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

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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Drug: Cyclophosphamide; Biological: Daratumumab; Drug: Fludarabine; Drug: Melphalan; Drug: Mycophenolate Mofetil; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Tacrolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (conditioning regimen, stem cell transplant); 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.

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Minimal Residual Disease-negativity	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.	Baseline up to 365 days post-transplant

Collaborators and Investigators

• Sponsor: Srinivas Devarakonda
• Investigators: Principal Investigator: Srinivas Devarakonda, M.D., Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2020
• Primary Completion (Actual): May 8, 2021
• Study Completion (Actual): November 22, 2021

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 18, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Daratumumab; Melphalan; Fludarabine; Tacrolimus; Mycophenolic Acid; Mechlorethamine; Nitrogen Mustard Compounds
• Other Study ID Numbers: OSU-19190; NCI-2019-07892 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No