Popat, Rakesh

Introduction: Cilta-cel is approved in the US and EU for the treatment (tx) of patients (pts) with len-refractory MM after ≥1 line based on the randomized, phase 3 CARTITUDE-4 trial (NCT04181827). At the first interim analysis (15.9-month [mo] median follow-up), cilta-cel significantly improved progression-free survival (PFS) vs SoC (hazard ratio [HR], 0.26 [protocol-specified weighted analysis]; P<0.0001). At the second interim analysis, overall survival (OS) was significantly improved with cilta-cel vs SoC (HR, 0.55; P=0.0009). MRD negativity is a prognostic marker of prolonged survival outcomes for pts with MM. We report MRD negativity, including overall and sustained MRD negativity, overall MRD-negative complete response or better (≥CR), and MRD-negative ≥CR at mo 12, from the prespecified second interim analysis of CARTITUDE-4. Methods: Eligibility criteria were previously described. Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). Pts in the cilta-cel arm underwent apheresis, received bridging therapy (PVd/DPd), and then a single cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5-7 days (d) after the start of lymphodepletion. PFS was the primary endpoint; ≥CR rate, overall response rate, overall MRD-negativity rate, and OS were key secondary endpoints. MRD was assessed centrally via next-generation sequencing (clonoSEQ v2.0; Adaptive Biotechnologies). MRD was evaluated at d 56 post infusion in the cilta-cel arm; and in both arms at suspected ≥CR and at 6, 12, 18, and 24 mo post infusion (cilta-cel arm) or cycle 1 d 1 (SoC arm), as well as yearly until progression/start of subsequent therapy in pts in ≥CR. Sustained MRD negativity (10−5) was defined as confirmed MRD negativity ≥12 mo apart and without MRD positivity in between. Pts were evaluable for sustained MRD negativity if they achieved MRD negativity and had ≥1 evaluable MRD sample ≥12 mo after the first negative result or progressed/died/started subsequent tx <12 mo after the first negative result. Results: 419 pts were randomized (intent-to-treat [ITT] set; cilta-cel, n=208; SoC, n=211); 176 pts in the cilta-cel arm received cilta-cel as study tx. As of May 1, 2024, median follow-up for the study was 33.6 mo. At the 10−5 threshold, 145 pts in the cilta-cel arm and 103 in the SoC arm were evaluable for MRD. MRD-negativity rates (10−5) in the ITT set and the MRD-evaluable subset were higher with cilta-cel vs SoC (ITT, 62% vs 18%; MRD evaluable, 89% vs 38%; both P<0.0001). Across subgroups, cilta-cel vs SoC consistently increased overall MRD-negativity rates (10−5). In the ITT set, 48% of the cilta-cel arm achieved MRD negativity (10−5) by d 56, with the MRD-negative rate rising to 60% by 6 mo post cilta-cel infusion. Overall MRD-negativity rates at the 10−6 threshold in the ITT set were higher with cilta-cel vs SoC (57% vs 9%; P<0.0001). In the cilta-cel arm, 119 (57%) pts vs 26 (12%) in the SoC arm achieved overall MRD-negative (10−5) ≥CR (P<0.0001). At the 12-mo MRD assessment, 92 (44%) pts in the cilta-cel arm vs 17 (8%) in the SoC arm (P<0.0001) had MRD-negative (10−5) ≥CR. In pts with MRD-negative (10−5) ≥CR at mo 12, median PFS was not reached (NR; 95% CI, not estimable [NE]-NE) with cilta-cel and 37.8 mo (95% CI, 25.0-NE) with SoC; median OS was NR (95% CI, NE-NE) and NR (95% CI, 37.8 mo-NE), respectively. Sustained MRD-negativity rates (10−5) in the ITT set were 40% in the cilta-cel arm vs 6% in the SoC arm (P<0.0001); among 110 and 26 evaluable pts for sustained MRD, sustained MRD-negativity rates were 75% vs 50% (P=0.0159). Among the 176 pts who received cilta-cel as study tx, overall MRD negativity at 10−5 was achieved by 129 (73%) pts (89% of 145 evaluable pts). Conclusions: At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates >3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was >3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity. Our MRD data demonstrate higher rates of deep and sustained MRD negativity achieved with cilta-cel vs SoC in tx of len-refractory MM as early as first relapse.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (<10-5). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2high v BCL2low) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2highsubgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2lowsubgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2high v BCL2low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2high or BCL2low) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]

Introduction Multiple myeloma (MM) is a clonal plasma cell malignancy and is the second most common type of hematologic cancer worldwide. Treatment options for MM have evolved in the last two decades with the introduction of novel therapeutic agents such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), anti-CD-38 monoclonal antibodies (anti-CD38 MoAb), and recently BCMA-directed therapies (BDT). The variable access globally, especially for novel agents, has been a concern. We aim to study the global availability of 14 chemoimmunotherapy options in addition to autologous stem cell transplant (ASCT) which is approved in the US (excluding BDT due to limited availability), to identify regions with restricted access and analyze the main barriers to access. Methods A global cohort of oncologists outside the USA who treat MM participated in an online survey to evaluate the patterns of accessibility of MM therapies worldwide. The survey, conducted in collaboration with the US Myeloma Innovations Research Collaborative (USMIRC), was sent electronically to 176 oncologists worldwide (outside the US) from June 18th, 2023, to July 17th, 2023. It included questions on demographics, access, and perceived barriers. The respondents chose a response for each therapy as being “easily accessible”, “moderately accessible,” “not readily accessible” or “no access”. Countries were then classified as having “adequate access” if 80-100% of respondents affirmed easy/moderately easy access, while &lt;30% were considered “limited access”, 60-79% were “high-intermediate access” and 30-59% were “low-intermediate access”. We classified countries into low- and high-income (LIC and HIC) based on the United Nations (UN) World Economic Classifications based on per capita gross national income (GNI). Means were calculated for regions of interest. An interim analysis is reported. Results Demographics: Ninety-Five (54%) oncologists from 33 countries completed the survey. Most were from Asia (56%). Others were Europe (19%), South America (12%), Africa (7%), Oceania (3%), and North America (Canada and Mexico, excluding the US) (3%). Only 17% specialized in plasma cell disorders; 50.5% were affiliated with university academic centers; 18% with private or community practices; 12% with community academic centers; and 17% were hybrid. Public-funded centers represented 61.1%, while 76% were transplant centers. Global Patterns: Most countries had adequate access to chemotherapies, IMiDs, PIs, Anti-CD38, MoAbs, and ASCT (Figure 1). Notably, ixazomib, isatuximab, and selinexor had low intermediate access, while elotuzumab had limited access. Access by Income: Most MM therapies were available in LIC and HIC. Of the therapies listed, 6 were adequately available in LIC and HIC: cyclophosphamide, lenalidomide, pomalidomide, daratumumab, bortezomib, and ASCT (Table 1). Elotuzumab and selinexor were limited in both LIC and HIC. Ixazomib and isatuximab were also limited in LIC but were low-intermediate in HIC. Access by Continent: Out of the 14 therapies, Europe had adequate or high-intermediate access to most modalities (12), followed by Oceania and Asia (10), and South America (9). North America and Africa had the lowest number of adequate or high intermediate access therapies (7) (Table 1). Barriers: The most common reason cited for limited access to MM therapies globally was the financial burden for the healthcare system, followed by limitations in local agency approval, inadequate chemotherapy suite resources, and inadequate staffing. Conclusion While most therapies were available, novel therapies such as isatuximab, ixazomib, selinexor, and elotuzumab were less readily accessible. Moreover, North America and Africa had the least access to therapies. This is likely because LIC and HIC have prioritized access to treatments with the best evidence of cost-effectiveness, while those with lower cost-effectiveness are generally limited. The financial burden on healthcare is a major limiting factor. USMIRC plans to investigate potential solutions and pursue global collaborative efforts to reduce disparities in therapies.

Introduction: Novel B cell maturation antigen (BCMA) directed therapies including chimeric antigen receptor- T (CART) such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have been approved since 2021. More recently in 2022, the first BCMA-directed T-cell-engager (TCE), teclistamab (tec), was also approved for the treatment of relapsed/ refractory multiple myeloma (RRMM). Unfortunately, limited access to these therapies worldwide appears to be a major challenge. This study aims to gain insight into the variation in access to these therapies, and barriers to access. Methods: This study was an electronic survey of 176 hematologists/oncologists in centers across the globe outside the USA who treat MM and was conducted in collaboration with US Myeloma Innovations Research Collaborative (USMIRC). The survey was distributed from June 18 th 2023, to July 15 th 2023. Sections included demographics of respondents, availability of drugs in the country, and barriers to access. The respondents categorized each medication as “easily accessible”, “moderately accessible,” “not readily accessible” or “no access”. To categorize a country/region as having “adequate access”, the cut-off was 60% of responders affirming easy/moderately easy access. We investigated whether higher healthcare spending in a country is associated with better drug accessibility. Health expenditure (HE) of a country's Gross domestic product (GDP) from the World Bank was utilized to categorize countries into two groups: “High healthcare investing nations” (HHIN), which included countries spending &gt;10% of their GDP on healthcare, while “Low healthcare investing nations” (LHIN) included countries spending &lt;10% on healthcare. An interim analysis is reported. Results: There were 95 (54%) completed responses from 33 countries. Most (51%) were university-based academic centers and only 17% were centers with a dedicated focus in plasma cell disorders. Only 17% reported adequate access to ide-cel and 16% to cilta-cel, while a limited, yet higher number of respondents had adequate access to tec (23%). Refer to Table 1 Access to CART (ide-cel and cilta-cel): Globally, only 3 of the 33 (9%) countries had access to ide-cel, cilta-cel or both (France, Morocco, Saudi-Arabia). All other countries had limited access. When grouped by continent, none of the continents had adequate access to CART. Both HHIN and LHIN countries had limited access to CART. Access to TCE (tec): Seven of the 33 (21%) countries had adequate access to tec (Switzerland, Netherlands, France, Portugal, Czech Republic, Morrocco, Saudi Arabia). All other countries had limited access. When grouped by continent, although Europe had the most access, none of the continents had adequate access to TEC. Both HHIN and LHIN countries had limited access to TCE, although relatively, TEC was more accessible compared to CART. Figure 1 summarizes access to CART and TCE Barriers to access: Other than Europe, the most common barrier for ide-cel, cilta-cel and tec was cited as financial burden for patients. Financial burden for patients as a top barrier for each of the products by continent was as follows: Asia (83%), South America (64%), Africa (71%) Australia (100%), and North America (100%). In Europe, for CART, financial burden remained a top barrier (50%) along with local agency approval (50% for ide-cel, 44% for cilta-cel). In Europe, the most cited barrier for TCE was the financial burden for patients (44%), while (33%) of oncologists reported no barrier to TCE. Reimbursement for CART and TCE in Europe requires phase 3 randomized controlled trial data, which is just emerging since 2022 for CART and relatively increased access may be due to the presence of compassionate use programs. Conclusion : The survey is the first attempt to highlight the significantly limited global access to novel therapies (ide-cel, cilta-cel, and tec) for the treatment of RRMM. All continents including HHIN had limited access to CART and TCE. Noticeably, CART is less accessible than TCE, even though approved earlier. The main barrier to both CART and TCE is reported as financial burden for patients. USMIRC in collaboration with oncologists worldwide, global agencies, governments, regulatory agencies, policymakers and industry partners, is planning to further explore restrictions to access to CART and TCE and strategies to overcome these barriers.

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) &gt;75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl &lt;30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl &lt;30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

TPS8068 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells resulting in T cell- mediated cytotoxicity. In preclinical studies, elranatamab has demonstrated anti-myeloma activity and delayed disease progression. In the ongoing phase 1 MagnetisMM-1 study, elranatamab has demonstrated clinical efficacy and a manageable safety profile in patients with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Elranatamab maximum tolerated dose has not yet been reached. Subcutaneous (SC) elranatamab at the recommended dose of 76 mg QW on a 28-d cycle with a 2 step-up priming dose regimen administered during the first week is currently being evaluated in a phase 2 study, MagnetisMM-3 (Lesokhin et al, Blood, 2021). Methods: MagnetisMM-9 (start date: Oct 2021; estimated completion date: Apr 2025) is an open-label, multicenter, non-randomized phase 1/2 study evaluating an alternative priming regimen to further mitigate cytokine release syndrome (CRS) incidence and severity and to evaluate SC elranatamab Q2W and Q4W dosing regimens in patients with relapsed/refractory MM. In part 1 of the study, patients will receive premedications and 2 step-up priming doses on cycle 1 D1 (4 mg) and D4 (20 mg), followed by elranatamab 76 mg QW for 6 cycles, and a dose Q2W thereafter if partial response or better is achieved and maintained. In part 2, higher doses of elranatamab ( > 76 mg) at increased intervals between doses will be evaluated. The primary endpoint is grade ≥2 CRS rate during cycle 1. Secondary endpoints include dose-limiting toxicities (part 2 only), objective response rate, duration of response, progression-free survival, overall survival, minimal residual disease negativity rate, safety, and pharmacokinetics. Eligible patients should be ≥18 years of age with a MM diagnosis and measurable disease according to IMWG criteria, refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody, relapsed/refractory to their last treatment regimen, and have an ECOG performance status ≤1. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 weeks of enrollment, active, uncontrolled bacterial, fungal, or viral infections, or any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or previous treatment with an anti-BCMA bispecific antibody. The study is open at centers in the USA, UK, Japan, and Taiwan. Clinical trial information: NCT05014412.