Anderson, Larry D

8036 Background: Ide-cel, a BCMA-directed CAR T cell therapy, showed promising efficacy in patients (pts) with RRMM in the KarMMa study with an ORR of 73% and a CRR of 33% across target doses of 150–450 × 106 CAR+ T cells (Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503). Associations of neurotoxicity (NT) with pt and disease characteristics, pt management, and impact on outcomes in the KarMMa study are reported here. Methods: Enrolled pts were triple-class exposed and refractory to their last regimen, with ide-cel given at target doses of 150, 300, or 450 × 106 CAR+ T cells after lymphodepletion (NCT03361748). Investigator-identified NT events were captured under the single preferred term of neurotoxicity and graded according to NCI CTCAE v4.03. Events were managed with corticosteroids (CS), anakinra (ANR), and tocilizumab (Toci) as needed. Results: Of 128 pts treated with ide-cel, NT was reported in 23 (18%); 12 pts (9%) had maximum grade (gr) 1 NT, 7 (5%) had gr 2, and 4 (3%) had gr 3. No gr 4 or 5 NT occurred. Most baseline characteristics were similar in pts with and without NT, including stage III disease (22% and 15%), high-risk cytogenetics (39% and 34%), and extramedullary disease (35% and 40%); exceptions were high tumor burden (65% and 48%) and sex (48% and 62% men). NT (any gr/gr 3) occurred in 0%/0%, 17%/1%, and 20%/6% of pts at doses of 150, 300, and 450 × 106 CAR+ T cells. Median time to onset was similar regardless of gr, and there were no late-onset events (Table). NT was managed with CS in 10 pts (43%), Toci in 3 (13%), and ANR in 1 (4%). Median (range) time to first use of CS was 2 d (1–6). ORR and DOR were similar in pts with and without NT (Table). All NT occurred in the proximity of cytokine release syndrome (CRS) events with the start date of NT events either overlapping with or occurring within 1 wk of the start of a CRS event. Conclusions: NT occurred early in the KarMMa study, was generally of short duration, and was mostly gr 1/2 with no gr ≥4 events. All NT was proximal to CRS. Pts with NT had a favorable ORR after ide-cel treatment. These results continue to demonstrate the durable efficacy and tolerability of ide-cel in pts with RRMM. Clinical trial information: NCT03361748. [Table: see text]

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Background: Multiple myeloma (MM) occurs most commonly among the older population, with a median age of 69 years at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options for patients with hematologic malignancies, including MM. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated deep and durable responses in the pivotal phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory MM (RRMM; Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall response rate (ORR), complete response (CR) rate, median duration of response (DOR), and median progression-free survival (PFS) were 73%, 33%, 10.7 months, and 8.8 months, respectively, among all 128 patients treated across the target dose levels of 150-450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells. The safety profile of ide-cel was consistent with the mechanism of action of CAR T cell therapies, with the most common toxicities across all dose levels being cytopenia (97%) and cytokine release syndrome (84%). In the present analyses, the efficacy and safety of ide-cel in elderly patients in the KarMMa study were evaluated. Methods: Patients enrolled in the KarMMa trial (NCT03361748) were required to have ≥3 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to their last regimen per International Myeloma Working Group (IMWG) criteria. Patients received ide-cel at target doses of 150, 300, or 450 × 106 CAR+ T cells after 3 days of lymphodepletion with cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) followed by 2 days of rest. The primary endpoint was ORR, and the key secondary endpoint was CR rate. Additional secondary endpoints included DOR, PFS, and safety. Patients were classified into ≥65 years and ≥70 years subgroups for analysis. Responses were assessed according to IMWG guidelines, and DOR and PFS were analyzed using Kaplan-Meier methods. Results: Of the 128 patients treated with ide-cel, 45 (35%) were aged ≥65 years and 20 (16%) were aged ≥70 years. The median age within these age groups was 69 years (range, 65-78) and 73 years (range, 70-78), the median number of prior antimyeloma regimens was 6 and 5, and the median time since initial diagnosis was 6.7 years and 6.1 years, respectively. Baseline characteristics were generally similar between age groups with the exception of tumor burden. Response rates for both age groups were comparable with those of the overall ide-cel treated population, with ORRs of 84% to 90% and CR rates of 31% to 35% (Table). Likewise, median DOR among responders in both age groups (10.9 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. At the time of analysis, overall survival data were still immature. No new safety signals were observed in either of the older age groups compared with those in the overall ide-cel treated population (Table). Conclusions: These results demonstrate deep and durable responses with ide-cel treatment together with a manageable safety profile in triple-class exposed patients with RRMM aged ≥65 years and ≥70 years. Outcomes were comparable with those observed in the overall ide-cel treated population. These data suggest ide-cel is safe and effective in older patients and provide further evidence supporting ide-cel as a promising treatment option in RRMM. Figure 1 Disclosures Berdeja: Karyopharm: Consultancy; Kite Pharma: Consultancy; Cellularity: Research Funding; Acetylon: Research Funding; Genentech, Inc.: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Lilly: Research Funding; Janssen: Consultancy, Research Funding; EMD Sorono: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glenmark: Research Funding; Kesios: Research Funding; Legend: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; CURIS: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Poseida: Research Funding. Raje:Takeda: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Immuneel: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Research Funding; Amgen: Consultancy. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Lin:Gamida Cells: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rodriguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Manier:Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene/BMS: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Jenssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Consultancy; Takeda: Consultancy. Einsele:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Sanford:BMS: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Jagannath:Takeda: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.