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A Phase II Trial If Nivolumab, Lenalidomide and Dexamethasone in High Risk Smoldering Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02903381
Recruitment Status : Suspended (FDA Partial Clinical Hold)
First Posted : September 16, 2016
Last Update Posted : January 5, 2022
Bristol-Myers Squibb
Multiple Myeloma Research Consortium
Blood Cancer Research Partnership
Information provided by (Responsible Party):
Irene Ghobrial, MD, Dana-Farber Cancer Institute

Brief Summary:

This research study is evaluating a new drug called "nivolumab" as a possible treatment for smoldering multiple myeloma in order to prevent or postpone development of active multiple myeloma.

- Patients with smoldering multiple myeloma do not have symptoms but are at risk for progressing to active multiple myeloma. Multiple myeloma is a cancer of the plasma cell, which is an important part of the immune system. Patients with active multiple myeloma generally require treatment.

Condition or disease Intervention/treatment Phase
Smoldering Multiple Myeloma Drug: Nivolumab Drug: Lenalidomide Drug: Dexamethasone Phase 2

Detailed Description:
  • This research study is a Phase II clinical trial, which tests the effectiveness of an investigational drug(s). The investigational drugs used in this research study are;

    • nivolumab
    • lenalidomide
    • dexamethasone.
  • Preliminary experience suggests that the combination of lenalidomide and dexamethasone may prevent or postpone smoldering multiple myeloma (SMM) from becoming active multiple myeloma. The purpose of this research study is to determine if the addition of nivolumab may improve the rate of prevention in combination with lenalidomide and dexamethasone.
  • "Investigational" means that the FDA (the U.S. Food and Drug Administration) has not approved the combination of nivolumab, lenalidomide and dexamethasone as a treatment regimen.
  • Lenalidomide is an immunomodulatory drug derived from thalidomide. Lenalidomide works by stopping blood flow to your cancer cells and signaling your cancer cells to die off. The FDA has approved lenalidomide for the treatment of many types of cancer including multiple myeloma, and myelodysplastic syndromes.
  • Dexamethasone, also FDA approved, is a type of steroid and is usually combined with other chemotherapy for the treatment of blood cancers, such as myeloma and leukemias.
  • Nivolumab is approved by the FDA for some lung cancers, some skin cancers, some kidney cancers, and Hodgkin lymphoma. It is currently being evaluated for use in the treatment of several other types of cancers. Nivolumab may kill or stop cancer cells from growing by blocking a signal in the cells allowing the immune system to fight the cancer. This drug is a human monoclonal antibody, which is a molecule that is made in a laboratory that is designed to act identically to cells in the immune system.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 41 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of the PD-1 Antibody Nivolumab in Combination With Lenalidomide and Low Dose Dexamethasone in Patients With High-Risk Smoldering Multiple Myeloma
Study Start Date : October 2016
Actual Primary Completion Date : September 16, 2021
Estimated Study Completion Date : February 2024

Arm Intervention/treatment
Experimental: Nivolumab, Lenalidomide, Dexamethasone
  • A treatment cycle is defined as 28 consecutive days.
  • Participants will receive 6 cycles of induction therapy followed by 6 cycles of maintenance therapy with lower doses of lenalidomide and no dexamethasone for a total of 12 months.
Drug: Nivolumab
Intravenous, predetermined dosage, Days 1 and 15 during cycles 1-12 and
Other Name: Opdivo®

Drug: Lenalidomide
Oral, predetermined dosage, Days 1-21 of cycle 1-12
Other Name: Revlimid

Drug: Dexamethasone
Oral, Days 1, 8, 15 of cycle 1-6
Other Names:
  • Decadron
  • Dexasone
  • Diodex
  • Hexadrol
  • Maxidex

Primary Outcome Measures :
  1. 2 Year Progression Free Rate [ Time Frame: 2 Year ]
    The primary endpoint will be the 2-year progression-free rate and will be analyzed using binomial probability and corresponding 90% confidence interval. All patients who have received one dose of study treatment will be included for the TTP analysis, including those who die or are lost to follow-up within 2 years.

Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 2 Years ]
    The objective response rate (partial response or better according to the modified International Myeloma Working Group (IMWG) criteria) and the proportion of patients with a Minimal Residual Disease (MRD), Complete Response (CR), Partial Response (PR) or Minimal Response (MR) will be reported with 90% exact binominal confidence interval (CI).

  2. Time to Progression Rate [ Time Frame: Baseline until documented progression ]
    Time to progression (TTP) is defined as the time from protocol therapy initiation until documented progression, censored at date last known progression-free for those who have not progressed, up to 48 months post initiation of therapy.

  3. Duration of Response Rate [ Time Frame: time from objective response to disease progression or death, or date last known progression-free and alive for those who have not progressed or died, up to 48 months post initiation of therapy. ]
    Kaplan-Meier method

  4. Progression Free Survival (PFS) Rate [ Time Frame: Baseline to e disease progression or death from any cause, censored at date last known progression free for those who have not progressed or died, up to 48 months post initiation of therapy. ]
    Kaplan-Meier method

  5. Overall Survival Rate [ Time Frame: Baseline to death or date last known alive, up to 48 months post initiation of therapy. ]
    Kaplan-Meier method

  6. Progression Free Survival Rate-Without cyclophosphamide [ Time Frame: 2 Years ]
    It is expected that approximately 20% of the patients will receive cyclophosphamide (CTX) for mobilization and this may influence the PFS. Therefore, in a secondary analysis the 2 year PFS rate will be evaluated among those patients who did not receive CTX.

  7. Number of Participants with Adverse Events [ Time Frame: Baseline to 2 Years ]
    For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age 18 years.
  • Must meet criteria of high risk smoldering MM based on the criteria described below:

    -- Definition of high-risk SMM:

    --- Bone marrow clonal plasma cells ≥10% and ≤60% and any one or more of the following:

    • Serum M protein ≥3.0g/dL (IgA, IgG, IgM, or IgD)
    • IgA SMM
    • Immunoparesis with reduction of two uninvolved immunoglobulin isotypes
    • Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)

      ----- Free Light Chain Smoldering Myeloma patients as defined in section 2.4 are not excluded

    • Progressive increase in M protein level (Evolving type of SMM)

      ----- Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6 month period

    • Bone marrow clonal plasma cells 50-60%
    • Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes
    • t (4;14) or del 17p or 1q gain
    • Increased circulating plasma cells
    • MRI with diffuse abnormalities or 1 focal lesion
    • PET-CT with one focal lesion with increased uptake without underlying osteolytic bone destruction
    • Urine monoclonal light chain excretion ≥500 mg/24 hours
  • ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)
  • The following laboratory values obtained 21 days prior to registration and confirmed prior to the first dose of study drug:

    • ANC ≥1000/ µL
    • PLT ≥ 50,000/µL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
    • Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if normal patient is eligible.)
    • AST ≤ 3 x institutional upper limit of normal (ULN)
    • ALT ≤ 3 x institutional upper limit of normal (ULN)
    • Creatinine ≤ 1.5 mg/dL
    • WBC ≥2000/μL
  • Ability to understand and willingness to sign a written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
  • Female patients who are postmenopausal for at least 1 year before the screening visit or are surgically sterile. Females of childbearing potential* must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMS®) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. Females of reproductive potential must agree to follow instructions for method(s) of contraception for the duration of treatment with any study drug(s) plus 5 half-lives of study plus 30 days (duration of ovulatory cycle) for a total of 120 days post treatment completion. Women must not breastfeed. -- A female of childbearing potential is a sexually mature female who:

    • Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or
    • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)
  • All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
  • Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
  • Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy during the entire study treatment period and through 154 days after the last dose of study drug 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.)

Exclusion Criteria:

  • No evidence of CRAB criteria* or new criteria of active MM which including the following:

    • Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL) related to MM
    • Renal insufficiency (attributable to MM)
    • Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
    • Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
    • Bone marrow plasma cells ≥60%
    • Serum involved/uninvolved FLC ratio ≥100, provided the absolute level of the involved free light chain is at least 100 mg/L and repeated twice (light chain smoldering myeloma as described in section 2.4 is not an exclusion criteria).
    • MRI with two or more focal lesions that are at least 5 mm or greater in size --- *Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
  • Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Prior therapy with bisphosphonate is allowed. Prior therapy for smoldering myeloma MM may not be an exclusion criterion, discussion with Principal Investigator must occur before enrolling patients with prior treatments. Prior radiation therapy to a solitary plasmacytoma is allowed.
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune pneumonitis, autoimmune vasculitis [eg, Wegener's Granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia, Gravis). Patients with Hashimoto's thyroiditis are eligible to go on study.
  • Pregnant or nursing women will be excluded from the study because lenalidomide is an agent with the potential for teratogenic or abortifacient effects.
  • History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to Nivolumab or lenalidomide.
  • Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
  • Major surgery within 4 weeks before enrollment.
  • Myeloma-related central nervous system involvement.
  • Known Amyloid involvement.
  • Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
  • Prior CVA with persistent neurological deficit.
  • Inability to tolerate thromboprophylaxis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02903381

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United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Dana-Farber Cancer Institute
Bristol-Myers Squibb
Multiple Myeloma Research Consortium
Blood Cancer Research Partnership
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Principal Investigator: Irene M. Ghobrial, MD Dana-Farber Cancer Institute
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Responsible Party: Irene Ghobrial, MD, Prinicipal Investigator, Dana-Farber Cancer Institute Identifier: NCT02903381    
Other Study ID Numbers: 16-242
CA209-607 ( Other Identifier: Bristol-Myers Squibb )
First Posted: September 16, 2016    Key Record Dates
Last Update Posted: January 5, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Irene Ghobrial, MD, Dana-Farber Cancer Institute:
Smoldering Multiple Myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Smoldering Multiple Myeloma
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Precancerous Conditions
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal