Multiple Myeloma
Conditions
Keywords
Multiple Myeloma
Brief summary
This research study is evaluating a combination of four drugs -- lenalidomide, bortezomib, dexamethasone and elotuzumab -- as therapy for newly diagnosed multiple myeloma.
Detailed description
This research study is a Phase II clinical trial testing the safety and effectiveness of an investigational drug (in this case elotuzumab) in combination with lenalidomide, bortezomib and dexamethasone to learn more about the side effects of this regimen and whether it is effective in newly diagnosed multiple myeloma. Investigational means that the drug elotuzumab and the combination of this agent with lenalidomide, bortezomib, and dexamethasone are being studied. It also means that the the U.S. Food and Drug Administration (FDA) has not yet approved elotuzumab for the treatment of cancer. The drugs, lenalidomide, bortezomib, and dexamethasone are approved by the FDA. Participants in this trial will have the option to undergo autologous stem cell transplantation (ASCT) following initial therapy with elotuzumab, lenalidomide, bortezomib, and dexamethasone. ASCT is a standard of care in the treatment of multiple myeloma. All participants, including those who undergo ASCT and those who choose not to, will receive what is referred to as maintenance therapy - or continuous treatment - after the initial cycles of treatment with elotuzumab, lenalidomide, bortezomib, and dexamethasone. The specific maintenance regimen will be determined by risk category.
Interventions
Sponsors
Bristol-Myers Squibb
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
* Patients must meet the following criteria on screening examination to be eligible to participate in the study. All laboratory assessments should be performed within 21 days of initiation of protocol therapy unless otherwise specified.Subject is, in the investigator's opinion, willing and able to comply with the protocol requirements. * Subject has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix 1). * Subject is a candidate for high-dose therapy and autologous SCT based on standard criteria at the institution where this treatment will be administered. * Newly diagnosed untreated, symptomatic, documented MM based on standard diagnostic criteria (Rajkumar 2009) with measurable disease, defined as any of the following: * Serum Immunoglobulin G (IgG), Immunoglobulin (A) IgA, or Immunoglobulin M (IgM) M-protein ≥ 0.5 g/dL, or * Serum Immunoglobulin D (IgD) M-protein ≥ 0.05 g/dL, or * Urinary M-protein excretion of more than 200 mg/24 hours, or * Serum free light chains (FLC) of at least 100 mg/dL with an abnormal FLC ratio * Subject agrees to refrain from blood donations during therapy on study and for 8 weeks after therapy is completed. * Men and women, age ≥18 years or legal age of consent per local regulations (whichever is greater). * Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting Lenalidomide 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 through 90 days after the last dose of study drug. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy from the time of signing the informed consent form through 90 days after the last dose of study drug. All patients must be registered in and must comply with all requirements of the Revlimid Rems™ program.
Exclusion criteria
* Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study. * Diagnosed with smoldering MM, monoclonal gammopathy of undetermined significance, Waldenstrom's macroglobulinemia, Plasma cell leukemia, POEMS syndrome or amyloidosis. * Participant has ≥ Grade 2 peripheral neuropathy on clinical examination within 21 days before initiation of protocol therapy. * Renal insufficiency, defined as creatinine clearance \< 30 mL/min (either actual or calculated value), within 21 days of initiation of protocol therapy. The Cockgroft-Gault formula should be used for calculating creatinine clearance values: * (140-age) x Body mass (kg) x 0.85 (female) or 1.0 (male) serum creat (mg/dL) x 72 * Ideal body weight (IBW) should be used if actual body weight is \> 20% above IBW * Platelet count \<75,000 cells/mm3 at time of screening evaluation. Transfusion may not be used to meet platelet eligibility criteria within 7 days of obtaining screening evaluation. * Participants with an absolute neutrophil count (ANC) \< 1000 cells/mm3 at time of screening evaluation. Growth factor may not be used to meet ANC eligibility criteria within 14 days of obtaining screening evaluation. * Participants with hemoglobin level \< 8.0 g/dL, at time of screening. Transfusion may not be used to meet eligibility criteria within 7 days of obtaining screening evaluation. * Participants with hepatic impairment, defined as bilirubin \> 1.5 x institutional upper limit of normal (ULN) or AST (Aspartate aminotransferase; SGOT), ALT (Alanine aminotransferase; SGPT), or alkaline phosphatase \> 3x institutional ULN, within 21 days of initiation of protocol therapy * Other ongoing or prior anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. q.d. or its equivalent) for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to study treatment.) * Known significant cardiac abnormalities including: * Congestive heart failure, New York Heart Association (NYHA) class III or IV * Uncontrolled angina, arrhythmia or hypertension * Myocardial infarction within the past six months * Any other uncontrolled or severe cardiovascular condition * Prior cerebrovascular event with residual neurologic deficit * Serious, intercurrent illness including, but not limited to, clinically relevant active infection, known active hepatitis B or C viral infection, known HIV infection, uncontrolled diabetes mellitus, or serious co-morbid medical conditions such as chronic restrictive pulmonary disease, and cirrhosis. * Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study. * Prior malignancy (within the last 5 years) except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer * Known hypersensitivity to acyclovir or similar anti-viral drug * Known intolerance to steroid therapy * Contraindication or prior intolerance to thromboembolic prophylaxis with aspirin, warfarin or low-molecular weight heparin * Participants with known brain metastases. * Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to dexamethasone, boron or mannitol. * Female participants pregnant or breast-feeding. * Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of the surgery. * Participants with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 4 Cycle Response Rate | Participants were followed up to 12 weeks. | Disease response was defined as the proportion of patients who achieved a response of partial response or better using International Myeloma Working Group (IMWG) response criteria. Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry. The Clopper and Pearson method was used to estimate the 95% CIs for the response rate at Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 4 Cycle Ever Dose Modification (DM) Rate | Participants were followed up to 12 weeks. | The 4 cycle ever DM rate is the proportion of participants who started therapy and required dose modification of any study drug during the first four cycles of E-RVD. |
| Grade 3 and 4 Treatment-Emergent Adverse Event (TEAE) Rate | The adverse event observation period defined as the time on treatment (+30d) is 278 weeks. | Grade 3 and 4 TEA rate was defined as the proportion of participants who experienced a grade 3 or 4 adverse event of any attribution based on NCI Common Toxicity Criteria for Adverse Events Version 4 (CTCAEv4) on treatment. |
| Successful Stem Cell Mobilization (SC Mob) Rate | The most distant time of stem cell mobilization from time of registration is 21.4 weeks with a median of 15.14 weeks. | Successful SC Mob defined as the proportion of participants with the ability to collect a total of at least 2\*10\^6 CD34+ cells/kg. |
| Objective Response Rate (ORR) at End of 8 Cycles of Induction Therapy. | Participants were followed up to 24 weeks. | ORR was defined as the proportion of patients who achieved a disease response of partial response (PR) or better using IMWG response criteria. PR defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry. |
| Median Time to Response | Participants were followed up to 92 days. | Time to response is defined as the time from the first dose of study drug to the first documentation of response partial response (PR) or better. Disease response was assessed using International Myeloma Working Group (IMWG) response criteria: Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry. |
| Best Responses to E-RVD. | Participants were followed up to 273.6 weeks. | Best responses to E-RVD was assessed using International Myeloma Working Group (IMWG) response criteria: Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from May 2015 to April 2016.
Participants by arm
| Arm | Count |
|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone Participants will receive therapy with the combination of lenalidomide, bortezomib, and dexamethasone and elotuzumab (E-RVD). Induction cycles (1 to 8) are 21-day cycles.
* Elotuzumab will be administered by intravenous (IV) infusion
* Bortezomib as a subcutaneous injection
* Lenalidomide single daily oral dose
* Dexamethasone as oral tablets and IV infusion
* Stem cell mobilization will be performed for all subjects at the end of Cycle 4.
Subjects may elect to stop E-RVD at the end of Cycle 4 and proceed to autologous SCT. Subjects who do not proceed to SCT may receive 8 cycles of induction therapy.
The maintenance schedule (28 days) will start after 8 cycles of induction regimen for subjects not proceeding with SCT, or after recovery from SCT for subjects proceeding with it.
Maintenance therapy with E-RVD will be administered to all patients, with the specific maintenance regimen determined by risk category. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Induction Period | Adverse Event | 7 |
| Induction Period | Didn't meet criteria for maintenance therapy | 1 |
| Induction Period | Other | 1 |
| Induction Period | Withdrawal by Subject | 2 |
| Maintenance Period | Adverse Event | 2 |
| Maintenance Period | Death | 1 |
| Maintenance Period | Disease Progression | 5 |
| Maintenance Period | Patient Non-compliance | 1 |
| Maintenance Period | Still on maintenance | 16 |
| Maintenance Period | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 8.6 |
| Cytogenetic risk classification High | 6 Participants |
| Cytogenetic risk classification Missing | 15 Participants |
| Cytogenetic risk classification Standard | 19 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 | 26 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 | 13 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 | 1 Participants |
| International Staging System (ISS) Multiple Myeloma Stage Stage I | 24 Participants |
| International Staging System (ISS) Multiple Myeloma Stage Stage II | 10 Participants |
| International Staging System (ISS) Multiple Myeloma Stage Stage III | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 40 |
| other Total, other adverse events | 39 / 40 |
| serious Total, serious adverse events | 10 / 40 |
Outcome results
Primary
4 Cycle Response Rate
Disease response was defined as the proportion of patients who achieved a response of partial response or better using International Myeloma Working Group (IMWG) response criteria. Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry. The Clopper and Pearson method was used to estimate the 95% CIs for the response rate at Week 12.
Time frame: Participants were followed up to 12 weeks.
Population: The analysis dataset is comprised of 34 efficacy-evaluable participants, where it was defined as participants who were dosed, had a post-baseline scan and also had at least 4-cycles of induction.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | 4 Cycle Response Rate | 0.971 proportion of participants |
Secondary
4 Cycle Ever Dose Modification (DM) Rate
The 4 cycle ever DM rate is the proportion of participants who started therapy and required dose modification of any study drug during the first four cycles of E-RVD.
Time frame: Participants were followed up to 12 weeks.
Population: The analysis dataset is comprised of participants who were dosed (parallel with the safety population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | 4 Cycle Ever Dose Modification (DM) Rate | .40 proportion of participants |
Secondary
Best Responses to E-RVD.
Best responses to E-RVD was assessed using International Myeloma Working Group (IMWG) response criteria: Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry.
Time frame: Participants were followed up to 273.6 weeks.
Population: Best responses to E-RVD in the safety population, defined as participants with Multiple Myeloma who received one or more dose of elotuzumab. Out of the 40 participants included in the safety population, one participant did not receive or more dose of elotuzumab, and was not included in the best response analysis population.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Best Responses to E-RVD. | Sustained complete response (sCR) | 9 Participants |
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Best Responses to E-RVD. | Complete response (CR) | 8 Participants |
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Best Responses to E-RVD. | Very good partial response (VGPR) | 16 Participants |
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Best Responses to E-RVD. | Partial response (PR) | 5 Participants |
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Best Responses to E-RVD. | Minimal response (MR) | 1 Participants |
Secondary
Grade 3 and 4 Treatment-Emergent Adverse Event (TEAE) Rate
Grade 3 and 4 TEA rate was defined as the proportion of participants who experienced a grade 3 or 4 adverse event of any attribution based on NCI Common Toxicity Criteria for Adverse Events Version 4 (CTCAEv4) on treatment.
Time frame: The adverse event observation period defined as the time on treatment (+30d) is 278 weeks.
Population: All participants in the safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Grade 3 and 4 Treatment-Emergent Adverse Event (TEAE) Rate | 0.70 proportion of participants |
Secondary
Median Time to Response
Time to response is defined as the time from the first dose of study drug to the first documentation of response partial response (PR) or better. Disease response was assessed using International Myeloma Working Group (IMWG) response criteria: Partial Response (PR) defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry.
Time frame: Participants were followed up to 92 days.
Population: This analysis population was restricted to the subjects whose best response was PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Median Time to Response | 22.0 days |
Secondary
Objective Response Rate (ORR) at End of 8 Cycles of Induction Therapy.
ORR was defined as the proportion of patients who achieved a disease response of partial response (PR) or better using IMWG response criteria. PR defined as 50% reduction of serum M-protein and reduction in 24h urinary M-protein by ≥90% or to \<200mg/24h; Very Good Partial Response (VGPR) defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100mg/24h; Complete Response (CR) defined as negative immunofixation on serum and urine and, disappearance of any soft tissue plasmacytomas and, \<5% plasma cells in BM; Stringent Complete Response (sCR) defined as normal FLC ratio and absence of clonal cells in BM by immunohistochemistry or 2-4 color flow cytometry.
Time frame: Participants were followed up to 24 weeks.
Population: Safety population comprised of 40 patients, of which 19 received ASCT and 12 completed 8 full induction cycles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Objective Response Rate (ORR) at End of 8 Cycles of Induction Therapy. | 0.950 proportion of participants |
Secondary
Successful Stem Cell Mobilization (SC Mob) Rate
Successful SC Mob defined as the proportion of participants with the ability to collect a total of at least 2\*10\^6 CD34+ cells/kg.
Time frame: The most distant time of stem cell mobilization from time of registration is 21.4 weeks with a median of 15.14 weeks.
Population: The analysis population is comprised of participants who underwent stem cell mobilization after completing 4 cycles of induction therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab, Lenalidomide, Bortezomib, and Dexamethasone | Successful Stem Cell Mobilization (SC Mob) Rate | 0.968 proportion of participants |