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

Trial Status: Approved

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. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving a reduced 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.

Inclusion Criteria

  • High risk relapsed multiple myeloma (MM) patients and who have received at least 2 prior lines of therapy, and have obtained at least a partial response from their salvage chemotherapy (chemo). High risk patients are one or more of the following: 1: patients who progressed within 24 months from their first autologous stem cell transplant (criteria from the Blood and Marrow Transplant Clinical Trials Network [BMT/CTN] 1302 (clinicaltrials.gov identifier: NCT02440464); 2: Patients with at least 2 prior lines of therapy with progression within 12 months from their last line of therapy; 3: Patients with with high risk markers (del13 by converter [conv.] karyotyping only; hypodiploidy, 1q amplification or 1p deletion, t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization [FISH] or conv. karyotyping; Revised Multiple Myeloma International Staging System [R-ISS] 3; or Beta-2M >= 5.5 mg/L)
  • Patients with nonsecretory myeloma are eligible for the study. Assessments of response will be based on positron emission tomography (PET) scans
  • Prior radiation is allowed as this is a very vital management of myeloma bone disease
  • Patients with >= partial response (PR) prior to allo-HSCT
  • First allogenic transplant
  • Ejection fraction >= 45%
  • Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault formula and actual body weight)
  • 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 (Patient who have been diagnosed with Gilbert’s disease are permitted to exceed the defined bilirubin value of 2 x the upper limit of normal)
  • Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) through 90 days after the last dose of maintenance therapy
  • Male subjects (even if surgically sterilized) must agree to one of the following: practice effective barrier contraception, or practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of from the time of signing the informed consent through 90 days after last dose of maintenance therapy
  • Understand and voluntarily sign an informed consent
  • Able to comply with the study visit schedule and other protocol requirements
  • PRIOR TO INITIATING MAINTENANCE THERAPY: Platelet count >= 75,000/mm^3
  • PRIOR TO INITIATING MAINTENANCE THERAPY: Absolute neutrophil count (ANC) >= 1000/mm^3
  • PRIOR TO INITIATING MAINTENANCE THERAPY: Total bilirubin < 2 x the upper limit of the normal range (ULN), except in patients with Gilbert’s syndrome
  • PRIOR TO INITIATING MAINTENANCE THERAPY: ALT/AST < 2.5 x the upper normal limit
  • PRIOR TO INITIATING MAINTENANCE THERAPY: No >= grade 2 visceral (gut or liver) acute GVHD. No >= grade 3 any other acute GVHD
  • PRIOR TO INITIATING MAINTENANCE THERAPY: All non-hematologic toxicities should have resolved to =< grade 1
  • PRIOR TO INITIATING MAINTENANCE THERAPY: Negative for hepatitis B virus by polymerase chain reaction (PCR)
  • PRIOR TO INITIATING MAINTENANCE THERAPY: Patients must be in at least a partial response
  • STEM CELL DONOR AND SOURCE: Matched related
  • STEM CELL DONOR AND SOURCE: Matched unrelated
  • STEM CELL DONOR AND SOURCE: 1 antigen mismatch related or unrelated
  • STEM CELL DONOR AND SOURCE: Haploidentical
  • STEM CELL DONOR AND SOURCE: Peripheral stem cell source will be used except in haploidentical where Bone marrow stem cells will be required

Exclusion Criteria

  • Karnofsky performance score < 70%
  • Planned pre-emptive/prophylactic administration of donor lymphocytes
  • Active central nervous system (CNS) involvement with multiple myeloma defined as cerebral spinal fluid (csf) positivity for plasma cells or a parenchymal CNS plasmacytoma
  • Patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS), Waldenstrom macroglobulinemia
  • Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement) at time of enrollment)
  • 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
  • Patients seropositive for the human immunodeficiency virus (HIV)
  • Patient with active hepatitis B or C determined by serology and/or nucleic acid amplification test (NAAT)
  • Patients with > grade 2 sensory peripheral neuropathy
  • Myocardial infarction within 6 months prior to enrollment, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant
  • Failure to have fully recovered (i.e. no toxicities > grade 1) from the reversible effects of prior chemotherapy
  • Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study
  • Hypersensitivity to any of the drugs involved in this trial
  • Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial
  • Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy
  • Major surgery within 14 days of start of trial
  • Patients unable or unwilling to adhere to the study assessment schedule
  • Female patients who are pregnant or breastfeeding. A negative pregnancy test will be required for all women of child bearing potential
  • DONOR: Donors will be excluded if they are an identical twin of the recipient
  • DONOR: Females who are pregnant (positive serum beta human chorionic gonadotropin [HCG]) or uninterruptible breastfeeding will be excluded
  • DONOR: HIV seropositive donors will be excluded
  • DONOR: Donors receiving experimental therapy or investigational agents will be excluded unless approved by the protocol chair and officer
  • DONOR: Donors not willing and able to donate peripheral blood stem cells (PBSC) will be excluded
  • DONOR: Related and unrelated donors will be identified according to institutional guidelines

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: APPROVED
Contact: Yvonne Adeduni Efebera
Phone: 614-293-2268

PRIMARY OBJECTIVES:

I.To obtain preliminary data on the effect of the combined treatment regimen on clinical outcomes.

Ia. To develop a platform for allogeneic (allo) hematopoietic stem cell transplantation (HSCT) in relapsed multiple myeloma patients to obtain preliminary data on the effect of combined treatment regimen on clinical outcomes.

SECONDARY OBJECTIVES:

I. To determine the 2 year progression-free survival (PFS).

II. To determine 2 year overall survival (OS).

III. To determine the cumulative incidence of grade II-IV acute-graft-versus-host-disease (aGVHD) at day 100 and 180.

IV. To determine the 100 days, 1 year and 2 year cumulative incidence of treatment-related mortality (TRM).

V. To assess one-year GVHD-free relapse-free survival (GRFS).

VI. To determine the cumulative incidence of chronic graft-versus-host disease (cGVHD).

VII. To assess overall and best response rates 100 days after allo hematopoietic cell transplantation (HCT), 3 months, 6 months and every 6 months thereafter until end of daratumumab maintenance.

VIII. To determine rate of relapse after allo HSCT followed by maintenance.

IX. 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.

IX. 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 IV on days 3 and 4, tacrolimus orally (PO) 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 1 year after end of daratumumab treatment.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Ohio State University Comprehensive Cancer Center

Principal Investigator
Yvonne Adeduni Efebera

  • Primary ID OSU-19190
  • Secondary IDs NCI-2019-07892, 2019C0218
  • Clinicaltrials.gov ID NCT04205240