Garfall, Alfred L.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Abstract Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542

Abstract Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40 mL/min. CrCl <30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell–associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.

Extramedullary multiple myeloma (EMM), defined in this review as soft tissue plasmacytomas resulting from hematogenous spread, is characterized by the ability of MM cells to proliferate outside of the bone marrow microenvironment. It is aggressive, often associated with high-risk cytogenetics and early relapse, and independently portends significantly shorter progression-free and overall survival, even in the era of highly effective immunotherapies. The molecular and microenvironmental factors underlying extramedullary MM dissemination continue to be studied to inform the development of better treatments. In this review, we discuss our current understanding of the biology of EMM, focusing on its distinct molecular and microenvironmental characteristics vis-à-vis MM. We also review the current treatment strategies, acknowledging the paucity of large, randomized studies specific to this population.

Background: Teclistamab (Tec) received regulatory approval for the treatment of relapsed refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. The risk of CRS and ICANS with Tec is well established with a manufacturer's recommendation of inpatient observation for 48-hours for CRS/ICANS monitoring after the initial 3 step up doses. There are limited real-world data on the characteristics of and risk factors for CRS and ICANS with Tec. Such data could inform management of Tec patients (pts), including patient selection for inpatient or outpatient step-up dosing. Methods: RRMM pts treated with standard-of-care Tec across 13 U.S. academic institutions were included in this analysis. The follow-up data cutoff was 30 April 2024. CRS and ICANS classification was based on the American Society for Transplantation and Cellular Therapy consensus grading criteria. Multivariable logistic regression models were fitted to estimate the effects of covariates on CRS and ICANS events, with a particular focus on grade ≥2 CRS, any-grade ICANS, and the combination of CRS grade ≥2 and/or any-grade ICANS. Results: 385 pts were included in the analysis, with a median of 6 lines of prior therapy. Median age was 68 years (range 31-92), 88 patients (25% of pts with available data) had ECOG ≥2, and 301 pts (78%) would have been ineligible for MajesTEC-1. 48 (33%) of 145 evaluable pts with a baseline bone marrow (BM) prior to Tec had >50% BM plasma cells, 139 pts (36%) had extramedullary disease (EMD) (either paraskeletal or true-EMD) and 5 pts (1%) had plasma cell leukemia prior to start of Tec. 224 pts (59%) received Tec with an accelerated step-up dosing regimen, defined as having at least one step-up dose interval of ≥ 2 days. 220 pts (57%) developed any-grade CRS [Grade 1: 46% (N=179), grade 2: 10% (N=37), grade 3: 0.8% (N=3), grade 4: 0.3% (N=1)]. Median time to CRS from start of Tec was 3 days (range, 0-15). Fifty-four pts (14%) developed any-grade ICANS [Grade 1: 7% (N=26), Grade 2: 5% (N=18), grade 3: 3% (N=10), grade 4: none]. There were no grade 5 CRS or ICANS events. Median time to onset of ICANS from start of Tec was 4 days (range, 0-25). There was one case of hemophagocytic lymphohistiocytosis in the entire cohort. 38% of pts received tocilizumab and 17% of pts received corticosteroids. In univariate analysis (UVA), baseline platelet <50, triple-class refractory, penta-refractory status, and EMD prior to start of Tec were associated with increased risk for CRS grade ≥2 (p-values <0.1) and incorporated in MVA. Baseline platelet <50, age >60, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, and ferritin or CRP in the upper quartile were associated with increased risk for any-grade ICANS in UVA (p-values <0.1). Baseline platelet <50, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, ferritin or CRP in the upper quartile, and prior BCMA exposure were associated with increased risk of CRS grade ≥2 and/or any-grade ICANS in UVA (p-values <0.1). Accelerated step-up dosing, renal impairment (CrCl < 30 mL/min) and baseline LDH in the upper quartile were not associated with an increased risk of either CRS or ICANS in UVA. Baseline BM plasma cells >50% was excluded from multivariable analysis (MVA) due to high number of missing data, since most pts (62%) did not undergo BM biopsy prior to start of Tec. In MVA, risk factors for CRS grade ≥2 included baseline platelet <50 at the start of Tec treatment (OR: 2.35, 95% CI 1.08-5.08; p=0.03) and penta-refractory disease (OR: 2.48, 95% CI 1.13-5.45; p=0.02). Risk factors for any-grade ICANS included platelet <50 (OR: 4.18, 95% CI 1.88-9.28; p=0.0004), age >60 (OR: 7.54, 95% CI 1.63-34.89; p=0.01) and CRP in the upper quartile (OR: 2.51, 95% CI 1.16-5.43; p=0.02). Risk factors for CRS grade ≥2 and/or any-grade ICANS included platelet <50 (OR: 2.65, 95% CI 1.42-4.94; p=0.002) and ECOG ≥2 (OR: 2.07, 95% CI 1.19-3.61; p=0.01). Conclusions: This real-world analysis of RRMM pts treated with Tec revealed comparable rates CRS and ICANS relative to the MajesTEC-1 study, and these were mostly limited to grade 1/2. MVA demonstrated a significantly higher risk of CRS grade ≥2 and/or any-grade ICANS in pts with baseline platelet <50 and/or ECOG ≥2, the former may reflect BM disease burden. These results may help identify pts who are at higher risk for IEC related toxicities with Tec that would warrant inpatient monitoring during initial step-up dosing. OP, AA, & LF: co-first authors. AG, HCL & JK: co-senior authors

Background: Teclistamab (Tec), a first-in-class BCMA bispecific T-cell antibody, received regulatory approval for the treatment of RRMM based on the MajesTEC-1 study [Moreau et al, NEJM, 2022] which demonstrated an overall response rate (ORR) of 63% and median progression free survival (PFS) of 11.3 months. However, less than 15% (N=24) of patients (pts) enrolled in MajestTEC-1 were ≥75 years, an age cohort that is often underrepresented in clinical trials and comprises approximately one third of MM pts at diagnosis [SEER 22 2017-2021]. In this multicenter retrospective study, we report the real-world safety and efficacy of a large cohort of elderly (≥75 years) RRMM pts treated with Tec. Methods: Pts with RRMM who received standard-of-care Tec across 13 U.S. academic institutions were included in the study. The follow-up data cutoff was 30 April 2024. Pts were divided by age into two groups: age <75 years (<75 group) and age ≥75 years (≥75 group). High-risk cytogenetic abnormalities (HRCA) were defined as the presence of del(17p), t(4;14), t(14;16) and/or gain or amplification of 1q21. Disease response and progression was evaluated using IMWG criteria. Time-to-event analyses were evaluated using the Kaplan-Meier method. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) assessment was based on the American Society for Transplantation and Cellular Therapy consensus grading. Results: Among 385 pts, 83 (22%) were in the ≥75 group (median age 78, range 75-92) and 302 (78%) in the <75 group (median age 65, range 31-74). Compared to pts in the <75 group, those in the ≥75 group were more often white (78% vs. 63%, p=0.009). Both the ≥75 and <75 age groups had a median of 6 prior lines of therapy, a similar proportion with ECOG ≥2 at start of Tec (29% vs. 24%, respectively; p=0.37), and a high proportion of pts with triple-class-refractory disease (77% vs. 85%, p=0.06) and pts who would have been ineligible MajesTEC-1 (73% vs. 80%, p=0.20). In contrast, pts in the ≥75 group had a lower incidence of adverse MM risk factors compared to the <75 group, including HRCA (44.6% vs. 57.9%, p=0.03), ultra high-risk (≥2 HRCA) MM (12% vs. 24%, p=0.02), extramedullary disease (22% vs. 40%, p=0.02), hemoglobin <8 g/dL (10% vs. 21%, p=0.02) or albumin <3 g/dL (6% vs. 19%, p=0.04) at the time of starting Tec. Moreover, a lower proportion of pts in the ≥75 group had prior autologous stem cell transplantation (43% vs. 72%, p<0.0001) or prior BCMA-directed therapy (33% vs. 55%, p=0.0003). The median time from diagnosis to start of Tec was longer for pts in the ≥75 group (7.21 years vs. 5.81 years, p=0.02). There was no significant difference in rates of any-grade CRS (52% vs. 59%, p=0.27), CRS grade 2-4 (10% vs. 11%, p=0.74) or any-grade ICANS (19% vs. 13%, p=0.12) between the ≥75 and <75 age groups, respectively. Four pts in the entire cohort developed CRS grade 3-4, one of whom was in the ≥75 group. Ten pts developed grade 3 ICANS (none grade 4), three of whom were in the ≥75 group. There was no significant difference between the ≥75 group and <75 group in ORR (62% vs. 53%, p=0.17) and ≥very good partial response (VGPR) rate (53% vs. 44%, p=0.14). After a median follow-up period of 9.9 months (95% CI 9.6-10.6 months), the median PFS in the ≥75 group was 10.7 months (95% CI 6.6-NR) vs. 5.2 months (95% CI 6.6-NR) in the <75 group (p=0.005). At the time of data cut-off, the median overall survival (OS) for pts in the ≥75 group had not been reached (95% CI NR - NR) compared to 16.1 months (95% CI 14.0 - NR) in the <75 group (p=0.048). In multivariable analysis for the entire cohort, age ≥75 was not significantly associated with either PFS (HR 0.87, 95% CI 0.54-1.39; p=0.55) or OS (HR 0.60, 95% CI 0.30-1.19; p=0.15). Conclusions: This analysis of a large cohort of RRMM pts treated with Tec in the real-world setting demonstrates comparable efficacy and safety outcomes in elderly (aged ≥75 years) pts to those reported in the overall study population of MajesTEC-1. The adverse baseline disease characteristics and inferior efficacy in pts <75 years age compared to ≥75 years likely reflect patient selection and prescribing patterns in the early era of access to commercial BCMA bispecific therapy with Tec. In multivariable analysis there was no significant impact of age ≥75 on survival outcomes. OP, DD & LF: co-first authors. KKP, HCL & AGC: co-senior authors

Background: Tec is a BCMA-directed bispecific antibody (BsAb) approved for RRMM after ≥4 prior lines of therapy (LOT) based on the MajesTEC-1 trial. However, patients who had previously received a BCMA-DT were excluded from MajesTEC-1. Herein, we evaluated outcomes of RRMM patients with prior exposure to BCMA-DT treated with standard-of-care Tec. Methods: This was a multicenter retrospective cohort study. We compared variables between different groups using Chi-squared and Kruskal-Wallis tests, and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards model. We used the maximally selected rank statistics method to determine the optimal cut-off point for continuous variables to find the most significant difference in PFS among different groups. Results: A total of 385 patients were included in this study. 193 patients had received a prior BCMA-DT, of whom 77%, 22%, and 1% had received 1, 2, and 3 prior anti-BCMA agents, respectively. In patients who had received a prior BCMA-DT, 35% were aged ≥70 years, 24% had ECOG performance status (PS) ≥2, 61% had high-risk FISH, 32% had extramedullary disease (EMD) at Tec initiation, and 42% were penta-refractory. Compared to the cohort without prior BCMA-DT (n=192), patients who were treated with prior BCMA-DT were more likely to have high risk FISH (61% vs 49%, p=0.02), and higher median number of prior LOT (7 vs 5, p <0.001). The specific types of prior BCMA-DTs with the respective overall response rate (ORR) to the most recent prior BCMA-DT were: antibody drug conjugate only (ADC, n=47, ORR 43%), chimeric antigen receptor T-cell therapy only (CAR T, n=99, ORR 86%), BsAb only (n=6, ORR 100%), ADC + CAR T (n=36, ORR 56%), and other ADC/CAR T/BsAb combinations (n=5, ORR 60%). Median follow up was 9.9 (95% CI:9.5-10.6) months. Patients with prior receipt of BCMA-DT had a lower ORR (51.4% vs 61.5%; p=0.012) and ≥very good partial response rate (39.4% vs 52.6%, p=0.009), but similar ≥complete response rate (22.3% vs 24%; p=0.78) to Tec compared to those without prior BCMA-DT. Moreover, patients with prior BCMA-DT had worse median PFS compared to patients without prior BCMA-DT (prior BCMA-DT: 4.6 months, 95% CI: 2.7-7.5; without prior BCMA-DT: 8.2 months, 95% CI: 5.7-12.2; p=0.017). On multivariable analysis incorporating prior BCMA-DT, age, cytogenetics, EMD, and ECOG PS, receipt of prior BCMA-DT was not independently associated with PFS (HR 1.25, 95% CI 0.95-1.64, p=0.1). The estimated 1-year OS rate was 58.9% (95% CI: 51.64-67.2) for the prior BCMA-DT group vs 65.1% (95% CI: 58.1-73.1) for the group without prior BCMA-DT, p=0.16. For the prior BCMA-DT cohort, response rates to Tec were numerically higher in patients who received CAR T (ORR 51.2%) followed by ADC (ORR 45.5%), and bispecific (ORR 30%) as their most recent prior BCMA-DT (p=0.39). No significant difference in PFS was noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Patients who responded to Tec had a numerically longer median time from most recent BCMA-DT exposure to Tec initiation compared to non-responders: 10.5 vs 7.5 months, p=0.48. We found that the optimal cut-off for time from last BCMA-DT exposure to Tec initiation was 8.7 months. Patients with > 8.7 months between last exposure to prior BCMA-DT and Tec initiation had a superior median PFS with Tec (8.1 months, 95% CI: 4.6-11.7) compared to patients with < 8.7 months from last exposure to prior BCMA-DT (2.5 months, 95% CI: 1.1-5.7), p=0.001. The toxicity profile for patients with prior BCMA-DT was similar to those who had not received a prior BCMA-DT. Grade ≥2 CRS occurred in 8.7% vs 13% (p=0.18), and grade ≥2 ICANS in 7.7% vs 6.7%, (p=0.85) of patients with and without prior BCMA-DT, respectively. Patients in the prior BCMA-DT cohort were more likely to have grade 3 thrombocytopenia in the first 30 days after Tec initiation (10.7% vs 6.6%; p=0.08). Conclusion: This is the largest study to date of any BCMA-directed BsAb among BCMA-exposed patients. Receipt of prior BCMA-DT was associated with a trend toward worse PFS, although not statistically significant, and lower likelihood of attaining an overall response. Waiting >9 months between sequencing BCMA therapies may be associated with improved PFS. D.D., M.A.V.M., J.A.D: co first authors; F.A., C.F., L.S.: co senior authors

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.