The Use of Combination PACE Regimens for Patients with Relapsed and Refractory Multiple Myeloma (MM) and Their Impact on Stem Cell Transplantation (SCT)

The treatment of newly diagnosed multiple myeloma (MM) has dramatically improved with the introduction of immune modulating agents and proteasome inhibitors. However, the management of patients with relapsed or refractory disease remains challenging. For these patients, one approach is the use of the chemotherapy combination PACE (cisplatin, adriamycin, cyclophosphamide, and etoposide) in conjunction with thalidomide, lenalidomide or often bortezomib. At Memorial Sloan-Kettering Cancer Center (MSKCC), these PACE-based regimens are utilized as salvage option, prior to first autologous stem cell transplantation (ASCT) for patients with disease refractory to usual induction therapy or as salvage regimen in patients with relapsed, often heavily pre-treated MM in an attempt to proceed to salvage SCT. The objective of this study is to describe the experience in using PACE regimens in relapsed and refractory patients with MM at MSKCC and their impact on SCT.

We preformed a retrospective chart review of all patients with MM who were treated with a combination regimen of VDT (bortezomib, dexamethasone and thalidomide)-PACE, DT (dexamethasone and thalidomide)-PACE, or DR (dexamethasone and lenalidomide)-PACE between 1/2007 and 6/2010 at MSKCC. After obtaining IRB-waiver, patient demographics, baseline disease characteristics, treatment and transplant history were collected using the hospital's pharmacy database and electronic medical records. Responses were graded according to the International uniform myeloma response criteria. The number of patients that were able to undergo stem cell collection and/or transplant, as well as transplant-related mortality and overall survival were also determined.

A total of 32 refractory/relapsed patients with MM who received either VDT-PACE, DT-PACE, or DR-PACE regimen were included in the study. Ten patients received the treatment as a bridge to first ASCT (upfront cohort) and 22 as salvage prior to second or third ASCT or allogenic SCT (salvage cohort). Half of the patients in the upfront cohort received VDT-PACE (N=5), and the remainder received either DT-PACE (N=4) or DR-PACE (N=1). The majority of patients in the salvage cohort received DT-PACE (N=19), but others received VDT-PACE (N=2) and DR-PACE (N=1). Of the 10 patients in the upfront cohort, 20% achieved a partial response (PR), 40% stable disease (SD), 10% had progression of disease (PD) and 30% could not be assessed. Eighty percent of patients were successfully mobilized (defined as CD34+ > 2 × 10⁶cells/kg) and 50% (N=5) proceeded to ASCT. The remaining 50% did not undergo autologous SCT, due to disease progression (N=3), treatment-related debility (N=1) and (N=1) was lost to follow up. In the salvage cohort, 18% achieved a complete response CR, 9% very good partial response VGPR, 23% PR, 14% SD and 36% PD following treatment with PACE combinations. Fifty-five percent of patients proceeded to SCT, including 6 patients who received salvage autologous SCT and 6 allogenic SCT. Transplant related mortality in both cohorts was 6% (1/17) with a single death occurring in a relapsed patient (salvage cohort) who underwent allogenic SCT. The median overall survival in the upfront cohort was significantly longer for patients who proceeded to SCT compared to those who did not, 12 versus 3.5 months. The median overall survival of patients in the salvage cohort who received SCT was 9.3 compared to 5.8 months in those who were not able to undergo SCT.

At MSKCC PACE regimens controlled disease in patients with relapsed/refractory MM with responses seen in patients who were heavily pretreated including those with prior transplantation. This treatment allowed over half of the patients to proceed to SCT and those who underwent autologous or allogeneic SCT after PACE regimens had a longer survival. However, outcomes for relapsed and refractory patients with MM remain poor and other strategies such as maintenance or immunotherapy following first or subsequent transplant should be studied in order to extend the survival of these patients.

Giralt:CELGENE: Consultancy, Honoraria, Speakers Bureau; MILLENIUM: Consultancy, Honoraria, Speakers Bureau; NOVARTIS: Consultancy, Honoraria; GENZYME: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria; ONYX: Consultancy, Honoraria.