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A Second Autologous Stem Cell Transplant (ASCT2) Induces Superior Durability Of Response (DuR) Following Bortezomib-Containing Re-Induction Therapy For Relapsed Multiple Myeloma (MM): Final Results From The BSBMT/Ukmf Myeloma X (Intensive) Trial

Gordon Cook, Cathy D. Williams, David A Cairns, Marie Fletcher, J. D. Cavenagh, John A Snowden, Christopher Parrish, John Ashcroft, Kwee L Yong, Jim Cavet, Hannah Hunter, Jennifer Bird, Sheila J O'Connor, Julia MB Brown and Treen Morris

Abstract

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Introduction Although ASCT in MM is standard consolidative therapy in first line treatment definitive evidence for its use in salvage therapy is lacking. The principal aim of this multi-centre phase III randomised controlled trial was to evaluate the durability of response (DuR) of a second ASCT compared with a less intensive alkylating agent consolidation, after a bortezomib-containing re-induction strategy.

Patients and Methods Eligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with PAD therapy (Bortezomib 1.3mg/m2 iv D1, 4, 8 & 11; Doxorubicin 9mg/m2/day iv D1-4; Dexamethasone 40mg/day PO D1-4: additionally D8-11 & D15-18 on cycle 1 only) delivered in 4-6 21-day cycles before 1:1 randomization to either a second ASCT (Melphalan 200mg/m2 iv; ASCT2 supported by either stored stem cells or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (C-weekly). Response assessment (by IMWG criteria) was analyzed after re-induction and 100 days post-randomization and time-to-disease progression (TTP) determined. Patients were stratified by β2microglobulin (β2M) at trial entry and response to re-induction and analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4,14), t(14,16) and del17p). The primary endpoint was Time-to-progression (TTP) with secondary endpoints of OS, overall response rate (to PAD and randomized intervention), feasibility of stem cell mobilization in salvage therapy, safety & quality of life.

Results The Data and Safety Monitoring Board (DSMB) recommended randomization closure and early result release owing to the primary end-point having been met. 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n = 89, C-weekly n = 85. Median age was 61 (range 38 -75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4%% with 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher in ASCT2 (39.3%, 95% CI 29.1, 50.3) than C-weekly (22.4%, 95% CI 14.0, 32.7) cohorts with more patients upgrading response to sCR/CR in the ASCT2 (n = 22) than C-weekly (n = 7) cohorts. At the time of analysis, 125 of 174 patients have progressed, 57 in the ASCT2 (64%) and 68 in the C-weekly (80%) cohorts. Median TTP was 19 months (95% CI 16, 25) for ASCT2 compared with 11 months (95% CI 9, 12) for C-weekly (HR 0.36 95% CI 0.25, 0.53; Cox regression analysis p<0.0001). Response to re-induction therapy (HR 2.90, 95% CI 1.45, 5.63; p = 0.0017) and DuR from ASCT1 (HR 3.49, 95% CI 1.07, 11.45; p = 0.039) had a significant impact on TTP. The median β2M level at registration was 2.7mg/L (range 1.3- 11.6) with a trend to improved TTP in patients undergoing ASCT2 when a β2M was <3.5 vs ≥ 3.5mg/L (HR 0.48, 95%CI 0.21, 1.08; p = 0.077). The presence of unfavorable iFISH did not impact on TTP in the C-weekly cohort but had a significant impact on TTP in the ASCT2 cohort (interaction HR 0.08, 95% CI 0.02, 0.41; p = 0.0024). TTP in patients with unfavorable iFISH was similar in the ASCT2 and C-weekly cohorts. Overall, 15 (17%) in the ASCT2 and 17 (20%) in the C-weekly arms have died with PD accounting for 8 and 9 deaths, respectively. Currently, there is no impact of the post-randomization intervention on OS (HR 0.62, 95%CI 0.3, 1.3; p = 0.193), though interpretation is limited by the current short follow-up and patients in the C-weekly cohort who received a second ASCT after reaching the primary end-point.

Conclusion The final analysis demonstrates a clear advantage in terms of durability of response when a second high dose Melphalan-conditioned ASCT consolidates re-induction therapy with a bortezomib-containing regimen in myeloma patients at first relapse. The impact on overall survival and quality of life remains to be clarified.

Disclosures: Cook: Janssen: Honoraria, Research Funding, Speakers Bureau. Williams: Janssen: Honoraria, Speakers Bureau. Snowden: Janssen: Honoraria, Research Funding, Speakers Bureau. Cavet: Janssen: Research Funding.

  • * Asterisk with author names denotes non-ASH members.

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