Callander, Natalie S.

Abstract Over the past decade, significant improvements in survival outcomes have been experienced by multiple myeloma (MM) patients. However, MM remains an incurable disease and patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment algorithm of relapsed/refractory MM (RRMM), with high overall response rates. Nevertheless, a significant proportion of patients ultimately relapse despite achieving deep remission and show poor outcomes with subsequent treatment post anti-BCMA immunotherapies.1 Iopofosine I-131 (iopofosine) is a first-in-class phospholipid ether radio-conjugate that targets lipid raft microdomains on tumor cells and is internalized. Here we present seven cases of triple class refractory MM patients that relapsed or were refractory to anti-BCMA immunotherapy and treated with iopofosine plus low dose dexamethasone (LoDEX). Patient received a single fractionated cycle of 30mCi/m2 of iopofosine (15 mg/m2 dosed day 1 and day 15) and received LoDEX (40 mg/week for 12 weeks) with an optional second cycle of iopofosine approximately 60 days later. Six of the seven patients achieved the minimum required total administered dose of 60 millicuries (mCi) to be in the evaluable population and 50% achieved a partial response (PR) or better.

8054 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. Herein we provide survival outcomes on the first randomized trial in newly diagnosed HRMM, S1211, to follow-up on the previously reported progression-free survival (PFS) (NCT01668719, Usmani SZ et al, Lancet Haem 2021). Methods: S1211 is a randomized phase II trial comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab (RVd-Elo). Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14;16), t(14;20), del(17p), amplification 1q21, primary plasma cell leukemia (pPCL), or elevated serum LDH (> 2X ULN). Median PFS was the primary endpoint, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n=54, RVd-Elo n=49. 74% had ISS II/III, 48% amp1q21, 38% del(17p), 11% t(14;16), 9% GEPhi, 7% pPCL, 5% t(14;20) and 4% elevated LDH (17% >1 feature). With median follow-up of 72 months (mos.), no difference in median PFS was observed [RVd-Elo=29 mos., RVd= 34 mos., HR = 1.11 (80% CI=0.82, 1.49, p=0.66]. No difference in OS was observed [RVd-Elo = median not reached (NR), RVd= 68 mos., HR = 0.85 (80% CI: 0.59, 1.23), p-value = 0.58]. 76% pts had >Grade 3 AEs, no differences in the safety profile were observed. Amongst patients with gain/amp 1q21, median PFS was [RVd-Elo=31 mos., RVd= 37 mos., HR = 1.48 (80% CI= 0.95, 2.31), p=0.25], median OS was [RVd-Elo = 61 mos., RVd= 68 mos., HR = 1.23 (80% CI: 0.72, 2.10), p-value = 0.63]. In patients with del(17p), median PFS was RVd-Elo=41 mos., RVd= 30 mos.[HR = 0.98 (80% CI= 0.60, 1.58), p=0.95], median OS RVd-Elo = NR, RVd= 72 mos., [HR = 0.77 (80% CI: 0.40, 1.48), p-value = 0.61]. Conclusions: In the first randomized HRMM study reported to date, the addition of Elo to RVd induction and maintenance did not improve PFS and OS with a median follow-up of 6 years. Although the median PFS for Del17p subgroup on RVd-Elo arm is higher than RVd, it did not achieve statistical significance. The PFS and OS observed for gain/amp 1q21 and del17p in the RVd control arm may serve as important benchmarks for future enrichment design HRMM clinical trials. The PFS and OS in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination induction/maintenance therapy for this population. Clinical trial information: NCT01668719.

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Abstract Background: Phospholipid ethers (PLE) provide a novel mechanism to target tumor cells. Tumor cells contain increased amounts of lipid rafts in their cell membranes, which are thought to enhance signaling and resist apoptosis. Phospholipid drug conjugates (PDC) are specifically designed to have high affinity for lipid rafts which upon binding results in trans-membrane inversion with the ability to deliver an attached therapeutic directly to the cytosol. Iopofosine I-131 (formerly identified as CLR 131) is a novel PDC delivering I-131 as a targeted tumor cell radiotherapy. Iopofosine I-131 is being examined in relapsed or refractory multiple myeloma (RRMM) patients through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the safety and efficacy of Iopofosine I-131 in heavily pretreated MM patients. Eligibility criteria for MM patients include progression or relapsed disease that is refractory to at least 1 proteasome inhibitor and 1 immunomodulatory agent unless intolerable/ineligible to receive such agents with no upper limit to the number of prior lines of therapy. Iopofosine I-131 is administered in up to 4 IV infusions (15-20 min) over 3 months, with doses given 1-2 weeks apart each cycle for a maximum of 2 cycles, along with dexamethasone 40 mg weekly (20 mg in patients > 75), for up to 12 weeks. Following iopofosine I-131 administration, no other antineoplastic or targeted therapy was given until clinically indicated by the investigator. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2016 International Myeloma Working Group criteria. Results: Eleven patients with at least triple class refractory (immunomodulatory agent, proteasome inhibitor and monoclonal antibody) MM have been enrolled in this Phase 2 study with data current as of 28 May 2021. Patients had a median age of 72 (range 34-77), mean prior regimens of 7.2 (range 3-17) and received a mean total body dose of 75.4 mCi (range 59.7-118.7) of iopofosine I-131. The overall response rate (ORR) was 45.5% (5/11), the clinical benefit rate (CBR) was 72.7% (8/11) and disease control rate (DCR) was 100%. Median progression free survival (PFS) was 3.4 months. In a subset of patients who are quad/penta drug refractory, efficacy increased with an ORR of 80.0% (4/5) and CBR of 100% (5/5). The primary treatment emergent AEs in patients with MM included cytopenias (87.5%), in line with prior experience with iopofosine I-131. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (62.5%), anemia (62.5%), neutropenia (62.5%) and decreased white blood cell count (50%). There were no infusion-related reactions or AEs. Conclusions: Initial results for iopofosine I-131 show efficacy with a promising ORR of 45.5% and a CBR or 72.7% in heavily pretreated triple class refractory multiple myeloma patients. Interestingly, iopofosine I-131 showed its highest efficacy in patients that were quad/penta drug refractory with ORR of 80%, highlighting its potential as a later line therapy. Iopofosine I-131 is a novel cancer radiotherapeutic that may provide benefit to patients that are refractory/unresponsive to traditional MM therapies. CLOVER-1 is actively enrolling MM patients that are at least triple class refractory across the United States. Disclosures Ailawadhi: AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Cellectar: Research Funding; GSK: Consultancy, Research Funding; Genentech: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi: Consultancy; Medimmune: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Xencor: Research Funding; Takeda: Consultancy; Beigene: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding; Cellectar: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Cull: Aptevo: Research Funding. Friend: Cellectar: Current Employment. Longcor: Cellectar: Current Employment. Oliver: Cellectar: Current Employment.

Abstract Background: MM that is refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody (CD38MoAb) is labeled triple-class refractory (TCR) and recognized as a modern therapeutic challenge. In recent years, new agents have shown activity in this setting in single arm trials and many more are in development. The assessment of the impact of new agents in the TCR setting is impaired by limited information on the therapeutic outcomes of these patients when treated with non-investigational therapies. Methods: We utilized an independent RWD dataset of patients with MM refractory to CD38MoAb built from academic collaboration (MAMMOTH study) to identify patients with TCR MM who received subsequent therapy. Patients with MM that was CD38MoAb refractory but not TCR were followed longitudinally and only included if, after subsequent lines of therapy, MM became TCR. Patients were excluded if they had plasma cell leukemia, poor renal function (serum creatinine > 2 mg/dl) or if next therapy after TCR status included experimental agents. Refractoriness to a MM agent was defined as lack of objective response and/or progression while receiving therapy or within 60 days of last dose as per International Myeloma Working Group (IMWG) criteria. Time zero for analysis was initiation of next therapy after MM became TCR. Response to therapy and progression were adjudicated utilizing IMWG criteria. MM that was TCR but also exposed to 2 PIs, 2 IMiDs and a CD38MoAb was considered penta-exposed, and when refractory to 2 PIs, 2 IMiDs and a CD38MoAb, it was considered penta-refractory. Results: Data collection occurred between 2016 and 2018 (prior to commercial availability of selinexor, belantamab mafodotin, melflufen or ide-cel). Of 275 patients in the MAMMOTH study, 177 were included. Median age was 65 years (range 27-90), 53% were male, 76% white, 28 % had International Staging System stage 3, and 29% high risk cytogenetics [t(4;14), t(14;16) or del(17p)]. Median number of prior lines of therapy was 5 (range 3-17), median time from diagnosis to TCR was 4.8 years (range 0.9-19.4), 73% had received prior autologous hematopoietic cell transplantation, 84% were refractory to bortezomib or ixazomib, 58% were refractory to carfilzomib, 87% to lenalidomide and 74% to pomalidomide. Penta-exposed patients were 58% and penta-refractory 30%. The first regimen after MM became TCR included cytotoxic chemotherapy in 45%, CD38MoAb in 25%, SLAMF7 MoAb in 7%, carfilzomib in 24%, and pomalidomide in 34% of cases. Overall response rate (ORR) was 30% (20.9% PR, 7.3% VGPR and 1.7% CR). Median progression-free survival (PFS) was 2.8 mo. (95% C.I. 2.3-3.2) and overall survival (OS) 8.6 mo. (95% C.I. 6.8-10.3),(Figure). For Patients with MM that was penta-exposed (N=102), ORR was 30%, median PFS was 2.7 mo (95% C.I 2.1-3.2), and median OS 7.7 mo (95% C.I. 6.0-9.4). For patients with penta-refractory MM (N=53), ORR was 32%, median PFS was 2.5 mo. (95% C.I. 1.7-3.3), and median OS 6.9 mo. (95% C.I. 4.9-8.9). PFS or OS was similar among patients who were TCR but not penta-exposed, TCR plus penta-exposed but not penta- refractory or TCR plus penta-refractory (Figure). Outcomes according to next regimen after MM became TCR are outlined in the Table. In multivariable analysis, no factor was predictor of PFS while refractoriness to carfilzomib (HR 2.2, 95% C.I. 1.5-3.3), presence of high-risk chromosome abnormalities (HR 1.5, 95% C.I. 1.0-2.2) and short interval from diagnosis to TCR (HR 0.92, 95% C.I. 0.85-0.99) were predictors of shorter OS. Conclusions: Patients with TCR MM have a uniformly low chance of response to subsequent conventional therapy with short PFS and OS even when not penta-exposed or penta-refractory. This dataset provides efficacy benchmark for new therapies being developed in this setting. Figure 1 Figure 1. Disclosures Costa: BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cornell: Abvvie: Current Employment. Chhabra: GSK: Honoraria. Liedtke: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Kansagra: GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees. Giri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Malek: Amgen: Honoraria; Janssen: Other: Advisory board ; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; BMS: Honoraria, Research Funding; Sanofi: Other: Advisory Board; Medpacto Inc.: Research Funding; Takeda: Honoraria. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Usmani: Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding. Hari: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Kumar: Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; Beigene: Consultancy; Oncopeptides: Consultancy; Sanofi: Research Funding.

8030 Background: CARTITUDE-1 is a single arm study of Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) anti-BCMA CAR-T cell therapy in US patients (pts) with relapsed multiple myeloma (RRMM) refractory to both IMiD and proteasome inhibitor (PI) or with at least 3 prior lines of therapy and previously exposed to anti-CD38 monoclonal antibody (MoAb). While recently reported efficacy results of cilta-cel were encouraging, it is unknown how they compare with similar pts receiving conventional (non CAR-T) treatment. Methods: We utilized a contemporary US-based dataset of pts with MM refractory to anti-CD38 MoAb (MAMMOTH) to identify pts who would meet eligibility for CARTITUDE-1 and who received conventional therapy. We analyzed the intent-to-treat population (ITT) in CARTITUDE-1, defined as pts who underwent apheresis (N=113) and a modified ITT population (mITT) defined as subset of pts who received cilta-cel at the RP2D (N=97). From the MAMMOTH dataset, we identified a population corresponding to CARTITUDE-1 ITT (N=190) and a mITT population, pts without death or progression within 47 days (median time between apheresis and cilta-cel infusion) from onset of therapy (N=122). We calculated propensity scores (PS) with demographics, N of prior therapies, cytogenetics and refractoriness to MM agents as covariates. An analyst blinded to outcomes performed nearest neighbor 1:1 PS matching. We analyzed overall response rate (ORR), progression-free (PFS) and overall survival (OS) for ITT and mITT in CARTITUDE-1 vs matching MAMMOTH cohorts. Results: Ninety-five ITT (75 received bridging therapy, 82 received cilta-cel) and 69 mITT (54 received bridging) CARTITUDE-1 pts matched MAMMOTH pts (Table). Among the pts in the MAMMOTH ITT cohort 34% received pomalidomide, 24% anti-CD38 MoAb, 19% carfilzomib and 35% cytotoxic chemotherapy in next therapy. ORR in the ITT cohorts was higher in CARTITUDE-1 (84% vs. 28%). Compared to their MAMMOTH counterparts, pts in CARTITUDE-1 ITT cohort had improved PFS (12 mo. 73% vs. 12%) and OS (12 mo. 83% vs 39%). Between the mITT cohorts, CARTITUDE-1 pts had superior ORR (96% vs. 30%), PFS (12 mo 79% vs. 15%) and OS (12 mo. 88% vs. 41%). Conclusions: In pts with RRMM beyond therapy with IMID, PI, and anti-CD38 MoAb, treatment with cilta-cel is associated with higher response rate and superior PFS and OS when compared to conventional treatment.[Table: see text]