A relapse within 36 months of upfront quadruplet therapy and autologous stem cell transplantation (ASCT), rather than the historical 18-month benchmark, may best identify patients with functional high-risk multiple myeloma, according to a multicenter retrospective analysis published in Cancer.¹ Among patients whose disease progressed early, T-cell–redirecting therapy (TCRT) was associated with substantially higher response rates and improved survival, supporting its prioritization in this difficult-to-treat population.
What did the study show about functional high-risk multiple myeloma?
The analysis included 310 patients with newly diagnosed multiple myeloma who received quadruplet induction therapy followed by ASCT after a median follow-up of 41.8 months and 66 progression events. The cumulative incidence of progression was 2.6% within 12 months, 6.2% within 18 months, 10.1% within 24 months, and 16.4% within 36 months of treatment initiation. The median second progression-free survival (PFS2) and overall survival (OS) from the start of second-line therapy were 3.0 months (95% CI, 2.2-3.7) and 8.1 months (95% CI, not estimable [NE]-17.1), respectively, for progression within 12 months; 2.7 months (95% CI, 2.3-3.1) and 8.1 months (95% CI, 5.5-10.7) for within 18 months; 3.3 months (95% CI, 2.3-4.3) and 15.7 months (95% CI, 5.2-26.1) for within 24 months; and 5.8 months (95% CI, 2.4-9.3) and 23.8 months (95% CI, 16.2-31.3) for within 36 months. These data pointed to 36 months as the optimal cutoff to define functional high-risk disease in the era of quadruplet therapy plus ASCT.
“We identify that, with modern therapy, myeloma relapsing within 36 months [vs the prior definition of 18 months] can be considered as having functional high-risk disease,” said lead author Gayathri Ravi, MD, an assistant professor in the University of Alabama at Birmingham Division of Hematology and Oncology, in a press release on the data.²
How did T-cell–redirecting therapy perform in patients with an early relapse?
Among patients who progressed after quadruplet therapy and ASCT, the overall response rate to second-line treatment was 91% with TCRT vs 47% without it (P = .009). At 1 year, the PFS2 rate was 80% with TCRT vs 23% without, and the OS rate at 12 months was 90% vs 73%, respectively. In multivariable analysis, TCRT was independently associated with a substantially improved PFS2 even after adjustment for functional high-risk status. The findings suggest that TCRT, including CAR T-cell therapy and bispecific antibodies, may offer an important option for patients whose disease returns early despite frontline treatment.
How was the study designed?
Investigators assessed 310 patients with newly diagnosed multiple myeloma who underwent quadruplet therapy plus ASCT based on previously published data from the phase 2 MASTER trial (NCT03224507) and a prospectively maintained database at the University of Alabama at Birmingham.3 Patients received 4 cycles of induction therapy consisting of daratumumab (Darzalex) plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone followed by ASCT. After ASCT, patients received 0, 4, or 8 cycles of daratumumab, carfilzomib, lenalidomide, and dexamethasone based on their minimal residual disease status.
The study evaluated the cumulative incidence of disease progression based on International Myeloma Working Group criteria for patients who experienced progression within 12 months, 18 months, 24 months, and 36 months from the beginning of induction therapy. Relevant end points included PFS2 and OS.
What are the study’s implications?
The authors concluded that, in the current era of quadruplet therapy plus ASCT, the definition of functional high-risk multiple myeloma should encompass patients with disease progression in the first 36 months of therapy, and that the study provides benchmark data for clinical trials evaluating agents in this population. The investigators recommended that future trials incorporate the 3-year benchmark when identifying high-risk populations and continue evaluating the earlier use of TCRT to improve outcomes.
“These patients should be prioritized for treatments engaging the patient’s immune system with [CAR T-cell] therapy or bispecific antibodies, resulting in improved responses and durable cancer control,” Ravi stated.²
References
- Ravi G, Dhakal B, Callander NS, et al. Redefining functional high-risk multiple myeloma in the context of upfront quadruplet therapy and autologous stem cell transplantation. Cancer. Published online July 20, 2026. doi:10.1002/cncr.70478
- New research redefines functional high-risk multiple myeloma in era of modern therapies. News release. University of Alabama at Birmingham. July 20, 2026. Accessed July 20, 2026. https://tinyurl.com/4nh5uauc
- Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901. doi:10.1016/S2352-3026(23)00236-3
