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

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.

• Allogeneic Hematopoietic Stem Cell Transplantation (Procedure), also known as Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic: Undergo allogeneic hematopoietic stem cell transplantation
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719: Given IV
• Daratumumab (Biological), also known as Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414: Given IV
• Fludarabine (Drug), also known as Fluradosa: Given IV
• Melphalan (Drug), also known as Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813: Given IV
• Mycophenolate Mofetil (Drug), also known as Cellcept, MMF: Given IV or PO
• Tacrolimus (Drug), also known as FK 506, Fujimycin, Hecoria, Prograf, Protopic: Given PO or IV

Primary outcomes

• 2-year Progression-free Survival (PFS) [From the date of transplant until the date of relapse or date of death from any cause, assessed at 2 years]: 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.

Secondary outcomes

• Incidence of Adverse Events [Up to 2 years post-transplant]: 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.
• Number of Patients With Grade II-IV Acute Graft-versus Host Disease (GvHD (aGVHD) [Up to 6 weeks]: 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.
• Rate of Relapse [From the date of transplant to relapse treating death from any cause as a competing risk, assessed up to 2 years]: 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.
• Overall Survival (OS) [From the date of transplant to death or last contact date if no death, assessed up to 2 years]: A similar analysis approach described above for PFS will be applied for the OS analysis.
• 1- Year GVHD-free Relapse-free Survival (GRFS) [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]: 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.
• 100-day Cumulative Incidence of Treatment-related Mortality (TRM) [From the date of transplant to date of death, assessed up to 100 days]: 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.
• 1-year Cumulative Incidence TRM [From the date of transplant to date of death, assessed at 1 year]: 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.
• 2-year Cumulative Incidence of TRM [From the date of transplant to date of death, assessed at 2 years]: 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.
• Overall Response Rate [Up to 2 years post-transplant]: The proportion of each type of response with a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution.
• Number of Patients With a Partial Response [Approximately 11 months]: The proportion of each type of response with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution.

Other outcomes

• Rate of Minimal Residual Disease-negativity [Baseline up to 365 days post-transplant]: Will be defined as the proportion of patients who achieved minimal residual disease-negative status at the respective time point, in accordance with the International Myeloma Working Group criteria. Minimal residual disease was evaluated by next-generation sequencing using ClonoSEQ Assay.

Sex: All, ages: 18 Years to 75 Years

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

Participant flow

Outcome results

• 2-year Progression-free Survival (PFS) (Primary)
• Incidence of Adverse Events (Secondary)
• Number of Patients With Grade II-IV Acute Graft-versus Host Disease (GvHD (aGVHD) (Secondary), Number, participants: Treatment (Conditioning Regimen, Stem Cell Transplant) 0
• Rate of Relapse (Secondary)
• Overall Survival (OS) (Secondary)
• 1- Year GVHD-free Relapse-free Survival (GRFS) (Secondary)
• 100-day Cumulative Incidence of Treatment-related Mortality (TRM) (Secondary)
• 1-year Cumulative Incidence TRM (Secondary)
• 2-year Cumulative Incidence of TRM (Secondary)
• Overall Response Rate (Secondary)
• Number of Patients With a Partial Response (Secondary), Number, patients: Treatment (Conditioning Regimen, Stem Cell Transplant) 1
• Rate of Minimal Residual Disease-negativity (Other pre specified)

Adverse events

Time frame: Adverse event information was collected for patients from baseline through study completion utilizing the CTCAE version 5.0 to determine the severity of the reaction for adverse event reporting from baseline to after study completion up to 1 year.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The trial was terminated early due to poor patient accrual

• Study Protocol and Statistical Analysis Plan (PDF, 2021-03-11)
• Informed Consent Form (PDF, 2021-03-11)

• Srinivas Devarakonda, M.D., Principal investigator, Ohio State University Comprehensive Cancer Center