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3376 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)

Program: Oral and Poster Abstracts
Session: 654. Multiple Myeloma: Pharmacologic Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Plasma Cell Disorders, Diseases, Treatment Considerations, Lymphoid Malignancies, Non-Biological therapies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Donna E Reece, MD1, Giovanni Piza Rodriguez, MD2*, Mariela A Pantoja, PhD, MSc3*, Eshetu G Atenafu, MSc, PStat4*, Darrell White, MD, MSc5, Irwindeep Sandhu, MD6, Julie Stakiw, MD7, Michael Sebag, MD, PhD8, Terrance Comeau, MD9, Kevin Song, MD10, Jean Roy, MD11, Martha L Louzada, MD, MSc12, Arleigh McCurdy, MD13, Vishal Kukreti, MD, MSc14, Suzanne Trudel, MD15*, Anca Prica, MD2, Rodger E Tiedemann, MBChB, PhD16 and Christine I Chen, MHPE, MD17

1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre- University Health Network, Toronto, ON, Canada
2Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
3Princess Margaret Cancer Centre, Toronto, ON, CAN
4Princess Margaret Cancer Centre / University Health Network, Toronto, ON, Canada
5Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
6Cross Cancer Institute, Edmonton, AB, Canada
7Saskatoon Cancer Centre, University of Saskatchewan, Saskatoon, SK, Canada
8McGill University, Montréal, QC, Canada
9Saint John Regional Hospital, Saint John, NB, Canada
10BC Cancer Agency, Vancouver General Hospital, Vancouver, BC, Canada
11Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
12London Health Sciences Centre, London, ON, Canada
13The Ottawa Hospital, Ottawa, ON, Canada
14Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
15Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, Canada
16Princess Margaret Cancer Centre, Toronto, ON, Canada
17Princess Margaret Cancer Centre - University Health Network, Toronto, ON, Canada

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.

Disclosures: Reece: BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; ORIC: Research Funding; GSK: Honoraria; Pfizer: Honoraria; Takeda: Research Funding; Forus Therapeutics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. White: BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Forus: Honoraria; Antengene: Honoraria; Amgen: Honoraria. Sandhu: Janssen, Celgene/BMS, Pfizer, Sanofi, GSK, Forus, Beigene: Consultancy; Janssen, Celgene/BMS, Pfizer, Sanofi, GSK, Forus, Beigene: Honoraria. Sebag: Janssen: Honoraria, Research Funding; BMS: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Comeau: Kire-Gilead: Honoraria. Song: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; GSK: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roy: Forus Therapeutics: Consultancy; Kite: Honoraria; AbbVie: Honoraria; Janssen: Consultancy; Amgen: Consultancy; Gilead: Honoraria; ExCellThera Inc.: Patents & Royalties: Royalties from sales of UM17; Sanofi: Consultancy; Astra Zeneca: Honoraria. Louzada: BMS: Research Funding; Janssen: Research Funding. Trudel: Genentech: Other: Research Funding; K36 Therapeutics: Other: Research Funding; BMS: Consultancy, Other: Research Funding; Amgen: Honoraria, Other: Research Funding; Sanofi: Honoraria; Roche: Consultancy, Other: Research Funding; Janssen: Honoraria, Other: Research Funding; Pfizer: Honoraria, Other: Research Funding; GSK: Consultancy, Honoraria, Other: Research Funding; Forus: Honoraria. Prica: AbbVie: Honoraria; Kite-Gilead: Honoraria; Astra Zeneca: Honoraria. Tiedemann: Pfizer: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Chen: Eli Lilly and Company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: IV busulfan is approved for use, with cyclophosphamide, as conditioning therapy before transplantation for CML, not myeloma.

*signifies non-member of ASH