36-Month Relapse Window May Define High-Risk Myeloma
Key Takeaways
- After upfront quadruplet therapy plus autologous stem cell transplantation for newly diagnosed multiple myeloma, progression within 36 months was presented as the cutoff that best preserved the historical functional high-risk concept, with median overall survival from second-line therapy of 23.8 months for FHR36 versus 8.1 months for the historical FHR18 group.
- Among 310 patients followed for a median of 41.8 months, cumulative incidence of progression was 2.6% at 12 months, 6.2% at 18 months, 10.1% at 24 months, and 16.4% at 36 months.
- Among relapsed patients, next-line T-cell–redirecting therapy was associated with higher 12-month second progression-free survival and overall survival than no T-cell–redirecting therapy, and the authors cautioned that only 11 patients received it.
The cohort included 310 patients with newly diagnosed multiple myeloma treated with upfront quadruplet therapy plus ASCT, with a median follow-up of 41.8 months and 66 progression events, and the investigators prespecified an optimal cutoff as one identifying post-progression overall survival of about 2 years. The analysis framed the 36-month threshold as a prognostic redefinition within current treatment patterns rather than as a treatment recommendation.
The analysis combined patients from the previously published MASTER trial and a prospectively maintained University of Alabama at Birmingham database. Frontline therapy consisted of quadruplet induction with an anti-CD38 antibody, proteasome inhibitor, immunomodulatory agent, and dexamethasone followed by upfront ASCT; MASTER used daratumumab, carfilzomib, lenalidomide, and dexamethasone for four cycles before transplant, whereas the standard-of-care cohort used daratumumab, bortezomib, lenalidomide, and dexamethasone for four cycles, with matched post-ASCT consolidation parameters and usually lenalidomide maintenance despite variation in maintenance approach. Candidate functional high-risk windows were progression within 12, 18, 24, or 36 months from induction start. Second progression-free survival was defined as time from progression after initial therapy to IMWG-defined progression on second-line therapy or death, and overall survival as time from that first progression to death from any cause. The post-relapse survival pattern, rather than relapse incidence alone, drove the 36-month cutoff.
Across the candidate cutoffs, median second progression-free survival and overall survival were 3.0 and 8.1 months for FHR12, 2.7 and 8.1 months for FHR18, 3.3 and 15.7 months for FHR24, and 5.8 and 23.8 months for FHR36. In the direct threshold comparison, FHR36 versus progression beyond 36 months was associated with median second progression-free survival of 5.8 versus 8.1 months and overall survival of 23.8 months versus not reached, with p=.003 and p=.005, respectively. This pattern led the investigators to conclude that the 36-month group most closely matched the historical concept of post-relapse survival of roughly 2 years.
Among relapsed patients, 11 patients, or 17%, received next-line T-cell–redirecting therapy, defined here as autologous CAR T-cell therapy or a bispecific T-cell engager. In T-cell–redirecting therapy outcomes after relapse, overall response rate was 91% with T-cell–redirecting therapy versus 47% without, and 12-month second progression-free survival and overall survival were 80% versus 23% and 90% versus 73%, respectively. The study also reported a directionally persistent association with improved second progression-free survival in multivariable analysis adjusted for either first-remission duration or FHR36 status.
The authors noted that interpretation is limited by the retrospective combined-cohort design, heterogeneity across induction, consolidation, maintenance, and subsequent therapy, exclusion of rare progression before ASCT, small sample and event counts, only 11 patients receiving T-cell–redirecting therapy, and lack of external validation.
Clinician Questions
What relapse window best defined functional high-risk multiple myeloma after upfront quadruplet therapy and ASCT?
In 310 patients with newly diagnosed multiple myeloma treated with upfront quadruplet therapy plus ASCT, the investigators compared progression within 12, 18, 24, and 36 months from induction start and concluded that progression within 36 months best fit the functional high-risk concept because post-relapse overall survival for FHR36 was 23.8 months, close to the historical benchmark of about 2 years.
What were second-line survival outcomes for FHR12, FHR18, FHR24, and FHR36 multiple myeloma in this cohort?
For multiple myeloma in this cohort, median second progression-free survival and overall survival were 3.0 and 8.1 months for FHR12, 2.7 and 8.1 months for FHR18, 3.3 and 15.7 months for FHR24, and 5.8 and 23.8 months for FHR36.
How was T-cell–redirecting therapy associated with outcomes after relapse following quadruplet therapy and ASCT in multiple myeloma?
Among relapsed patients with multiple myeloma after upfront quadruplet therapy and ASCT, 11 patients received next-line T-cell–redirecting therapy, defined as autologous CAR T-cell therapy or a bispecific T-cell engager; 12-month second progression-free survival was 80% versus 23% without T-cell–redirecting therapy, 12-month overall survival was 90% versus 73%, and overall response rate was 91% versus 47% with p=.009.
The investigators described this as an exploratory, noncausal signal, and the association with improved second progression-free survival persisted in multivariable analysis adjusted for first-remission duration or FHR36 status.