- 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.
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.
