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
Authors: Cook Gordon , Williams Cathy D. , Cairns David A , Fletcher Marie , Cavenagh J. D. , Snowden John A , Parrish Christopher , Ashcroft John , Yong Kwee L , Cavet Jim , Hunter Hannah , Bird Jennifer , O'Connor Sheila J , MB Brown Julia , Morris Treen 
Published: October 2019

Abstract

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.