Superior Outcomes With Bortezomib Or Thalidomide Incorporated Into Autologous Stem Cell Transplantation (ASCT) Versus Novel Agent-Based Treatments For Elderly Patients With Newly Diagnosed Multiple Myeloma (MM): A Case-Match Comparison

Whether incorporation of novel agents into ASCT can improve the outcome in comparison to novel agent-based treatments alone in newly diagnosed MM patients (pts) over 65 years of age still remains an open issue.

In this retrospective analysis we evaluated the outcome of 63 pts with a median age of 68 years (range 66-72) who were considered eligible to receive up-front novel agents and ASCT. To more carefully highlight the role of ASCT in this subset of older, but still fit, pts, we subsequently performed a pair-matched analysis with a population of pts treated with novel agent-based combinations without ASCT. At diagnosis, 50% of ASCT-eligible pts had ISS stage 2-3 and 24% had renal impairment. Cytogenetic abnormalities were evaluable in half of the pts: t(4;14) was present in 19% of them and 17p deletion in 15%. Induction therapies were bortezomib-based (37 pts) or thalidomide-based (26 pts) (median number of cycles received: 4) and affected at least VGPR in 57% and 36% of the pts, respectively. A median of 7.2 x 10⁶ CD34+ cells/kg (IQR 5.8-10.9) was collected following cyclophosphamide plus G-CSF (58 pts) or G-CSF alone (5 pts). Melphalan dose prior to ASCT was 200 mg/m² in 39/63 pts, while it was reduced to 140 mg/m²in the remaining pts, due to impaired renal function. Sixteen pts received a tandem ASCT. Hematologic recovery occurred at day 12 both for platelets and neutrophils (range 7-16 and 10-15, respectively). No transplant-related mortality was observed at 100 days. Two pts experienced grade 4 mucositis, while 13 pts (20%) presented grade 3 toxicities, mainly mucositis and infections. Overall, 98% of the pts achieved at least PR, including 79% at least VGPR and 51% CR. With a median follow up of 48 months, 4-years OS was 77%, median TTP and PFS were 42 and 43.4 months, respectively.

In order to better assess the potential additional benefits of ASCT with respect to novel agents alone, we performed a case-match comparison with a series of pts who were enrolled in two Gimema clinical trials for elderly pts (Palumbo et al, Lancet 2006 and Palumbo et al, JCO 2010) and were treated with either melphalan-prednisone-thalidomide (MPT) (78 pts) or melphalan-prednisone-bortezomib (MPV) (111 pts). Case matching was performed with a 1:3 ratio, with respect to the following patient characteristics at baseline: age (+/- 2 years), ISS stage and year of treatment; pts who had received bortezomib-based induction therapy were matched with pts treated with MPV, while pts who had received thalidomide-based induction were matched with pts treated with MPT. Baseline characteristics were similar between pts who received or not ASCT, including the frequency of high-risk cytogenetic abnormalities. The median number of MPT or MPV cycles actually received was 6; <10% of the pts received less than 2 cycles of therapy. The probability to achieve CR as a best response was significantly higher in the ASCT group in comparison to the control group (51% vs 29%, P= 0.002). Moreover, novel agent-based ASCT significantly prolonged both TTP (median, 43 vs 25 months for the control group, P=0.0013) and PFS (median, 43 vs 24 months for the MPT+MPV group, P=0.0007). Benefit with ASCT was evident also in terms of time to next treatment (TTnT) (median, 33 vs 23 months for the MPT+MPV group, P=0.0077). OS was similar between the two groups (66% at 48 months), as well post relapse OS (41% at 48 months in both groups). Appreciating that the treatments incorporating or not ASCT were conducted over different time periods, we performed a multivariate Cox regression analysis, that included different therapies, along with baseline and treatment-related features as prognostic factors. Variables significantly related to extended TTP and PFS included application of ASCT (P= 0.006 and P= 0.003), ISS 1 vs 2 and 3 (P= 0.03 and P= 0.01) and bortezomib-based therapy (P= 0.02 and P= 0.03). Prolonged OS was significantly related to attainment of CR as a best response and ISS 1 (P= 0.005 for both).

In conclusion, this analysis suggests that ASCT is feasible and well tolerated in selected MM pts aged >65. With the limitations of a retrospective case-match analysis and differences in the treatments, novel agents incorporated into ASCT seem to offer better outcomes in comparison with novel agent-based treatments alone and should be considered a valid option for fit elderly pts.