Outcomes Of Allogeneic Blood Or Marrow Transplantation (AlloBMT) In Multiple Myeloma With Post-Transplantation Cyclophosphamide (PTCy)

AlloBMT is a potentially curative treatment for multiple myeloma (MM). However, its effectiveness has been compromised by high transplant related mortality (TRM) and acute and/or chronic graft-versus host disease (GvHD). Our development of PTCy has reduced the incidence of GvHD allowing safe and effective related haploidentical alloBMT. PTCy promotes tolerance in both alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloBMT.

As part of an IRB-approved study we performed a retrospective analysis on all patients with MM who underwent alloBMT followed by PTCy. A total of 39 patients who were transplanted between 2003 and 2011 were identified. All patients received 2 doses of PTCy 50mg/kg on days 3 and 4 after alloBMT. High risk MM was defined as having any one of the following: del(13q) by cytogenetics or t(4;14), t(14;16), t(14;20), -17p ,+1q21 on FISH/cytogenetics. International Staging System (ISS) stage was based on beta2 microglobulin and albumin at diagnosis of symptomatic MM. The definitions of progression, stable disease and response were as per the International Myeloma Working Group criteria. Survival probability was determined using Kaplan-Meier method and differences assessed with the log-rank test. Cox regression was used to model prognostic factors with respect to progression-free (PFS) and overall survival (OS) rates.

The median follow-up for living patients was 80 months (22-115). The minimum follow up was 23 months. The median age at BMT was 54 (range 37-70). 30 patients (77%) received a transplant from a matched sibling donor. Of the remaining 9 patients, 7 (18%) received a transplant from a haploidentical donor and 2 (5%) from a matched unrelated donor. 28 patients (72%) were in > PR at the time of alloBMT. Only 1 patient (3%) was in a CR prior to alloBMT. Thirty patients (77%) received reduced intensity conditioning and the remaining 9 patients (23%) received myeloablative conditioning. 28 patients (72%) received unmanipulated bone marrow, while remaining 11 patients (28%) received mobilized peripheral blood cells. The median time between diagnosis and alloBMT was 10.6 months (4.1-178.7). Cytogenetics and FISH for evaluating high risk MM were available for 26 patients (66.6%) and of those 15 patients (58%) had high risk features. 28 patients (72%) were evaluable for ISS at diagnosis and of those 13 patients (46%) had ISS III at diagnosis. 36 patients (92%) had been treated with either bortezomib based or immunomodulatory (Imid) based therapy prior to alloBMT. 7 patients (18%) had received an autologous transplant prior to alloBMT. 20 patients (51%) are alive after a median follow up of > 6 years after alloBMT. Only 1 (2.5%) patient died from complications related to alloBMT. At last follow up, 6 patients (15%) are in sustained first complete remission after alloBMT. Of the 9 patients who received myeloablative prep, 6 are alive and 3 are in sustained CR. At 6 months following alloBMT, 12 patients (31%) were in a deeper response compared to their pre-transplant status. 15 patients (38%) developed > grade 2 acute GvHD at a median of 1.5 (range 0.6-4.5) months. Only 3 patients (8%) developed grade 3 acute GvHD and there was no grade 4 acute GVHD. 14 (36%) patients received systemic treatment for acute GvHD. 5 (13%) patients developed chronic GvHD. The median OS was 96 months, and the median PFS was 14 months (95% CI 6.2-32.8). Chronic GvHD was significantly associated with PFS, with a median PFS of 90 months in patients who developed cGvHD compared to 11 months in patients who did not (hazard ratio = 0.3, 95% CI 0.07-1.25). The major cause of death was disease progression.

The use of PTCy led to a very low TRM in MM, including with related haploidentical donors. Although only a minority of patients maintained long-term PFS, the prolonged OS allows incorporation of novel post-alloBMT strategies to improve disease control.

Off Label Use: Outcomes of Allogeneic Blood Or Marrow Transplantation (AlloBMT) In Multiple Myeloma With Post-Transplantation Cyclophosphamide (PTCy).