Allogeneic Myeloma GM-CSF Vaccine With Lenalidomide in Multiple Myeloma Patients in Complete or Near Complete Remission

Study Overview
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Brief Summary
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This study seeks to determine whether addition of an allogeneic myeloma vaccine can augment clinical responses to lenalidomide in patients with near complete remission (nCR), or complete remission (CR) leading to a significant improvement in progression-free survival.This main objective of this study is to compare the 2-year progression free survival of patients with multiple myeloma in CR or nCR, treated with lenalidomide plus an allogeneic myeloma vaccine in combination with lenalidomide (with or without Prevnar vaccine) or versus placebo in combination with lenalidomide (control arm).

Detailed Description
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This is a single institution, three- arm, randomized controlled, Phase II study examining the clinical efficacy of an allogeneic GM-CSF secreting myeloma vaccine in combination with lenalidomide (with or without Prevnar) compared to lenalidomide and placebo (control arm). Patients enrolled in the study must have two disease measurements (including the last one) consistent with a near complete remission (M-spike negative with persistence of immunofixation), or complete remission (M-spike negative, negative immunofixation, and <5% clonal plasma cells on bone marrow) per criteria for response in a 3 month period. All patients must be minimal residual disease (MRD) positive by NGS sequencing at enrollment. Prior to enrollment, patients will have been treated with a lenalidomide containing regimen for a minimum of 6 cycles. All patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment. Patients will be randomized to receive either an allogeneic myeloma vaccine and Prevnar vaccine in combination with lenalidomide, or allogeneic myeloma vaccine without Prevnar vaccine in combination with lenalidomide, or lenalidomide in combination with placebo. Patients will receive allogeneic myeloma vaccine or placebo injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter for up to 3 years. If assigned to allogeneic myeloma vaccine plus Prevnar vaccine arm, Prevnar-13 will be administered with each allogeneic myeloma vaccine. If assigned to either of the two arms that do not include Prevnar, then patients will receive a placebo in lieu of Prevnar on the same schedule. All patients will be followed for a minimum of 3 years.

Official Title
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A Randomized, Double-blind, Placebo-Controlled Phase II Trial of an Allogeneic Myeloma GM-CSF Vaccine With Lenalidomide in Multiple Myeloma Patients in Complete or Near Complete Remission

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: GM-CSF vaccine
* Drug: Lenalidomide
* Drug: Prevnar13
* Other: Placebo Prevnar13
* Other: Placebo GM-CSF Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Myeloma eligibility criteria are the following: Near complete remission (nCR) for ≥ 3 months defined as no measurable M-spike, and a positive serum immunofixation For patients with a light chain only myeloma, they will be in deemed to be in a CR if they meet criteria for CR by International Myeloma Working Group (IMWG) consensus criteria 2016. For patients with a light chain only myeloma that meet criteria for Very Good Partial Response (VGPR) by IMWG consensus criteria 2016 and are IFE -ve (negative serum immunofixation), they will be considered to be in a near complete remission (nCR). Or complete remission (CR) (no measurable M-spike, immunofixation negative and bone marrow plasma cells <5%) NDMM or RMM in nCR or CR having completed a minimum of 6 cycles of a lenalidomide based regimen for a minimum of ≥ 3 months NDMM or RMM a patients who have been off corticosteroids for ≥ 4 weeks Patients with NDMM or RMM who have had autologous stem cell transplant are eligible, but must be ≥ 12 months from transplant All patients must be MRD positive at 10-4 or greater by NGS sequencing at enrollment All patients must be currently taking Revlimid at screening. Age >18 years ECOG performance scores 0-2 History of measurable serum or urine M protein or free light chains Life expectancy greater than 12 months Corrected serum calcium < 11 mg/dL, and no evidence of symptomatic hypercalcemia Serum creatinine< 2 mg/dl ANC >1000/µL Platelet >100,000/µL Total bilirubin <= 1.5 x ULN AST (SGOT) and ALT (SGPT) <= 3 x ULN. Ability to comprehend and have signed the informed consent. Have previously agreed to continue on maintenance therapy with lenalidomide concurrent with vaccine administration until disease progression, or clinical indication to cease therapy. Disease free of prior malignancies for at least 5 years with exception of currently treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the uterus, cervix or breast. 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. 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 starting lenalidomide with each cycle (prescriptions must be filled within 7 days) 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. 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 successful vasectomy. Able to take prophylactic anticoagulation (aspirin 81 or 325 mg/daily or, for patients intolerant to ASA, warfarin or low molecular weight heparin). Exclusion Criteria: Disease progression after stopping corticosteroids as defined as the appearance of a detectable serum or urine M-spike, or an absolute increase of >10 mg/dl between involved and uninvolved light chains, in the absence of measurable serum or urine M-protein . Patients who are MRD negative by NGS at screening. Patients with a known diagnosis of POEMS syndrome, plasma cell leukemia, CNS involvement, non-secretory myeloma and amyloidosis High-risk myeloma defined by presence of at least one of the following defining features on initial diagnostic, or most recent bone marrow biopsy: High risk chromosomal translocations by FISH: t(4;14), t(14;16), t(14;20), del(17p), del(1p), amplification 1q.; MyPRS GEP-70 high risk signature either from diagnosis or at time of registration for the study; LDH > 300 U/L at diagnosis; Relapse from prior therapy within 12 months. HIV disease, active infection requiring treatment with antibiotics, anti-fungal or anti-viral agents within 2 weeks of enrollment would be excluded from the study. Patients who have participated in any clinical trial, within the last four weeks, which involved an investigational drug. History of an active malignancy other than myeloma Autoimmune disease requiring active treatment. Known contra-indication to any component of allogeneic myeloma vaccine History of an allogeneic transplant

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All patients will continue on a standard dose of lenalidomide. Patients on the myeloma vaccine arm will receive injections in addition to lenalidomide unless otherwise clinically indicated, or until progression. Patients on myeloma plus Prevnar vaccine arm will receive injections of both allogenic myeloma vaccine and Prevnar vaccine in addition to lenalidomide unless otherwise clinically indicated, or until progression. Patients on the myeloma vaccine placebo arm will receive myeloma vaccine placebo on the same schedule as allogeneic myeloma vaccine. If assigned to either of the two arms that do not include Prevnar, then patients will receive placebo in lieu of Prevnar on the same schedule. The placebo will be saline. All patients will be followed for a minimum of 3 years.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide plus GM-CSF Vaccine plus Prevnar13<br>Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment. Patients assigned to vaccine therapy will receive injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter. Prevnar vaccine will be administered with the GM-CSF vaccine administration. | Biological: GM-CSF vaccine<br>* Each vaccination will consist of three total intra-dermal injections, on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months in the right and left anterior upper thighs, and one in the non-dominant upper arm (unless contraindicated). In the event that the specified limb is contraindicated, the dominant arm may be used. Vaccine injection sites shall be at least 5 cm at needle entry from the nearest neighbor. The approximate volume of each vaccination injection is approximately 0.7-0.8ml.<br>* Other names: GVAX;Drug: Lenalidomide<br>* Patients will be continued on the same dose of lenalidomide as they were prior to being enrolled in the study. Doses of lenalidomide for investigation can vary from 5-25 mg/day, orally on days 1 - 21 followed by 7 days rest (28 day cycle).<br>* Other names: Revlimid;Drug: Prevnar13<br>* Prevnar will be administered at the same time points as the GM-CSF vaccine (day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months), but on the opposite arm from GM-CSF vaccine.<br>* Other names: pneumococcal vaccine;|
| Placebo Comparator: Lenalidomide Only<br>Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment. Patients will also get placebo GM-CSF vaccine and placebo prevnar13. Placebo will be saline. | Drug: Lenalidomide<br>* Patients will be continued on the same dose of lenalidomide as they were prior to being enrolled in the study. Doses of lenalidomide for investigation can vary from 5-25 mg/day, orally on days 1 - 21 followed by 7 days rest (28 day cycle).<br>* Other names: Revlimid;Other: Placebo Prevnar13<br>* Saline will be used for placebo. Placebo prevnar will be administered at the same time points as the GM-CSF vaccine or Placebo GM-CSF Vaccine (day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months), but on the opposite arm from GM-CSF vaccine or placebo GM-CSF vaccine.<br>Other: Placebo GM-CSF Vaccine<br>* Saline will be used for placebo. Each placebo vaccine will consist of three total intra-dermal injections on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months in the right and left anterior upper thighs, and one in the non-dominant upper arm (unless contraindicated). In the event that the specified limb is contraindicated, the dominant arm may be used. Placebo injection sites shall be at least 5 cm at needle entry from the nearest neighbor. The approximate volume of each injection is approximately 0.7-0.8ml.<br>|
| Placebo Comparator: Lenalidomide plus GM-CSF Vaccine<br>Patients will continue on a standard dose of lenalidomide as a single agent until progression, or treatment limiting toxicity, following enrollment. Patients assigned to vaccine therapy will receive injections on day 14 (+/-3 days) of cycles 1, 2, 3 and 6 from enrollment, and then annually thereafter. Patients will also be administered a placebo prevnar13 vaccination. Placebo will be saline. | Biological: GM-CSF vaccine<br>* Each vaccination will consist of three total intra-dermal injections, on day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months in the right and left anterior upper thighs, and one in the non-dominant upper arm (unless contraindicated). In the event that the specified limb is contraindicated, the dominant arm may be used. Vaccine injection sites shall be at least 5 cm at needle entry from the nearest neighbor. The approximate volume of each vaccination injection is approximately 0.7-0.8ml.<br>* Other names: GVAX;Drug: Lenalidomide<br>* Patients will be continued on the same dose of lenalidomide as they were prior to being enrolled in the study. Doses of lenalidomide for investigation can vary from 5-25 mg/day, orally on days 1 - 21 followed by 7 days rest (28 day cycle).<br>* Other names: Revlimid;Other: Placebo Prevnar13<br>* Saline will be used for placebo. Placebo prevnar will be administered at the same time points as the GM-CSF vaccine or Placebo GM-CSF Vaccine (day 14 of cycles 1, 2, 3, 6 and annually for a minimum of 36 months), but on the opposite arm from GM-CSF vaccine or placebo GM-CSF vaccine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year progression free survival | Number of participants without disease progression at 2 years. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Conversion Rate | Number of participants who converted from near complete remission (nCR) to complete remission (CR) as measured by the International Myeloma Working Group Uniform Response Criteria. Near complete remission is defined as negative serum and urine electrophoresis, < 5% plasma cells in the bone marrow, and positive serum and/or urine immunofixation. Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells. | 3 years | 
| MRD Conversion Rate | Number of participants who convert from MRD (Minimal Residual Disease) positive status to MRD negative status as determined through next generation sequencing (NGS). | 3 years | 
| Time to Response | Median time for conversion of response from near complete remission (nCR) to complete remission (CR) as measured by the International Myeloma Working Group Uniform Response Criteria. Near complete remission is defined as negative serum and urine electrophoresis, < 5% plasma cells in the bone marrow, and positive serum and/or urine immunofixation. Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells as measured by immunofixation converting from positive to negative. | 3 Years | 
| Progression Free Survival (PFS) | Number of months without disease progression. | 3 and 5 years | 
| Evaluate toxicity of allogenic myeloma vaccine | Number of participants experiencing adverse events grade 3 or higher, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) | 3 years | 
| Measure tumor specific immunity and correlate with systemic immunity |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRD positive, Lenalidomide, M-spike negative, GVax, GM-CSF secreting myeloma vaccine