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

Early Phase 1

Active, not recruiting

Conditions: Smoldering Plasma Cell Myeloma

Interventions: Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab

Registration Number: NCT02603887

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: This pilot early phase I trial studies pembrolizumab in treating patients with slow growing (smoldering) multiple myeloma with intermediate or high-risk of spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description: PRIMARY OBJECTIVE:

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.

EXPLORATORY 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 20

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%
  - 1. Monoclonal spike >= 3 g/dL
  - 1. 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
  - 1. 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
  - 1. Involved free light chain >= 25 mg/dL
  - 1. 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)
- 1. Renal insufficiency: creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dL
- 1. Anemia: hemoglobin value < 10 g/dL or 2 g/dL < normal reference
- 1. 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)
- 1. Clonal bone marrow plasma cell percentage >= 60%
- 1. Involved: uninvolved serum free light chain ratio >= 100 measured by Freelite assay (The Binding Site Group, Birmingham, United Kingdom [UK])
- 1. > 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab)	Laboratory Biomarker Analysis	Patients receive pembrolizumab 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.
Treatment (pembrolizumab)	Pembrolizumab	Patients receive pembrolizumab 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.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	From cycle 1 to cycle 8, up to 168 days	Overall response rate is defined as patients who have achieved partial response or higher as described per IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab. Will be measured according to International Myeloma Working Group Criteria (IMWG) criteria. Response rate will be estimated accordingly. Each cycle has a duration of 21 days.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Time of start of treatment to death from any cause up to 2 years and 6 months	Participants in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease
Number of Participants That Had Progression to Multiple Myeloma	At 30 months from study entry	Progressive disease assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab.
Clinical Benefit Rate	From cycle 1 to cycle 8, up to 168 days	Minor response or better assessed by IMWG criteria for multiple myeloma after 8 cycles of therapy with pembrolizumab