Final Results of the Canadian Myeloma Research Group Trial of Cybord Induction, Double-Alkylator Conditioning with High-Dose Intravenous Busulfan + Melphalan, ASCT and Continuous Lenalidomide Maintenance for Patients with Newly Diagnosed Multiple Myeloma (CMRG-001)

Introduction: Real-world CMRG Database results in patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with the previous Canadian standard regimen of CyBorD induction, high-dose melphalan (HD-Mel) + single ASCT followed by lenalidomide (len) maintenance until progression/toxicity yielded a benchmark median PFS of 4.5 and median OS of 9.4 years (yrs) (Cote J, et al. Blood Cancer J 2023; 13:137). The CMRG-001 trial was designed over a decade ago to try to optimize results in ASCT-eligible NDMM patients (pts). Study pts received the same standard induction in use during this time (typically weekly CyBorD) as well as len maintenance 10 mg daily until disease progression/toxicity, but the pre-ASCT conditioning consisted of double-alkylator HD therapy with intravenous (IV) busulfan and melphalan (BuMel) rather than HD-Mel (Reece D, et al. Blood 2019; 134 [Suppl 1]: 4570). Results: Between 03/2013-05/2016, 78 pts were entered. Median age was 57 yrs (range 34-69); 51 (65.4%) were male; median beta-2 microglobulin level was 3.07 mg/L (range 1.7-20). High-risk (HR) FISH cytogenetics were identified in 15 (19.2%) pts and consisted of t(4;14) in 9 (11.5%), t(14;16) in 7 (9%) and del17p in 4 (5%); 5 pts had 2 HR features. Median follow-up is now 7.2 yrs (range 0.4-8.9). The PFS rates at 5 and 8 yrs after ASCT are 60% (95% CI 48-70%) and 43% (95% CI 30-56%), respectively. The median PFS for those with standard-risk (SR) FISH has not yet been reached compared with 4 yrs for HR pts. In SR pts, the 5-yr PFS is 66% (95% CI 52-76%) and 8-yr PFS 50.2% (95% CI 35-64%), compared with the respective PFS rates in HR individuals of 32% (95% CI 10-57%) and 11% (7-37%) (p=0.008). No difference in PFS between HR pts with 1 versus 2 HR FISH aberrations was observed (p=0.41), although pt numbers were small. No early transplant-related mortality occurred. Twenty-three events of secondary primary malignancies (SPMs) have been diagnosed in 20 pts (including 1 pt with both colon and 3 non-melanoma skin cancers) as follows: skin cancers in 8 (1 melanoma and 7 non-melanoma [all resolved]), 7 heme malignancies (4 AML, 1 ALL, 1 Hodgkin's disease, 1 diffuse large B cell lymphoma) and 8 adenocarcinomas (1 prostate, 1 endocervical in situ, 2 colon, 1 lung, 1 pancreas, 2 unknown primary). Median time from ASCT until diagnosis of any SPM was 2.76 yrs, and 3.71 yrs in those with invasive/systemic SPMs; 5 of these pts had already discontinued len maintenance for other reasons. Nineteen (24.4%) of the 78 pts have died. The most common cause of death was MM progression (9 pts) while 7 pts succumbed to an SPM (2 from AML, 1 from ALL, 1 from Hodgkin's disease and 3 from adenocarcinoma). The median time from ASCT to death from SPM was 4.2 yrs. The other 3 deaths were due to pulmonary embolism in 1 pt and unknown causes in 2 pts. The median OS in all pts has not yet been reached. The 5- and 8-yr OS rates are 81% (95% CI 70-88%) and 71.5% (95% CI 59-81%). When evaluated by FISH cytogenetic risk, 5- and 8-yr OS rates are 85% (95% CI 73-90%) and 76% (95% CI 61-85%) for SR pts and 63% (95% CI 32-83%) and 54% (95% CI 24-76%) in HR pts, respectively (p=0.043). Summary/Conclusions: 1) Despite the caveats with cross-trial comparisons, the median PFS of 7.4 yrs and 5- and 8-yr OS rates of 81% and 71.5% with IV BuMel conditioning before ASCT compare favorably with our prior real-world Canadian benchmarks using similar CyBorD induction and len maintenance until progression but pre-ASCT conditioning with HD-Mel alone without Bu; 2) the results are not dissimilar to those reported with RVD induction, single ASCT using HD-Mel conditioning, RVD consolidation and continuous len maintenance (median PFS 5.6 yrs and 5-yr OS 79.2%; Richardson PG, et al. NEJM 2022; 387:132); 3) while just over half of the SR pts are alive without progression 8 yrs post-ASCT, the PFS and OS in HR pts remain suboptimal; 4) better preventative strategies are needed to reduce the incidence of fatal SPMs; 4) the PFS/OS survival results suggest a strong anti-myeloma effect of IV BuMel conditioning before ASCT, particularly given the absence of RVD before/after ASCT in this trial; 5) future ASCT studies evaluating IV BuMel conditioning with optimal induction, integration of immunotherapy and/or modified len maintenance schedules–perhaps based on factors such as MRD status–may be of interest.

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