Abstract 4108

Background:

The absence of contaminating tumor cells in the graft and the potential for a graft- versus- myeloma (GVM) effect make allogeneic hematopoietic stem cell transplantation (allo-HCT) a useful treatment option for patients with multiple myeloma (MM). Reduced-intensity conditioning (RIC) allo-HCT has led to a more acceptable TRM rate of approximately 10–15%, while preserving the GVM effect. We have previously studied the feasibility of a lower dose of melphalan (100 mg/m2) for allo-HCT for acute myeloid leukemia (AML) [Estey et al. Blood 2007].

Methods:

We conducted a randomized phase II trial of two RIC regimens, fludarabine + melphalan 140 mg/m2 (FM140) versus fludarabine + melphalan 100 mg/m2 (FM100) before allo-HCT from related or unrelated donors. The basic hypothesis was that a lower dose of melphalan would result in less toxicity and less GVHD without compromising the engraftment and disease control. Twenty-three patients received 4 weekly doses rituximab 375 mg/m2 as part of their preparative regimen to further reduce the risk of chronic GVHD (Kebriaei et al. BMT 2006). Patients were randomized fairly between the two treatment arms using adaptive dynamic allocation to balance on chemosensitivity and donor type (related vs. unrelated). GVHD prophylaxis consisted of tacrolimus and methotrexate.

Results:

Fifty allo-HCT patients were randomized between April 2002 and April 2011, 27 to FM140 and 23 to FM100. All patients had a prior auto-HCT and 80% patients had at least one relapse before allo-HCT. Patient characteristics were well matched between the 2 cohorts (Table). The FM100 had more related donors (91% vs. 65%, p=0.01). There were no significant differences between FM140 and FM100 in time to neutrophil engraftment (median 12 days; p=0.21), acute grade II-IV GVHD (22% vs. 21%; p=1.0), chronic GVHD (29% vs. 48%; p=0.24), or CR + VGPR (48 vs. 43%; p=1.0). One-year TRM was 15% in FM140 group, and 13% in the FM100 group (p=1.0). Median PFS for FM140 and FM100 were 8.3 and 11.7 months, respectively (p=0.12).The median OS for FM140 and FM100 were 1.6 and 2.9 years, respectively (p=0.38). The cumulative incidence of disease progression in FM140 and FM100 was 70% and 43%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM 140 (44%) and FM100 (26%). Eight patients (FM140 5, FM100 3) received donor lymphocyte infusions after allo-HCT, and only 6 patients (FM140 4, FM100 2) received maintenance therapy after allo-HCT. Multivariate Cox models showed patients with high-risk or standard-risk cytogenetic abnormalities had similar PFS and OS (p=0.10 and 0.64), and patients with chemoresistant (<PR or PD) or chemosensitive (>/=PR) disease at allo-HCT had similar PFS and OS (p=0.56 and 0.73).

Conclusions:

This single center, prospective, randomized trial illustrates that the reduction in melphalan dose had no adverse impact on engraftment, response rate, PFS or OS. RIC allo-HCT is safe and can overcome adverse impact of HR cytogenetics and chemoresistant disease in a subset of heavily pretreated patients. Disease relapse remains a problem. The use of post-transplant maintenance therapy, pre-emptive DLI and vaccines will be explored in future trials.

Table:

Patient Characteristics and Outcome

FM140FM100p Value
Male/Female 19/8 11/12 0.15 
Median age 52 53 0.21 
High-risk Cytogenetics 11 (40%) 8 (38%) 0.77 
> 2 prior auto-HCT 9 (33%) 4 (17%) 0.33 
Disease status at allo-HCT < PR 9 (33%) 8 (35%) 1.0 
Median Interval Diagnosis to allo-HCT (months) 30.7 34.6 0.56 
Donor: unrelated 12 (44%) 2 (9%) 0.01 
Rituximab 14 (52%) 9 (23%) 0.40 
Maintenance 0.71 
DLI 0.66 
Median days to ANC >500 12 12 0.21 
CR+VGPR 14 (52%) 11 (48%) 1.0 
CR+VGPR+PR (Final) 7+7+8 (81%) 6+5+8 (82%) 1.0 
100-day TRM 1 (3.7%) 0 (0%) 1.0 
1-year TRM 4 (15%) 3 (13%) 1.0 
Disease Progression 19 (70%) 10 (43%) *p=0.08 0.08 
Acute GVHD- grade 2-4 6 (22%) 5 (21%) 1.0 
Chronic GVHD 8 (29%) 11 (48%) 0.24 
Grade 3-4 toxicities 23 (85%) 19 (82%) 1.0 
FM140FM100p Value
Male/Female 19/8 11/12 0.15 
Median age 52 53 0.21 
High-risk Cytogenetics 11 (40%) 8 (38%) 0.77 
> 2 prior auto-HCT 9 (33%) 4 (17%) 0.33 
Disease status at allo-HCT < PR 9 (33%) 8 (35%) 1.0 
Median Interval Diagnosis to allo-HCT (months) 30.7 34.6 0.56 
Donor: unrelated 12 (44%) 2 (9%) 0.01 
Rituximab 14 (52%) 9 (23%) 0.40 
Maintenance 0.71 
DLI 0.66 
Median days to ANC >500 12 12 0.21 
CR+VGPR 14 (52%) 11 (48%) 1.0 
CR+VGPR+PR (Final) 7+7+8 (81%) 6+5+8 (82%) 1.0 
100-day TRM 1 (3.7%) 0 (0%) 1.0 
1-year TRM 4 (15%) 3 (13%) 1.0 
Disease Progression 19 (70%) 10 (43%) *p=0.08 0.08 
Acute GVHD- grade 2-4 6 (22%) 5 (21%) 1.0 
Chronic GVHD 8 (29%) 11 (48%) 0.24 
Grade 3-4 toxicities 23 (85%) 19 (82%) 1.0 

PR= partial remission, DLI= donor lymphocyte infusion, TRM= transplant-related mortality

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.

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