Refractory Multiple Myeloma
Conditions
Brief summary
This phase I/II trial studies the side effects of giving reduced-intensity conditioning followed by donor peripheral blood stem cell transplant (PBSCT) and how well it works in treating patients with multiple myeloma (MM). Giving low doses of chemotherapy, such as fludarabine phosphate and melphalan, and total-body irradiation (TBI) before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after transplant may stop this from happening.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the efficacy of this approach by determining the 1-year progression-free survival (PFS) and overall survival (OS). II. To evaluate day 100 non-relapse mortality. III. To determine the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD. OUTLINE: PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donors). After completion of study treatment, patients are followed up at 3, 6, 12, 18, and 24 months, and then annually thereafter for 5 years.
Interventions
DRUGfludarabine phosphate
Given IV
DRUGmelphalan
Given IV
RADIATIONtotal-body irradiation
Undergo TBI
DRUGmycophenolate mofetil
Given PO
DRUGcyclosporine
Given PO
PROCEDUREnonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo reduced-intensity allogeneic PBSCT
PROCEDUREperipheral blood stem cell transplantation
Undergo reduced-intensity allogeneic PBSCT
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Meet Salmon and Durie criteria for initial diagnosis of MM; transplant will be offered to patients with previously treated MM who meet one of the following criteria: * Patient received at least one prior autologous or syngeneic hematopoietic SCT (HSCT) and now has progressive disease (PD) (greater than 25% increase in serum or urine paraprotein levels compared to best response status after autograft or appearance of new lytic bone lesions or plasmocytomas) * Patient is not able to collect autologous PBSC due to poor marrow reserve (insufficient HSC-mobilization: \< 2.5 x 10\^6 cluster of differentiation \[CD\]34+ cells/kg); or contraindications to undergoing HSC-mobilization; patient now has PD and has received at least 4 cycles of standard chemotherapy (e.g. vincristine sulfate, doxorubicin hydrochloride, and dexamethasone \[VAD\]) in the past * Patients must have the capacity to give informed consent * DONOR: Human leukocyte antigen (HLA) genotypically identical sibling or phenotypically matched relative * DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria) * Matched for serologically recognized HLA-A or B or C antigens and at least five of six HLA-A or B or C alleles * Matched for HLA DRB1 and DQB1 alleles (defined by high-resolution typing) at the allele level * DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for PBSC collection * DONOR: Donor must have adequate veins for leukapheresis or agree to placement of a temporary central venous catheter
Exclusion criteria
* Karnofsky score \< 60% * Left ventricular ejection fraction \< 40% or symptomatic heart failure; ejection fraction is required if age \> 50 years or there is a history of anthracycline exposure or history of cardiac disease * Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL,or symptomatic biliary disease * Diffusion capacity of carbon monoxide (DLCO) \< 50% (corrected) or receiving continuous supplemental oxygen * Creatinine clearance \< 40 mL/min * Patients with poorly controlled hypertension * Seropositive for the human immunodeficiency virus (HIV) * Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \> 20% risk of disease recurrence * Pregnancy or breastfeeding * Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * Not fully recovered from previous high-dose therapy: * Persistent mucositis and gastrointestinal symptoms requiring hyperalimentation and/or intravenous hydration * On steroids for autologous/syngeneic GVHD * On IV antibiotics for documented infections * Cytomegalovirus (CMV)-antigenemia positive * On ganciclovir or foscarnet for previous CMV reactivation/infection; off of this therapy for less than two weeks despite documented CMV-antigenemia- negativity (identification \[ID\] should be consulted if there is persistent CMV antigenemia post autograft) * Ongoing radiotherapy * Patients who meet any of these criteria may be discussed with the principal investigator for recommendations as to the timing of the allograft * Patients with active bacterial or fungal infections unresponsive to medical therapy * DONOR: Identical twin * DONOR: Donors unwilling to donate PBSC * DONOR: Pregnancy * DONOR: Infection with HIV * DONOR: Inability to achieve adequate venous access * DONOR: Known allergy to G-CSF * DONOR: Current serious systemic illness * DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation * DONOR: Age \< 12 years * DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Chronic (Extensive) GVHD | Up to 5 years | Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. |
| PFS | At 1 year post-transplant | PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas. |
| Non-relapse Mortality | At day 100 | Early NRM will be monitored in a sequential fashion. |
| Incidence of Acute GVHD (Grades III-IV) | Up to 5 years | Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OS | At 6 months and then every year thereafter, up to 5 years | Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated. |
| Engraftment | Up to 5 years | Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion. |
| Relapse Rate | Up to 5 years | Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates. |
| Response Rate | Up to 5 years | Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates. |
Countries
Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Related Donor PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).
fludarabine phosphate: Given IV melphalan: Given IV
total-body irradiation: Undergo TBI
mycophenolate mofetil: Given PO
cyclosporine: Given PO
nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT
peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT
laboratory biomarker analysis: Correlative s | 12 |
| Unrelated Donor PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors).
fludarabine phosphate: Given IV melphalan: Given IV
total-body irradiation: Undergo TBI
mycophenolate mofetil: Given PO
cyclosporine: Given PO
nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT
peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT
laboratory biomarker analysis: Correlative s | 4 |
| Total | 16 |
Baseline characteristics
| Characteristic | Related Donor | Unrelated Donor | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 3 Participants | 13 Participants |
| Region of Enrollment Italy | 4 participants | 0 participants | 4 participants |
| Region of Enrollment United States | 8 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 12 | 1 / 4 |
| other Total, other adverse events | 9 / 12 | 2 / 4 |
| serious Total, serious adverse events | 4 / 12 | 1 / 4 |
Outcome results
Primary
Incidence of Acute GVHD (Grades III-IV)
Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Incidence of Acute GVHD (Grades III-IV) | 2 Participants |
| Unrelated Donor | Incidence of Acute GVHD (Grades III-IV) | 0 Participants |
Primary
Incidence of Chronic (Extensive) GVHD
Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Incidence of Chronic (Extensive) GVHD | 4 Participants |
| Unrelated Donor | Incidence of Chronic (Extensive) GVHD | 1 Participants |
Primary
Non-relapse Mortality
Early NRM will be monitored in a sequential fashion.
Time frame: At day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Non-relapse Mortality | 1 Participants |
| Unrelated Donor | Non-relapse Mortality | 1 Participants |
Primary
PFS
PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas.
Time frame: At 1 year post-transplant
Population: There were 4 patients who, although they did not have progression/relapse, died before the 1 year mark, and thus are not included in the 1 year PFS count.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | PFS | 4 Participants |
| Unrelated Donor | PFS | 1 Participants |
Secondary
Engraftment
Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Engraftment | 12 Participants |
| Unrelated Donor | Engraftment | 4 Participants |
Secondary
OS
Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated.
Time frame: At 6 months and then every year thereafter, up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Related Donor | OS | 2 Years | 4 Participants |
| Related Donor | OS | 6 Months | 8 Participants |
| Related Donor | OS | 1 Year | 5 Participants |
| Related Donor | OS | 3 Years | 3 Participants |
| Related Donor | OS | 4 Years | 3 Participants |
| Related Donor | OS | 5 Years | 3 Participants |
| Unrelated Donor | OS | 4 Years | 0 Participants |
| Unrelated Donor | OS | 2 Years | 0 Participants |
| Unrelated Donor | OS | 3 Years | 0 Participants |
| Unrelated Donor | OS | 6 Months | 3 Participants |
| Unrelated Donor | OS | 5 Years | 0 Participants |
| Unrelated Donor | OS | 1 Year | 2 Participants |
Secondary
Relapse Rate
Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Relapse Rate | 1 Participants |
| Unrelated Donor | Relapse Rate | 1 Participants |
Secondary
Response Rate
Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Related Donor | Response Rate | 2 Participants |
| Unrelated Donor | Response Rate | 1 Participants |