Kaur, Gurbakhash

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

Introduction. Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two anti-B-cell maturation antigen (BCMA) CAR T therapies, have demonstrated remarkable responses and improved survival among patients with relapsed/refractory multiple myeloma (RRMM) in the clinical trials and standard of care (SOC) setting. Here, we compare safety, efficacy, and survival for patients treated with SOC ide-cel and cilta-cel. Methods. Data were from a retrospective chart review of RRMM patients leukapheresed by 12/31/2022 with the intent to receive SOC ide- or cilta-cel at 19 institutions in the US Multiple Myeloma Immunotherapy Consortium. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type (cilta- vs. ide-cel), balancing on age, sex, race and ethnicity, performance status, extramedullary disease, high-risk cytogenetics, prior BCMA therapy, bone marrow plasma cells, penta-refractory status, lymphodepleting chemotherapy, baseline ferritin, low cell dose, and bridging therapy response. Logistic regression and Cox proportional hazard models were used to examine the association of treatment type with safety, efficacy, and survival accordingly, while adjusting for IPTW weights. We employed propensity score matching utilizing the same covariates to identify the association of treatment type with progression-free survival (PFS) within relevant patient sub-groups. Results. A total of 641 patients were leukapheresed by 12/31/2022 with ide-cel (n=386) and cilta-cel (n=255). 586 patients were infused (n=350 for ide-cel; n=236 for cilta-cel) with a median follow-up of 13.0 and 12.6 months, respectively. After IPTW, patient characteristics were well-balanced. Patients treated with cilta-cel were more likely to have grade ≥ 3 cytokine release syndrome (CRS) (OR=5.52, 95% CI=1.76-17.30, p=0.004), infections (OR=2.07, 95% CI=1.44-2.97, p<0.001), and delayed neurotoxicity (NT) (OR=20.97, 95% CI=4.75-92.42, p<0.001) compared to patients treated with ide-cel. In the cilta-cel cohort, 24 patients (10%) experienced delayed NT compared to 2 patients (1%) in the ide-cel cohort. Although not statistically significant, patients treated with cilta-cel were more likely to have any second primary malignancies (SPMs) (OR=1.87, 95% CI=0.94-3.71, p=0.08) and any SPMs excluding non-melanoma skin cancers (OR=1.78, 95% CI=0.78-4.10, p=0.2) but no association was observed for odds of hematologic SPMs (OR=0.98, 95% CI=0.26-3.61). No association was observed for therapy type with any or severe immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenias, and non-relapse mortality. Compared to ide-cel, cilta-cel was associated with better treatment responses of ≥ complete response (OR=2.38, 95% CI=1.61-3.51, p<0.001) and ≥ partial response (OR=1.74, 95% CI=0.99-3.05, p=0.06). Patients treated with cilta-cel had a longer PFS and overall survival (OS) than ide-cel (HR=0.47, 95% CI=0.35-0.62, p<0.001 and HR=0.63, 95% CI=0.42-0.93, p=0.02, respectively), and these findings were similar in the intention to treat cohort (PFS: HR=0.44, 95% CI=0.34-0.55, p<0.001; OS: HR=0.55, 95% CI=0.41-0.73, p<0.001, respectively). We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time-period as FDA approval for cilta-cel (≥ March 2022), restricting to patients with data on all covariates, and restricting to sites that contributed data for both products. In a propensity matched population, (n=380; n=190 for cilta-cel and n=190 for ide-cel), patients treated with cilta-cel had superior PFS compared to those treated with ide-cel in most subgroups with respect to age and disease characteristics including extramedullary disease, high-risk cytogenetics, and elevated baseline ferritin (p<0.05). Conclusion. Our results suggest superior efficacy of cilta-cel with a higher incidence of certain toxicities compared to ide-cel in the SOC setting. This study provides valuable information for patient counseling and guiding the selection of CAR T-cell therapy for specific patient populations. Further validation through similar large-scale real-world experiences or prospective studies is needed to confirm our results and enhance applicability in the clinical setting. *DH, LP, & DD are co-first authors * YL, KP, & SS are co-last 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

Abstract Despite the widespread use of carfilzomib (K) in relapsed/refractory multiple myeloma (RRMM), there is no consensus on optimal K dose in milligrams per square meter (mg/m2) or dosing schedule. We assessed three modern K prescribing patterns in RRMM using a large United States electronic health record-derived database. Our final cohort (n = 486) included 136 patients (28.0%) who received K 56 mg/m2 once weekly (K56-1x), 86 (17.7%) who received 56 mg/m2 twice weekly (K56-2x), and 264 (54.3%) who received 70 mg/m2 once weekly (K70-1x). Between 2016 and 2023, once-weekly dosing became more common: K70-1x proportions changed from 21.1% in 2016 to 50.6% in 2023, K56-1x from 15.8% to 37.0%, and K56-2x from 63.2% to 12.3%. Median real-world progression-free survival was 13.0 months [95% confidence interval (CI) 11.2-20.7] for K56-1x, 13.2 months (95% CI 9.0-28.1 months) for K56-2x, and 10.9 months (95% CI 9.9-15.3 months) for K70-1x; these differences were not statistically significant (log-rank p = 0.46). The prevalence of heart failure was comparable (<5% in all cohorts). In summary, our findings do not support improved outcomes with twice-weekly carfilzomib in RRMM. K56-1x may provide the best balance of efficacy, safety, and avoidance of time toxicity from frequent infusions.

7508 Background: Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy in patients with relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients with extramedullary disease (EMD) remain to be better characterized. Methods: We included patients from 11 US academic centers, who were evaluated for EMD and were infused with ide-cel between May 2021 and April 2023. Patients with soft tissue or visceral lesions non-contiguous from bony lesions were classified as having true EMD, with paraskeletal disease classified as non-EMD. Disease responses were evaluated using the IMWG criteria. Time-to-event analyses were performed from the date of ide-cel infusion. Results: Among 351 patients with RRMM treated with ide-cel, 84 (24%) had EMD prior to infusion. Median follow-up for the entire cohort was 18.2 months (95% CI: 17-19.3). Baseline characteristics at ide-cel infusion for EMD and non-EMD cohorts are depicted in the table. For the EMD and non-EMD cohorts, the Day 30 objective response rates (ORR) were 58% vs. 69% (p=0.1), Day 30 ≥complete response rates were 16% vs 24% (p=0.11), the Day 90 ORR were 52% vs 82% (p<0.001), and best ORR were 58% vs 82%, respectively. The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p<0.0001) for the non-EMD cohort. The median duration of response for EMD among day 30 responders was 6.4 months (95% CI: 5.1-8.4). In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.8 (95% CI: 1.2-2.5), p<0.001] after adjusting for ECOG status, revised ISS stage, penta-drug refractoriness, elevated ferritin, prior BCMA-directed therapy and use of bridging therapy. Pattern of progression in the EMD cohort (n=68/84) included EMD site only (21%), hematologic only (22%), or both (57%), with comparable PFS for type of progression (p=0.19). The median overall survival (OS) was 14.8 months [95% CI: 9-Not reached (NR)] for EMD and 26.9 months [95% CI: 26.3 vs NR, p=0.006)] for the non-EMD group. Rates of Grade ≥2 cytokine release syndrome or neurotoxicity syndrome were comparable between the two cohorts. Conclusions: Patients with EMD demonstrate significantly inferior Day 90 ORR and presence of EMD is an independent risk factor for inferior PFS. [Table: see text]

Introduction: Most induction regimens for multiple myeloma (MM) contain bortezomib. In most clinical trials, bortezomib has been prescribed either intravenously or subcutaneously twice per week in 21-day or 28-day cycles. However, several retrospective single-center studies have shown that once-weekly bortezomib has comparable efficacy and less peripheral neuropathy compared to twice-weekly bortezomib ( Sidana et al, PLoS One 2017; Cook et al, AJH 2021). These findings have also been confirmed by a secondary analysis of data from three prospective Phase 3 randomized studies ( Mateos et al, Haematologica 2014). As such, many clinicians have adopted once-weekly bortezomib regimens in routine care in the past decade. However, the real-world (RW) prevalence and efficacy of once-weekly vs twice-weekly bortezomib regimens in a larger population have not yet been characterized. Methods: This study used US nationwide longitudinal Flatiron Health electronic health record-derived de-identified data. We included patients aged 18-70 years with newly diagnosed MM between 2017-2022 with ≥ 6 months of follow-up and ≥ 2 clinical visits who were treated with a first-line (1L) bortezomib-containing regimen. Patients aged &gt;70 were excluded a priori given the likelihood of altered practice patterns and more frequent comorbidities. Twice-weekly bortezomib was defined as patients for whom the most frequent interval between two doses of 1L bortezomib within a cycle was 3.0-4.9 days, while once-weekly bortezomib was defined as a corresponding interval of 5.0-9.9 days. We used multivariable logistic regression to assess demographic and clinical factors associated with once-weekly vs twice-weekly (reference) bortezomib. RW progression free survival (rwPFS) and RW overall survival (rwOS) from 1L treatment initiation were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model including transplant as a time-varying covariate and adjustment for other demographic and clinical factors. Results: Of 2,522 patients included, 927 (36.8%) received twice-weekly while 1,522 (63.2%) received once-weekly bortezomib. Approximately half of patients (50.3%) were non-Latinx White, 21.7% non-Latinx Black, and 8.0% Latinx. Most patients were treated in the community setting (78.8%). Rates of once-weekly bortezomib administration were 66.2% and 62.1% among patients treated at academic and community practices, respectively. The frequency of weekly bortezomib use increased over time, from 58.0% between 2017-2019 to 68.8% between 2020-2022. In multivariate analysis, ECOG PS ≥ 2 (odds ratio [OR] 1.50; [95% CI 1.14 to 1.99] vs ECOG PS 0), and more recent year of diagnosis (OR 1.14; [95% CI 1.08 to 1.20] per year) were associated with higher odds of receiving once-weekly bortezomib. Conversely, Latinx patients vs non-Latinx White (OR 0.60 [95% CI 0.44 to 0.82]) and patients with ≥ 2 high-risk cytogenetic abnormalities (HRCA) vs 0 HRCA (OR 0.66 [95% CI 0.48 to 0.91]) had lower odds of receiving once-weekly bortezomib administration. No significant associations were found between gender, ISS stage, practice setting, insurance category, or baseline creatinine. There was no statistically significant difference in rwPFS among patients receiving once-weekly (median 37.3 months, 95% CI 33.8 to 42.5) vs twice-weekly bortezomib (median 39.2 months, 95% CI 32.9 to 42.8) (HR 0.87 [95% CI 0.77 to 1.00]) (Figure 1A). Similarly, there was no statistically significant difference in rwOS with median 25.5 months follow-up (Figure 1B). Median rwOS was not reached in either group (hazard ratio 0.89 [95% CI 0.75 to 1.07]). Discussion: We evaluated US bortezomib prescribing patterns for the first time in the modern era using a large nationwide RW-study. Whereas prescribing patterns have shifted towards once-weekly bortezomib over time, over 30% of patients diagnosed in the last three years received twice-weekly bortezomib. Importantly, once-weekly and twice-weekly bortezomib performed comparably with regard to rwPFS and rwOS. While our study did not analyze neuropathy or patient quality of life, once-weekly bortezomib is known to be associated with less neuropathy and less time in clinic. These data further support the conclusion that once-weekly bortezomib should be considered the standard of care for newly diagnosed patients with MM.

Background: Bortezomib (Velcade), a mainstay of treatment regimens for newly diagnosed multiple myeloma (MM), is often dosed twice-weekly in trials (i.e., Days 1, 4, 8, 11 in 21-day cycles). However, several analyses have shown that once-weekly bortezomib performs comparably and is associated with less peripheral neuropathy (Sidana PLoS One 2017, Mateos L&L 2020, Cook AJH 2021). Many centers thus use once-weekly bortezomib in MM induction regimens regardless of transplant eligibility, e.g. modified VRd or Dara-VRd in 28-day cycles with once-weekly subcutaneous (SC) bortezomib 1.3 mg/m 2 (McCaughan BJH 2022). Physician attitudes and perceptions regarding how bortezomib should be dosed, an important step toward establishing a global standard of care in MM, have not been investigated. Methods: We conducted a global online survey of hematologists/oncologists who had treated ≥1 patient with MM in the past 12 months. The survey was distributed via social media platforms as well as targeted emails to MM physicians, IMWG members, and outreach through professional societies. The survey comprised 14 questions including usage of once- vs twice-weekly bortezomib, usage of SC vs IV bortezomib, attitudinal questions about potential benefits/disadvantages of each approach, and perceived barriers to using once-weekly bortezomib. Statistics were analyzed descriptively with Wilcoxon rank-sum and signed-rank tests. Results: Of 317 webpage visits, 205 responses were recorded (65% completion rate).Most respondents were from US academic practices (25%, n=52), US community practices (22%, n=46), or Australian academic practices (6%, n=13); however, responses were recorded from 38 countries including 22 low- or middle-income countries (LMICs: 29% of responses, n=60).Over a third of respondents (37%, n=76) practiced in community settings, and most respondents (58%, n=119) reported &gt;20 patients with MM under their personal care . 93 respondents (45%) had previously helped write institutional or societal guidelines, including 21 IMWG members.Respondents reported using once-weekly bortezomib most of the time (median 95% of patients, IQR 80%-100%) and almost always used SC bortezomib (IQR 100%-100%).There were no significant differences in bortezomib frequency or route based on academic vs community practice, experience with MM, US vs non-US, or LMIC vs non-LMIC. Large majorities of respondents (Table 1) felt that once-weekly bortezomib is preferred by patients (94%), associated with comparable durations of response (79%), and associated with less peripheral neuropathy (89%). Conversely, 61% of respondents felt that twice-weekly bortezomib in superior in newly diagnosed MM with acute cast nephropathy.Physician estimates of the incidence of any-grade peripheral neuropathy were significantly lower with once-weekly bortezomib (median 30%, IQR 20-43%) vs twice-weekly bortezomib (median 50%, IQR 40-73%). Similarly, Grade 3+ neuropathy estimates were significantly lower with once-weekly (median 10%, IQR 5-17%) vs twice-weekly bortezomib (median 25%, IQR 15-38%), with p&lt;0.001 in all cases . The most common cited barriers to ordering once-weekly bortezomib (Table 2) were perceived lack of prospective data (31%), difficulty modifying treatment orders (24%), and resistance from pharmacist colleagues who prefer adhering to trial-studied regimens (13%). Discussion: In our survey of over 200 MM-treating physicians from 38 countries (including 22 LMICs), once-weekly subcutaneous bortezomib was overwhelmingly preferred regardless of practice setting or country. The only exception was acute cast nephropathy, where twice-weekly bortezomib may expedite renal recovery and is reasonable to use initially. Neuropathy estimates were similar to published incidences (32% with once-weekly bortezomib vs 47% with twice-weekly bortezomib) from prospective data collected from the ALCYONE, GIMEMA-QW, and VISTA randomized trials (Mateos L&L 2020). Our findings highlight the widening mismatch between what physicians routinely prescribe to patients versus what registrational trials typically require. Given that &gt;90% of physicians personally prefer once-weekly bortezomib and that &gt;90% report that their patients feel similarly, once-weekly bortezomib appears to have become the global standard of care. This consensus should be taken into consideration for clinical trial design in the future.

Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with a standard triplet combination in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Patients with no actionable mutation or mutations with allelic burden below 30% were randomly assigned to one of the “non-actionable” arms. Here we present the data for the Y3 arm which combines selinexor (60mg po days 1,8,15), ixazomib (4mg po days 1,8,15), pomalidomide (3mg po days 1-21) and dexamethasone (40mg po weekly) (Seli-IPD), given on a 28-day cycle. The primary objective of the Y3 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs). Results: 17 patients were enrolled into the Y3 arm. The average age was 62 (51-79), 65% were male with a median of 29 months since initial diagnosis and a median of 2 prior lines of therapy. The ORR (&gt; PR) was 52.9% with a clinical benefit rate (&gt; MR) of 58.8%. The median progression free survival was 10.2 months ( 95% CI: 3.9; 12.9) with a median overall survival which has not yet been reached; with all 17 patients still alive at the current data cutoff. No dose-limiting toxicities were seen. Eight patients (47.1%) experienced a serious AE with 2 patients (11.8%) experiencing an AE leading to treatment discontinuation. Two patients (11.8%) required dose reductions. The most common non-hematologic AEs were fatigue, nausea and constipation; all of which were grade 1 and 2. Conclusions: In this platform study of patients with relapsed, functionally high-risk MM, patients who received Seli-IPd exhibited significant efficacy and a manageable AE profile. Furthermore, this provides an all-oral option for patients wishing to minimize their office visits and parenteral therapy administrations.

Abstract Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor T-cell therapy to gain US Food and Drug Administration approval for patients with relapsed/refractory multiple myeloma (RRMM). The clinical outcomes of standard of care (SOC) ide-cel in racially and ethnically diverse populations have been understudied. This study pooled data from 207 patients with RRMM (28% patients of racial and ethnic minority groups) treated with SOC ide-cel across 11 institutions to examine racial and ethnic differences in the incidence of toxicities and adverse events, response to ide-cel, and survival. This study included 22 (11%) Hispanic, 36 (17%) non-Hispanic Black, and 149 (72%) non-Hispanic White patients with RRMM. Compared with Hispanic and non-Hispanic White patients, non-Hispanic Black patients had higher median levels of C-reactive protein (1.0, 0.8, and 3.5 mg/dL, respectively; P = .02) and baseline ferritin (362.0 vs 307.0 vs 680.5, respectively; P = .08) and were more likely to develop cytokine release syndrome (77%, 85%, and 97%, respectively; P = .04). Although best overall response rate was lower among Hispanic patients (59%) than among non-Hispanic Black (86%) and White patients (86%; P = .01), there were no racial and ethnic differences in progression-free or overall survival. We provide, to our knowledge, the first and largest investigation of clinical outcomes of SOC ide-cel by race and ethnicity. Despite differences in safety and response to ide-cel, our findings encourage the use of ide-cel in all patients with RRMM. These findings should be confirmed in larger samples of diverse patients with RRMM, with longer follow-up time.

Patients with multiple myeloma (MM) are at a high risk for developing cardiovascular complications. Global longitudinal strain (GLS) can detect early functional impairment before structural abnormalities develop. It remains unknown if reduced GLS is associated with reduced survival in patients with MM. We conducted a retrospective cohort analysis of patients diagnosed with MM between 1 January 2000 and 31 December 2017 at our institution. Patients with a 2D transthoracic echocardiogram completed within 1 year of MM diagnosis, left ventricular ejection fraction (LVEF) greater than 40%, and no history of myocardial infarction prior to MM diagnosis were included. GLS was measured using an artificial-intelligence-powered software (EchoGo Core), with reduced GLS defined as an absolute value of <18%. The primary outcome of interest was overall survival since myeloma diagnosis. Our cohort included 242 patients with a median follow up of 4.28 years. Fifty-two (21.5%) patients had reduced average GLS. Patients with reduced GLS were more likely to have an IVSd ≥ 1.2cm, E/E’ > 9.6, LVEF/GLS > 4.1, higher LV mass index, and low-voltage ECG. A Total of 126 (52.1%) deaths occurred during follow-up. Overall survival was lower among patients with reduced GLS (adjusted HR: 1.81, CI: 1.07–3.05).