Recurrent Plasma Cell Myeloma
Conditions
Brief summary
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
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.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
DRUGCyclophosphamide
Given IV
BIOLOGICALDaratumumab
Given IV
DRUGFludarabine
Given IV
DRUGMelphalan
Given IV
DRUGMycophenolate Mofetil
Given IV or PO
DRUGTacrolimus
Given PO or IV
Sponsors
Srinivas Devarakonda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic stem cell transplantation
Cyclophosphamide: Given IV
Daratumumab: Given IV
Fludarabine: Given IV
Melphalan: Given IV
Mycophenolate Mofetil: Given IV or PO
Tacrolimus: Given PO or IV | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Treatment (Conditioning Regimen, Stem Cell Transplant) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 1 / 1 |
Outcome results
Primary
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.
Time frame: From the date of transplant until the date of relapse or date of death from any cause, assessed at 2 years
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: From the date of transplant to date of death, assessed up to 100 days
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: From the date of transplant to date of death, assessed at 1 year
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: 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
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: From the date of transplant to date of death, assessed at 2 years
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: Up to 2 years post-transplant
Population: Data was unable to be collected and analyzed due to low patient accrual to study
Secondary
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.
Time frame: Approximately 11 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Conditioning Regimen, Stem Cell Transplant) | Number of Patients With a Partial Response | 1 patients |
Secondary
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.
Time frame: Up to 6 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Conditioning Regimen, Stem Cell Transplant) | Number of Patients With Grade II-IV Acute Graft-versus Host Disease (GvHD (aGVHD) | 0 participants |
Secondary
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.
Time frame: Up to 2 years post-transplant
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
Overall Survival (OS)
A similar analysis approach described above for PFS will be applied for the OS analysis.
Time frame: From the date of transplant to death or last contact date if no death, assessed up to 2 years
Population: Due to low patient accrual to study unable to collect and analyze data
Secondary
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.
Time frame: From the date of transplant to relapse treating death from any cause as a competing risk, assessed up to 2 years
Population: Due to low patient accrual to study unable to collect and analyze data
Other Pre-specified
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.
Time frame: Baseline up to 365 days post-transplant
Population: Due to low patient accrual to study unable to collect and analyze data