Study of Bortezomib,Lenalidomide,Dexamethasone & Elotuzumab in Newly Diagnosed MM

Study Overview
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Brief Summary
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This research study is evaluating a combination of four drugs -- lenalidomide, bortezomib, dexamethasone and elotuzumab -- as therapy for newly diagnosed multiple myeloma.

Detailed Description
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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.

Official Title
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An Open-Label, Single Arm, Phase 2a Study of Bortezomib, Lenalidomide, Dexamethasone and Elotuzumab in Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Elotuzumab
* Drug: Bortezomib
* Drug: Dexamethasone
* Procedure: Stem Cell Mobilization


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elotuzumab, lenalidomide, bortezomib, and dexamethasone<br>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 Induction Cycle 4 and proceed to autologous SCT. Subjects who do not proceed to SCT may receive a full 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. | Drug: Lenalidomide<br> <br> * Other names: Revlimid®;Drug: Elotuzumab<br> <br> * Other names: HuLuc63;Drug: Bortezomib<br> <br> * Other names: Velcade;Drug: Dexamethasone<br> <br> * Other names: Decadron;Procedure: Stem Cell Mobilization<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Participants were followed up to 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | The most distant time of stem cell mobilization from time of registration is 21.4 weeks with a median of 15.14 weeks. | 
| 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. | Participants were followed up to 12 weeks. | 
| 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. | The adverse event observation period defined as the time on treatment (+30d) is 278 weeks. | 
| 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. | Participants were followed up to 273.6 weeks. | 
| 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. | Participants were followed up to 24 weeks. | 
| 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. | Participants were followed up to 92 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma