Outcomes of Salvage Autologous Stem Cell Transplant (ASCT) in Multiple Myeloma Patients Relapsed After An Initial ASCT and Refractory to Bortezomib and Immunomodulatory Agents

Although the prognosis for patients with multiple myeloma (MM) has improved with the use of immunomodulatory drugs thalidomide and lenalidomide, as well as with the proteasome inhibitor bortezomib, eventually all patients relapse and become refractory to all available treatments. The prognosis for MM patients refractory to these two novel classes of therapies is dismal, with estimated progression free survival (PFS) and overall survival (OS) of only 5 and 9 months respectively (Kumar et al, ASH 2010). (Of note, only 60% of these patients had received prior stem cell transplants (SCT)). While clinical trials would be ideal for these patients, many have cytopenias (often due to heavy marrow replacement) that fail to meet standard inclusion criteria for clinical trials. Since autologous stem cells remain viable for many years, we have been performing intermediate or high dose chemotherapy with autologous stem cell transplant (ASCT) as a disease temporizing measure and also as a possible bridge to clinical trial participation. Although the safety and efficacy of salvage ASCT in relapsed MM has been reported (Olin et al, BMT 2009 and Qazilbash et al, Cancer 2006), no studies have focused on the novel agent refractory population. We review here the outcomes of salvage ASCTs in 63 patients with heavily pre-treated, relapsed, and novel agent refractory MM.

Of the patients with MM who underwent ASCT between 1999 to 2010 at St Vincent’s hospital, we first identified those patients who had a second autologous stem cell infusion at least 12 months after the first (i.e. non tandem SCTs). Of the 435 patients who met this criteria, 63 were found to have not only progressed on bortezomib containing regimens but also were refractory to IMids (thalidomide or lenalidomide).

The median age at time of salvage ASCT was 60 years [range 36–75] at a median of 5.6yrs [range 1.5 to 15.9] since the diagnosis of MM. Patients had a median of 5 lines of prior treatment [range 2–9] and a median of 58 months since the first auto SCT[range 12–164]. The median PFS in 59 evaluable patients after the initial ASCT was 21.6 months [range 4.5–76.8]. Of 58 evaluable patients, 56 patient were treated with a mephalan based conditioning regimen for the salvage ASCT including 11 at 200 mg/m2, 10 at 140 mg/m2, 24 at 100 mg/m2, and 11 who received 50–75 mg/m2. 27 of these patients received bortezomib with the melphalan conditioning and 3 patients received BCNU with melphalan. 2 other patients received VDT-PACE. 26 of these patients received their chemotherapy and stem cells in the outpatient setting. Of the available data, adverse effects included diarrhea in 3 patients, with grade 2 being the worst grade. Three patients had mucositis, one with grade 3.

Of the 58 patients evaluable for response at day 100 post salvage SCT, 7 had a CR, 3 near CR, 5 VGPR, and 16 PR for an overall response rate of 53% by IMWG criteria. An additional 2 patients had SD. 25 patients had PD including 3 patients who died of PD within 30 days. The median PFS was 5.5 months [1.1–36 months] in 32 evaluable patients and median OS in 59 evaluable patients was 8.5 months [8 days-60 months]. 6 patients remain alive at a median of 16 months [7.7 – 53 months].

Of 23 patients with baseline ANC < 1500 or plt < 50k making them ineligible for most clinical trials prior to salvage auto SCT, 20 (87%) exceeded those cut-offs at day 100 whereas 3 patients did not. Two of these patients died of PD at 3.1 and 6.4 months. The third had delayed platelet recovery and died of PD at 29 months. Results of univariate and multivariate analysis will be presented at the annual meeting.

In a heavily pretreated population of patients with MM (median 5 lines of prior therapy) refractory to bortezomib and IMIDs, salvage auto SCT was associated with an overall response rate of 53%, a median OS of 8.5 months and PFS 5.5 months. Importantly, 87% of patients with cytopenias precluding clinical trial participation demonstrated hematologic recovery post salvage ASCT. This study demonstrates a continuing role for salvage ASCT in cytopenic, heavily pretreated, novel agent refractory patients with MM as a possible bridge to clinical trials.

Chari:Millenium Takeda:; Celgene:. Jagannath:Celgene: Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees.