Smoldering Multiple Myeloma
Conditions
Keywords
Smoldering Multiple Myeloma
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.
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.
Interventions
DRUGNivolumab
Intravenous, predetermined dosage, Days 1 and 15 during cycles 1-12 and
DRUGLenalidomide
Oral, predetermined dosage, Days 1-21 of cycle 1-12
DRUGDexamethasone
Oral, Days 1, 8, 15 of cycle 1-6
Sponsors
Bristol-Myers Squibb
Multiple Myeloma Research Consortium
Blood Cancer Research Partnership
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2 Year Progression Free Percent | 2 Year | The primary endpoint will be the 2-year progression-free percent and will be reported with corresponding 90% confidence interval. All patients who have received one dose of study treatment will be included for the analysis, including those who die or are lost to follow-up before 2 years. Progression is defined as ≥ 25% increase and an absolute increase of ≥ 0.5g/dL from their nadir in their serum or urine m-spike or FLC with no CRAB features attributable to MM progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression Probability at 2-years | Baseline to documented progression, up to 24 months post initiation of therapy. | 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 24 months post initiation of therapy. |
| Duration of Response Probability at 2-years | 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 24 months post initiation of therapy. | Kaplan-Meier method, duration of response probability in patients with partial response or better. Events defined as confirmed progression or death from any cause |
| Progression Free Survival (PFS) Probability at 2-years | Baseline to disease progression or death from any cause, censored at date last known progression free for those who have not progressed or died, up to 24 months post initiation of therapy. | Kaplan-Meier method, percent of patients alive and progression-free at 2-years |
| Objective Response Percent | 2 Years | The percent of patients with objective response defined as achieving a partial response or better according to the modified International Myeloma Working Group (IMWG) criteria |
| Progression Free Survival Rate-Without Cyclophosphamide | 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. |
| Number of Participants With Adverse Events | Baseline to 2 Years | For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate. |
| Overall Survival Probability at 2-years | Baseline to death or date last known alive, up to 24 months post initiation of therapy. | Kaplan-Meier method, percent alive at 2-years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Nivolumab: Intravenous, predetermined dosage, Days 1 and 15 during cycles 1-12 and
Lenalidomide: Oral, predetermined dosage, Days 1-21 of cycle 1-12
Dexamethasone: Oral, Days 1, 8, 15 of cycle 1-6 | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Nivolumab, Lenalidomide, Dexamethasone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 60 years |
| ECOG Performance Status 00 - Fully Active | 5 Participants |
| ECOG Performance Status 01 - Restricted | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 8 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 1 / 8 |
Outcome results
Primary
2 Year Progression Free Percent
The primary endpoint will be the 2-year progression-free percent and will be reported with corresponding 90% confidence interval. All patients who have received one dose of study treatment will be included for the analysis, including those who die or are lost to follow-up before 2 years. Progression is defined as ≥ 25% increase and an absolute increase of ≥ 0.5g/dL from their nadir in their serum or urine m-spike or FLC with no CRAB features attributable to MM progression.
Time frame: 2 Year
Population: All patients receiving any amount of protocol treatment. Patients who have progressed or lost to follow-up prior to two years are counted as failures; only patients followed and progression-free for at least two years are counted as successes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | 2 Year Progression Free Percent | 62.5 percentage of participants |
Secondary
Duration of Response Probability at 2-years
Kaplan-Meier method, duration of response probability in patients with partial response or better. Events defined as confirmed progression or death from any cause
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 24 months post initiation of therapy.
Population: 7 of 8 patients achieved a confirmed objective response and are included in duration of response analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Duration of Response Probability at 2-years | 0.71 probability |
Secondary
Number of Participants With Adverse Events
For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.
Time frame: Baseline to 2 Years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Number of Participants With Adverse Events | 8 Participants |
Secondary
Objective Response Percent
The percent of patients with objective response defined as achieving a partial response or better according to the modified International Myeloma Working Group (IMWG) criteria
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Objective Response Percent | 87.5 percentage of participants |
Secondary
Overall Survival Probability at 2-years
Kaplan-Meier method, percent alive at 2-years
Time frame: Baseline to death or date last known alive, up to 24 months post initiation of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Overall Survival Probability at 2-years | 1.0 probability |
Secondary
Progression Free Survival (PFS) Probability at 2-years
Kaplan-Meier method, percent of patients alive and progression-free at 2-years
Time frame: Baseline to disease progression or death from any cause, censored at date last known progression free for those who have not progressed or died, up to 24 months post initiation of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Progression Free Survival (PFS) Probability at 2-years | 0.75 probability |
Secondary
Progression Free Survival Rate-Without Cyclophosphamide
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.
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Progression Free Survival Rate-Without Cyclophosphamide | 71.4 percentage of participants |
Secondary
Time to Progression Probability at 2-years
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 24 months post initiation of therapy.
Time frame: Baseline to documented progression, up to 24 months post initiation of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab, Lenalidomide, Dexamethasone | Time to Progression Probability at 2-years | 0.75 probability |