Evaluating the Interaction between Baseline Risk Stratification, Post-Transplant Measurable Residual Disease, and Long-Term Outcomes in Multiple Myeloma

Introduction: Measurable residual disease (MRD) is a well-validated prognostic marker and interim outcomes measure in patients with multiple myeloma (MM). Despite its broad acceptance as a robust prognostic marker, the MRD status is only available down the treatment line, and there is limited information on the markers at diagnosis that can predict achievement of MRD negativity post-transplant. This study explored the relationship between baseline risk factors and post-autologous stem cell transplantation (post-ASCT) MRD status, as well as the combined impact of these baseline factors and post-ASCT MRD status on progression-free survival (PFS) and overall survival (OS).

Patients and Methods: We conducted a retrospective, single-center study of patients achieving at least VGPR after ASCT between 01/01/2016 and 12/30/2023, majority (n=814, 98%) received ASCT in the frontline setting. MRD testing was performed between days 60-100 post-transplant using next-generation flow cytometry with a sensitivity of at least 1x10^5 nucleated cells (minimum 2x10^6 cells assessed). Treatment response and disease progression were determined by IMWG criteria. High-risk disease (HRD) was defined as presence of International Staging System ISS stage 3, high lactate dehydrogenase, 1q gain, 17p deletion, or t(4;14) chromosomal abnormalities. We calculated PFS/OS from transplant day 0 to first documented event (progression or death). Categorical variables were compared using chi-square and Fisher's exact tests. Non-parametric tests compared continuous variables, and logistic regression analyses tested associations between clinical/lab variables and MRD status post-ASCT. Time-to-event analyses were performed using Kaplan-Meier and compared using log-rank test. Multivariable analyses were conducted using the Cox regression model.

Result: The study cohort included 831 newly diagnosed MM patients. The median follow-up for the cohort was 50 months (95% CI: 48-51). 48% (n=402) achieved MRD negativity (MRD-neg) post-ASCT. Univariate analysis demonstrated that R2-ISS stage, depth of response pre-ASCT, and presence of t(11;14) to be associated with worse MRD-negativity rates. Multivariate analysis revealed that t(11;14) significantly decreased the odds of MRD-negativity (p<0.0001, OR=0.4, 95% CI: 0.3-0.6) and a deeper pre-ASCT response was associated with increase odd of MRD-negativity OR-4.7 (95%CI 3.2-7.4) p<0.0001.

Patients with MRD-positive disease post-transplant had an inferior estimated median PFS of 57.6 months (95% CI: 49-69) with a 5-year PFS of 49% (95% CI: 43-56), compared to an estimated median PFS of 83.3 months (95% CI: NA) and a 5-year PFS of 66% in MRD-negative patients (p<0.0001, HR=1.9, 95% CI: 1.5-2.5). Similarly, MRD positivity was associated with an inferior OS [estimated median of 92.6 months (95% CI NA) ,5-year OS 76% (95%CI 72-82) for MRD-pos vs. Median OS NR, 5-year OS 85%(95%CI NA) in MRD-neg; p=0.003, HR=1.69, 95% CI: 1.2-2.38)]. In MRD-neg patients, a baseline bone marrow plasma cells BMPC% >60% was significantly associated with worse PFS (HR=1.9, 95% CI: 1.26-2.99; p<0.01).

High-risk disease was not associated with an inferior PFS or OS in patients with MRD-negativity. For MRD-neg patients, estimated median PFS was not reached for those without HRD, 5-year PFS was 66% (95%CI 51-85), compared to 83 months(95%CI 65-NA) for those with HRD, 5-year PFS was 65%(95%CI57-74), p=0.6441. The median OS was not reached in either group (p=0.07). Five-year OS was 94% (95%CI 86-100) in MRD-neg without HRD vs. 81%(95%CI 75-87) with HRD (p=0.07). In MRD-pos patients, median PFS was 81 months (95%CI 58-NA) for those without HRD, 5-year PFS of 59% (95%CI 46-77), compared to PFS of 41 months(95%CI 36-52) for those with HRD ,5-year PFS of 39% (95%CI 31.3-47) , p=0.003. Median OS was not reached in MRD-pos patients without HRD, but it was 59.8 months ( for those with HRD (p=0.0012). Five-year OS was 94% (95%CI 89-99) in MRD-pos without HRD vs. 67%(95%CI 60-74) with HRD (p<0.0001).

For every 1 log increase in the residual cell % on MRD testing in MRD-pos patients, the hazard ratio for PFS increased by 42% (p=0.0002, HR=1.42, 95% CI: 1.2-1.7).

Conclusion: Patients with t(11;14) have a reduced likelihood of achieving MRD negativity post-ASCT, whereas high-risk cytogenetics did not impact MRD-negativity rates. Achievement of MRD negativity post-ASCT mitigates the impact of high-risk characteristics.

Gertz:Alexion: Honoraria; Johnson & Johnson: Other: personal fees; Astra Zeneca: Honoraria; Abbvie: Other: personal fees for Data Safety Monitoring board ; Medscape: Honoraria; Dava Oncology: Honoraria; Prothena: Other: personal fees; Sanofi: Other: personal fees; Janssen: Other: personal fees; Alnylym: Honoraria; Ionis/Akcea: Honoraria. Dispenzieri:Alnylam: Research Funding; Takeda: Consultancy, Research Funding; Alexion: Consultancy, Research Funding; Pfizer: Research Funding; Janssen: Research Funding; HaemaloiX: Research Funding; BMS: Consultancy, Research Funding. Muchtar:Protego: Consultancy. Kapoor:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Ichnos: Research Funding; Loxo Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Amgen: Research Funding; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Kourelis:Novartis: Research Funding; Pfizer: Research Funding. Dingli:Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; K36 Therapeutics: Research Funding; MSD: Consultancy, Honoraria; Sorrento: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Genentech: Consultancy. Leung:AbbVie: Current holder of stock options in a privately-held company; Checkpoint Therapeutics: Current holder of stock options in a privately-held company. Cook:Geron Corp: Other: Held $600 Geron Stock for one week and sold without profit . Lin:Genentech: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Celgene: Consultancy, Research Funding. Hwa:Pfizer: Other: Consulting fee located to Mayo Research fund; MultiMedia Medical, LLC: Consultancy; Shield Therapeutics: Honoraria; Janssen: Honoraria; GSK: Honoraria. Kumar:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee participation.