Manier, Salomon

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapies are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Idecabtagene vicleucel (ide-cel) is a B-cell maturation antigen-targeted CAR T-cell therapy approved for patients with RRMM with ≥2 prior lines of therapy. Developing a better understanding of the relationship between patient age and CAR T-cell therapy outcomes may help guide treatment and clinical practice. This analysis of data from the KarMMa-3 trial (NCT03651128) describes efficacy and safety outcomes in older and younger patients who received either ide-cel or standard therapy regimens. Methods: KarMMa-3 is an open-label, phase 3 trial that includes adults with RRMM who have received 2-4 prior treatment regimens with disease refractory to the last therapy. Enrolled patients were randomized (2:1) to receive either a one-time infusion of ide-cel or 1 of 5 standard regimens. This subgroup analysis evaluated the efficacy and safety of ide-cel compared with standard regimens in KarMMa-3 patients by age group (≥70 vs &lt;70 yrs). Outcome measures assessed include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), patient-reported quality of life (QoL), and incidence of selected adverse events. Results: A total of 386 patients were evaluated; 19.3% (49/254) of those receiving ide-cel and 20.5% (27/132) of those receiving standard regimens were aged ≥70 yrs. Compared with older patients, younger patients receiving ide-cel exhibited more high-risk baseline characteristics, including high-risk cytogenic abnormalities (44.4% vs 32.7%) and triple-class refractory disease (66.8% vs 55.1%). The median time to progression during the most recent prior anti-myeloma treatment was longer for patients aged ≥70 yrs who received ide-cel vs standard regimens (8.6 mo vs 6.7 mo) but was similar for patients aged &lt;70 yrs (6.5 mo vs 6.9 mo). ORR for patients aged &lt;70 yrs was 68.8% (95% CI: 62.4, 75.1) with ide-cel and 41.0% (95% CI: 31.5, 50.4) with standard regimens (P&lt;0.0001). Patients aged ≥70 yrs treated with ide-cel achieved an ORR of 81.6% (95% CI: 70.8, 92.5) vs 48.1% (95% CI: 29.3, 67.0) with standard regimens (P&lt;0.01). Median PFS for patients aged &lt;70 yrs was longer with ide-cel treatment vs standard regimens (12.5 mo [95% CI: 11.2, 15.4] vs 4.2 mo [95% CI: 3.5, 5.7]; P&lt;0.0001). Similar trends were seen in patients aged ≥70 yrs, where median PFS was 18.9 mo (95% CI: 12.1, 24.5) with ide-cel treatment and 5.7 mo (95% CI: 2.2, 12.2) with standard regimens (P&lt;0.01). Median OS was not reached in older patients in either treatment arm; in younger patients, median OS was 39.5 mo (95% CI: 27.8, NR) with ide-cel and 27.9 mo (95% CI: 20.6, NR) with standard regimens. Incidence of adverse events reported with ide-cel treatment was generally similar between age groups for cytokine release syndrome, neurotoxicity, and infections. Analyses of patient-reported QoL data and other relevant safety endpointsare ongoing and will be included in the presentation. Conclusions: In the KarMMa-3 trial, patients aged ≥70 years derived substantial benefit from ide-cel treatment, demonstrated by longer PFS and a notable ORR compared with standard regimens. While efficacy and safety outcomes of ide-cel treatment in older patients were consistent with younger patients, it is important to note that patients in the trial aged ≥70 yrs were more likely to have favorable baseline characteristics and less aggressive and heavily pretreated disease. This may reflect a selection bias towards enrolling older patients considered to be easier to treat. In contrast, real-world data from late-line settings suggest that older patients are undergoing treatment based on less restrictive selection criteria—eg, including those with higher-risk baseline features—reflecting a more representative and broader population. These observations reinforce the potential for durable benefit with a single ide-cel infusion in a real-world context without additional adverse safety signals, supporting its use across age groups.

Abstract Introduction: The CARTITUDE-4 study (NCT04181827), which enrolled patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy (pLOT), demonstrated a significant benefit of ciltacabtagene autoleucel (cilta-cel) over established triplet regimens. However, the benefit of cilta-cel for patients with standard-risk cytogenetics remains less defined. Here, we report outcomes in patients with standard-risk cytogenetics from the intent-to-treat and as-treated populations in CARTITUDE-4. Methods: InCARTITUDE-4, patients randomized to the cilta-cel arm underwent apheresis and bridging treatment with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), followed by lymphodepletion therapy with cyclophosphamide and fludarabine, and then a single cilta-cel infusion. Progression-free survival (PFS) was assessed using a validated computerized algorithm. The intent-to-treat population included 208 patients; 32 patients progressed or died on bridging therapy, resulting in an as-treated population of 176 patients. Patients with high-risk cytogenetics, defined as del(17p), t(14;16), t(4;14), gain/amp(1q) (n=105), or with unknown cytogenetics (n=12), were excluded from the as-treated analysis. The 12-month minimal residual disease (MRD)-negative complete response (CR) was defined per the International Myeloma Working Group criteria as the proportion of participants with CR or better prior to and at 12 months (±3 months), achieving MRD-negative status at 12 months (+3 months) after cilta-cel infusion, as determined by next-generation sequencing (10-5), prior to progressive disease or subsequent anti-myeloma therapy. For the as-treated population, PFS rates were measured from the time of cilta-cel infusion. Results: In CARTITUDE-4, in the intent-to-treat population, at a median follow-up of 33.6 months, patients with standard-risk cytogenetics had a 30-month PFS rate (95% CI) of 71.0% (58.8–80.2) in the cilta-cel arm (N=69) vs 43.2% (31.3–54.5) in the standard-of-care (SOC) arm (N=70). Patients with standard-risk cytogenetics in the as-treated population (n=59) had a 30-month PFS rate of 80.5% (95% CI, 67.2–88.8). In CARTITUDE-1 (NCT03548207), which evaluated cilta-cel in patients with heavily pretreated relapsed/refractory MM (RRMM; ≥3 pLOT), the 30-month PFS rate among patients with standard-risk cytogenetics (negative for del(17p), t(14;16), or t(4;14); n=68) was 59.9% (95% CI, 47.2–70.5). In the CARTITUDE-4 as-treated population with standard-risk cytogenetics, 8 PFS events occurred within 1 year and 4 PFS events beyond 1 year of cilta-cel infusion. Twenty-six patients achieved MRD-negative CR at 12 months after cilta-cel; 100.0% of these patients were progression free at 30 months. Fourteen patients were not evaluable for MRD due to: calibration failure (n=12), no sample availability for testing (n=1), or indeterminate results post baseline (n=1). Conclusions: The PFS rate at 2.5 years for patients with standard-risk RRMM was higher in CARTITUDE-4 compared with CARTITUDE-1, supporting the use of cilta-cel as early as second line in the treatment course. In CARTITUDE-4 (as-treated population), 80.0% of patients with standard-risk cytogenetics were progression free and off treatment at 2.5 years. In patients with standard-risk disease who achieved MRD-negative CR at 1 year, this rate increased to 100.0%. The low rate of progression events in cilta-cel-treated patients with standard-risk cytogenetics shows the profound benefit of a single cilta-cel infusion in this population.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

Abstract Outcomes are poor in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P &lt; .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

7529 Background: iAEs, such as cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), can occur after infusion of chimeric antigen receptor T cell therapies such as ide-cel, but are typically low-grade and manageable with tocilizumab and corticosteroids. Although high-grade iAEs are rare with ide-cel, identification of patients at increased risk may improve management and remains an unmet need. Three composite biomarkers (multivariate models) of iAE risk were previously developed in a discovery cohort from the KarMMa and KarMMa-2 studies of ide-cel in RRMM (Mashadi-Hossein A, et al. J Clin Oncol 2023;41(16_suppl):e20005). Here, we validate these 3 prototype models for risk of developing high-grade iAEs after ide-cel infusion. Methods: Two models used pretreatment patient and routine clinical laboratory parameters; the third model also included change in 6 exploratory cytokines from baseline to 1 day following ide-cel infusion. To validate, each model was retrospectively applied to KarMMa-3 (NCT03651128) data in a blinded fashion, and sensitivity and specificity to identify grade ≥3 CRS and any-grade MAS were determined. Model performance thresholds used for sensitivity and specificity were 90% and 50%, respectively. Performance for identifying grade 2 CRS was also analyzed post hoc. Results: The first and simplest model comprised a manual algorithm with 7 features; it identified patients with grade ≥3 CRS or MAS with 85% sensitivity and 60% specificity. The second model comprised 19 routinely measured pretreatment features; it identified grade ≥3 CRS with 91% sensitivity and 59% specificity, and any-grade MAS with 60% sensitivity and 88% specificity. The third and most complex model comprised 7 pretreatment clinical features and 6 exploratory cytokines; it identified grade ≥3 CRS with 100% sensitivity and 51% specificity, and any-grade MAS with 100% sensitivity and 81% specificity. None of the models identified grade ≥2 CRS with passable sensitivity or specificity. Clustering analyses across all features showed that only a subset of grade 2 CRS cases was within the previously identified high-risk iAE cluster while the remaining grade 2 CRS cases were spread across other clusters. Conclusions: Two of the 3 composite biomarkers met validation criteria for grade ≥3 CRS risk. Criteria were not met for grade 2 CRS, suggesting these models are specific to higher-grade events and that grade 2 CRS represents a more heterogeneous group of patients. While high-grade iAEs are rare with ide-cel, these models may further optimize the robust benefit–risk profile that ide-cel has demonstrated by helping identify, prior to or shortly after infusion, patients most at risk for severe events. Clinical trial information: NCT03651128 .

Summary: While the current approach to precursor hematologic conditions is to “watch and wait,” this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit–risk assessment.

Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P &lt; 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (&gt; 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P &lt; 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P &lt; 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.