Associate Professor London Health Sciences Centre, Western University, London, ON, Canada, Ontario, Canada
Introduction: Multiple myeloma (MM) is an incurable plasma cell neoplasm characterized by multiple relapses. Typically, each subsequent line of therapy is associated with a shorter progression-free survival (PFS). There is paucity of data regarding the use and outcomes of third-line (3L) therapy. Our study assessed the regimens utilized and their long-term outcomes with 3L therapy in CMRG centres.
Methods: This Canadian multicentre retrospective study utilized the CMRG database to track real-world outcomes of patients treated at major Canadian institutions. Eligibility included adult myeloma patients initiating 3L therapy between 1-Jan-2015 to 31-Dec-2020.
Results: 1126 of 7911 patients fulfilled eligibility criteria and were included in the study. At MM diagnosis 205 (24%) had high-risk (HR) cytogenetics. Prior to 3L therapy, 482 (43%) had received ASCT, 998 (88%) lenalidomide (len), 996 (88%) bortezomib (bort), 109 (10%) CD38 monoclonal antibody (MoAb) and 53 (5%) pomalidomide. 106 of 1126 (9.4%) were triple-class exposed and/or refractory. At 3L, 548 patients (49%) received a triplet combination. 184 (16%) participated in clinical trials. Daratumumab (dara)-len-dex showed the best outcome with median duration of treatment (DOT) of 12.3 months and median time to next therapy (TTNT) of 32.2 followed by dara-bort-dex with DOT of 6 months and TTNT of 9.0. CD38 MoAb ± steroid, DOT=11 and TTNT=18.5. Outcomes with doublet combinations of IMiD (DOT= 5.7; TTNT=7.5) or proteasome inhibitors (PI) (DOT= 5.9; TTNT=8.9) were similar to dara-bort-dex. TTNT of 32 months was significantly better than 9 (p < 0.0001) and 18 months (p=0.001). Median PFS (mPFS) and OS from the start of 3L were stratified according to cytogenetics, previous ASCT, age, prior PI, len, pomalidomide, or CD38 MoAb. Overall mPFS was 7.5 (95%CI 6.5-8.5) months; dara-len-dex produced the best PFS: 21.4 (95%CI 16.0-28.7) months although HR patients in this group had a PFS of 10.7 [95%CI,4.4- 22.7] versus 21.4 (95%CI 16.0- 28.4) months for standard-risk. For those receiving doublets, mPFS was 6.7 (95% CI 5.6 -8.2) months. Median OS for all patients was 29.7 (95%CI 26.4-32.8) months. There was no significant difference between subgroups and type of treatment; however standard-risk dara-len-dex patients experienced a mOS of 42.9 (95%CI 34.8- 55.0) versus 29.1 (95%CI 13.2- 45.0) months in HR patients (p=0.100). Those without prior exposure to PI that were given triplets containing IMiD ± PI at 3L had the best OS: 37.3 (95%CI 27.2-48.7) months. Prior CD38 MoAb exposure negatively impacted 3L OS: 14.5 (95%CI 9.2-19.6) versus 32.6 (95% CI 28.8- 36.0) months. The most common reason for discontinuation of 3L was MM progression (39%) followed by toxicity and death, each 9%.
Conclusions: In Canadian myeloma centres, 3L patients have been preferably treated with triplet IMiD-based combinations with dara-len-dex showing the best outcomes. The time period assessed in this study reflects previous limited access to dara-based regimens at 2L in Canada.
