Velayati, Arash

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.