma (SMM) are
eligible; patients need to have clonal bone marrow plasma cells >= 10% and/or
monoclonal spike in blood of >= 3 g/dL and/or monoclonal urine component (Bence jones
proteinuria) >= 500 mg/24 hours and need to meet subject inclusion criteria and
exclusion criteria as per below

- Patients must have histologically confirmed SMM based on the following criteria:

- (A) Mayo clinic criteria (patient must have at least 2 risk factors present):

- 1. Bone marrow core biopsy plasma cell involvement by cluster of
differentiation (CD)138 immunohistochemistry >= 10%

- 2. Monoclonal spike >= 3 g/dL

- 3. Free light chain ratio in serum < 0.125 or > 8; *2 of 3 risk factors:
intermediate risk for progression at a rate of 51% at 5 years, *3 of 3 risk
factors: high risk for progression at a rate of 76% at 5 years

- OR (B) Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) criteria
(patient must have at least 1 risk factor present)

- 1. >= 95% abnormal plasma cells/total plasma cells in bone marrow
compartment

- 2. Immunoparesis *1 of 2 risk factors: intermediate risk for progression at
a rate of 46% at 5 years, *2 of 2 risk factors: high risk for progression at
a rate of 72% at 5 years

- OR (C) Southwestern Oncology Group (SWOG) criteria (patient must have 2 risk
factors present or one risk factor if this risk factor is a 70-gene signature
(GEP70) score of > 37.2)

- 1. Monoclonal spike >= 3 g/dL

- 2. Involved free light chain >= 25 mg/dL

- 3. GEP70 risk score > 37.2 *>= 2 risk factors: high risk of progression at a
rate of 70% at 2 years*; we would also include patients with 1 risk factor
as long as this risk factor is GEP70 risk score > 37.2 since patients with
this risk factor have an intermediate risk of progression at a rate of 50%
at 2 years

- Creatinine clearance >= 50 ml/min; creatinine clearance (CrCl) will be calculated by
Cockcroft-Gault method

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

- Absolute neutrophil count (ANC) >= 1.0 x 10^9 /L

- Hemoglobin >= 10 g/dL

- Platelet count >= 50 x 10^9/L

- Bilirubin < 1.5 x the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN

- Subjects must be able to give informed consent

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; if
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required

- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

- Evidence of myeloma defining events or biomarkers of malignancy due to underlying
plasma cell proliferative disorder meeting at least one of the following

- 1) Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper
limit of normal or > 2.75 mmol/L (> 11 mg/dL)

- 2) Renal insufficiency: creatinine clearance < 40 ml/min or serum creatinine > 2
mg/dL

- 3) Anemia: hemoglobin value < 10 g/dL or 2 g/dL < normal reference

- 4) Bone lesions: one or more osteolytic lesions on skeletal radiography,
computerized tomography (CT) or 2-deoxy-2[F-18] fluoro-D-glucose positron
emission tomography CT (PET-CT)

- 5) Clonal bone marrow plasma cell percentage >= 60%

- 6) Involved: uninvolved serum free light chain ratio >= 100 measured by Freelite
assay (The Binding Site Group, Birmingham, United Kingdom [UK])

- 7) > 1 focal lesions on magnetic resonance imaging (MRI) studies (each focal
lesion must be 5 mm or more in size), if clinically indicated

- Prior or concurrent systemic treatment for SMM; a) bisphosphonates are permitted; b)
treatment with corticosteroids is not permitted; c) radiotherapy is not permitted; d)
prior treatment for smoldering multiple myeloma with chemotherapy agents approved for
the treatment of multiple myeloma is not permitted

- Plasma cell leukemia

- Pregnant or lactating females; breastfeeding should be discontinued if the mother is
treated with pembrolizumab

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

- Has a known history of active TB (bacillus tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has 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); replacement therapy (eg., 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

- Has an active infection requiring systemic therapy

- Has a 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

- Has 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

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death
ligand 2 (PD-L2) agent

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has 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)

- Has received a live vaccine within 30 days of planned start of study therapy; Note:
seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
attenuated vaccines, and are not allowed

- Evidence of interstitial lung disease