A Phase II Trial If Nivolumab, Lenalidomide and Dexamethasone in High Risk Smoldering Myeloma
Condition: Smoldering Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma
Intervention: Nivolumab; Lenalidomide; Dexamethasone
Intervention description: Intravenous, predetermined dosage, Days 1 and 15 during cycles 1-12 and; Oral, predetermined dosage, Days 1-21 of cycle 1-12; Oral, Days 1, 8, 15 of cycle 1-6
Intervention MeSH terms: Dexamethasone; Nivolumab; Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Smoldering Multiple Myeloma

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.
    

Eligibility criteria:

        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.