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

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.

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.

Eligibility Criteria:
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