Reduce Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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This phase II trial studies how well a reduced intensity conditioning regimen after donor stem cell transplant works in treating patients with multiple myeloma that has come back (relapsed). Drugs used in chemotherapy, such as cyclophosphamide, tacrolimus, and mycophenolate mofetil, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as daratumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving a reduce intensity conditioning regimen consisting of cyclophosphamide, tacrolimus, mycophenolate mofetil, and daratumumab after donor stem cell transplant may improve survival and reduce the risk of multiple myeloma coming back.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the 2-year progression-free survival (PFS) for haploidentical, matched or mismatched, related or unrelated reduce intensity allogenic hematopoietic stem cell transplantation (allo HSCT) in relapsed multiple myeloma (MM) patients. SECONDARY OBJECTIVES: I. To determine 2 year overall survival (OS). II. To determine the cumulative incidence of grade II-IV acute-graft-versushost-disease (aGVHD) at day 100 and 180. III. To determine the 100 days, 1 year and 2 year cumulative incidence of treatment-related mortality (TRM). IV. To assess one-year GVHD-free relapse-free survival (GRFS). V. To determine the cumulative incidence of chronic graft-versus-hostdisease (cGVHD) Va. To assess overall and best response rates 100 days after allo HCT, 3 months, 6 months and every 6 months thereafter until end of daratumumab maintenance. VI. To determine rate of relapse after allo HSCT followed by maintenance. VII. To determine rate of minimal residual disease (MRD) negativity using next generation sequencing (Food and Drug Administration [FDA] approved) in patients achieving a very good partial response (VGPR) or better. CORRELATIVE OBJECTIVE: I. To determine immune reconstitution pattern on days +30, +100, +180 and +365 following allo HSCT. OUTLINE: Patients receive fludarabine intravenously (IV) on days -5 to -2 and melphalan IV on days -3 to -2, then undergo stem cell transplantation on day 0. Patients receive cyclophosphamide on days 3 and 4, tacrolimus orally (PO) or twice daily (BID) or IV starting on day 5, and mycophenolate mofetil IV or PO three times daily (TID) on days 5 to 35. Patients also receive daratumumab IV starting between day 90-150 for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 2 years post stem cell transplantation.

Official Title
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Reduce Intensity Conditioning (RIC) Allogenic Hematopoietic Stem Cell Transplantation (Allo HSCT) for Patients With Relapsed Multiple Myeloma: A Pilot Study

Conditions
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Recurrent Plasma Cell Myeloma

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Biological: Daratumumab
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a partial response (PR) or better prior to allo-transplantation Relapsed MM with chemo sensitivity disease, with or without prior autologous HSCT First allogenic transplant Donors can be haploidentical, mismatch or matched related or unrelated. Stem cell source will be peripheral blood except for haploidentical where stem cell source will be bone marrow Ejection fraction >= 45% Estimated creatinine clearance greater than 40 mL/minute Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% (adjusted for hemoglobin) Forced expiratory volume in 1 second (FEV1) >= 50% Total bilirubin < 2 x the upper limit of normal Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper normal limit Signed informed consent Exclusion Criteria: Patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS), Waldenstrom macroglobulinemia Uncontrolled bacterial, viral or fungal infection Patients with prior malignancies < 3 years except resected basal cell/squamous cell carcinoma, treated carcinoma in-situ. Other cancers treated with curative intent < 3 years previously will not be allowed unless approved by the principal investigator Female patients who are pregnant or breastfeeding. A negative pregnancy test will be required for all women of child bearing potential

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment (conditioning regimen, stem cell transplant)<br>Patients receive fludarabine IV on days -5 to -2 and melphalan IV on days -3 to -2, then undergo stem cell transplantation on day 0. Patients receive cyclophosphamide on days 3 and 4, tacrolimus PO BID or IV starting on day 5, and mycophenolate mofetil IV or PO TID on days 5 to 35. Patients also receive daratumumab IV starting between days 90-150 for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic hematopoietic stem cell transplantation<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Daratumumab<br>* Given IV<br>* Other names: JNJ-54767414;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Drug: Mycophenolate Mofetil<br>* Given IV or PO<br>* Other names: MMF;Drug: Tacrolimus<br>* Given PO or IV<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-free Survival (PFS) | Patients who do not relapse or die will be censored at the date of last clinical assessment. Kaplan-Meier curves will be generated to estimate the PFS rates at 2 years posttransplant. To evaluate the potential association between patient characteristics and PFS, the log-rank test will be used to compare the PFS curves and Cox proportional hazard regression model will be used to estimate the hazard ratio. | From the date of transplant until the date of relapse or date of death from any cause, assessed at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Adverse events by grade will be summarized. The occurrence of grade 3+ adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) will be summarized as well. Adverse events will initially be reviewed regardless of attribution, but also according to whether adverse events are possibly, probably, or definitely related to treatment. | Up to 2 years post-transplant | 
| Number of Patients With Grade II-IV Acute Graft-versus Host Disease (GvHD (aGVHD) | The event will be onset of grade II-IV aGvHD and time to aGvHD will be defined as the period of time from transplantation to the event of aGvHD. Death and early relapse without aGvHD will be competing risks. Cumulative incidence rate of aGVHD with 95% confidence intervals will be estimated from the cumulative incidence curves. To evaluate the association between patient characteristics and aGVHD, the Gray's test accounting for competing risks will be used to compare the cumulative incidence curves and a proportional hazards model for the sub distribution of competing risks will be used to estimate the hazard ratio. The cumulative incidence of chronic GVHD (cGVHD) will be similarly analyzed. | Up to 6 weeks | 
| Rate of Relapse | Patients without relapse or death will be censored at last clinical assessment date. The similar analysis approach used for outcome of aGVHD will be applied. | From the date of transplant to relapse treating death from any cause as a competing risk, assessed up to 2 years | 
| Overall Survival (OS) | A similar analysis approach described above for PFS will be applied for the OS analysis. | From the date of transplant to death or last contact date if no death, assessed up to 2 years | 
| 1- Year GVHD-free Relapse-free Survival (GRFS) | Patients who do not experience an event will be censored at the date of last clinical assessment. A similar analysis approach described above for PFS will be applied for the GRFS analysis. | From the date of transplant until the date of grade II-IV acute GVHD, chronic GVHD, disease relapse or progression, or death from any cause, whichever occurs first, assessed at 1 year | 
| 100-day Cumulative Incidence of Treatment-related Mortality (TRM) | The event will be death due to reasons other than disease. The competing risk for non relapsed mortality (NRM) will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points. | From the date of transplant to date of death, assessed up to 100 days | 
| 1-year Cumulative Incidence TRM | The event will be death due to reasons other than disease. The competing risk for NRM will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points. | From the date of transplant to date of death, assessed at 1 year | 
| 2-year Cumulative Incidence of TRM | The event will be death due to reasons other than disease. The competing risk for NRM will be death due to disease. The cumulative incidence curve accounting competing risks will be generated to estimate the cumulative incidence rate at various time points. | From the date of transplant to date of death, assessed at 2 years | 
| Overall Response Rate | The proportion of each type of response with a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution. | Up to 2 years post-transplant | 
| Number of Patients With a Partial Response | The proportion of each type of response with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution. | Approximately 11 months |