Good Partial Response Research Articles

Real-world schedule de-escalation of teclistamab in patients with relapsed/refractory multiple myeloma.

7536 Background: Teclistamab (Tec) is the first BCMAxCD3 bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma (RRMM). The MajesTEC-1 study demonstrated an overall response rate (ORR) of 63% and a median progression-free survival (mPFS) of 11.3 months (mos). Herein, we examined real-world pt characteristics and outcomes associated with Tec in (1) pts treated within the first 4 mos of Tec approval (early initiators who were expected to have high disease burden) as compared to recent initiators, and (2) any pts who switched to de-escalated dosing schedules. Methods: This is a retrospective study of pts with RRMM treated with Tec at Memorial Sloan Kettering Cancer Center from 11/29/22 to 11/30/23 (analysis cut-off: 12/31/23). Responses were evaluated per IMWG Response Criteria. Pt characteristics were summarized by frequency (%) or median (interquartile range [IQR]). PFS was evaluated using the Kaplan-Meier method. Results: In 77 pts who received ≥1 Tec dose, the median age was 70 (IQR 63-77); 55% male; 14% Black; and 42% had high-risk cytogenetic abnormalities (HRCA). The ORR was 62% for 69 response-evaluable pts, including 42% with ≥very good partial response (VGPR). The median time to first response was 1.9 mos (IQR 1.0-2.4). After a median follow-up (mFU) of 7.6 mos, 6-mo PFS rate was 52.3% (95%CI 41.5-66%). The median duration of response has not been reached. In the cohort of early initiators (n=34), pts had more prior lines of therapy (LOT; median 8 vs 5, P=0.002) and higher proportion of prior BCMA therapy use (62% vs 23%; P=0.002) as compared to recent initiators treated after 3/31/23 (n=43). ORR was 67% and 59%, respectively (P=0.80; Table). Among all pts at data cut-off, 25 (32%) switched from weekly to every-other-week or monthly Tec after a median time of 3.1 mos from Tec initiation (95%CI 1.8-4.6) and based on achieving ≥PR and/or toxicity. At mFU of 5.3 mos since switching, 6-mo PFS rate was 94.1% (95%CI 83.6-100%). Conclusions: In this real-world study, Tec demonstrated comparable ORR to MajesTEC-1. Both early and recent Tec initiators had high baseline risk features. A higher proportion of early initiators had prior BCMA therapy and more LOTs, but both cohorts yielded consistently high treatment response rates. In pts who responded, schedule de-escalation was feasible with a high subsequent 6-mo PFS. Updated multicenter findings will be presented at the meeting. [Table: see text]

Exposure-response analyses for optimal therapeutic dose selection of ABBV-383 in patients with relapsed/refractory multiple myeloma (RRMM).

7541 Background: ABBV-383 is a fully human, B-cell maturation antigen (BCMA) × CD3 T-cell–engaging IgG4 bispecific with an effector-silenced Fc region, 2 high-affinity BCMA- and a low-affinity CD3-binding domains. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM (Blood 2023;142[suppl 1]:3378). Here, exposure-response (ER) analyses of efficacy and safety endpoints supporting the optimal therapeutic ABBV-383 dose selection are reported in alignment with US FDA’s Project Optimus. Methods: Efficacy (n=218) and safety (n=220) data from the phase 1 study (NCT03933735) escalation cohorts of 0.025 - 120 mg Q3W and expansion cohorts of 20, 40, 60 mg Q3W and 60 mg Q4W including objective response rate (ORR), very good partial response or better (≥VGPR), stringent complete response (sCR)/CR, adverse events (≥G3 and serious), infections (≥G3, overall and serious), cytokine release syndrome (CRS; any-grade, G1, G2, and ≥G2) were modeled. Total(unbound + bound to soluble BCMA) and free (unbound + partially bound to soluble BCMA) Cycle 1 AUCinf, Cmax, and Ctrough and population pharmacokinetic model-derived up to the time of event Cavg and avgCtrough metrics were utilized in the ER analyses (logistic regression; R Version 4.2.2). Relevant pt-specific covariates were tested. Dexamethasone premedication (36 vs 10 mg) was included in CRS models. The ER relationships were utilized to predict the probabilities of efficacy and safety endpoints for relevant doses and thereby, support justification of the optimal therapeutic dose selection. Results: Based on overall assessment, ORR, ≥VGPR, sCR/CR and ≥G3 neutropenia strongly correlated with free Cavg; CRS endpoints (any-grade CRS and G1 only CRS) strongly correlated with Cycle 1 total Cmax (p <0.05). No other endpoints had ER relationships (p >0.05). Only MM type (IgG vs Others) was selected in ≥VGPR and sCR/CR models. ER relationships suggested high response rates of >63% ORR, >53% ≥VGPR, and ≥30% sCR/CR for 40, 60 mg Q3W and 60 mg Q4W. Predictions demonstrated that 20 mg Q3W (<39% ORR and ≥VGPR; <13% sCR/CR) and untested 40 mg Q4W (<60% ORR, <45% ≥VGPR and <23% sCR/CR) provide suboptimal efficacy. The 60 mg Q4W with 36 mg dexamethasone in Cycle1 (limited follow-up and data) was predicted to have ~30% sCR/CR and 31% ≥G3 neutropenia (≈ 40 mg Q3W) and substantially lower any-grade CRS events compared with 40 and 60 mg doses with 10 mg dexamethasone in Cycle 1. Conclusions: While ER analyses indicated promising efficacy and acceptable safety profiles for 40, 60 mg Q3W, and 60 mg Q4W, they support 60 mg Q4W as the optimal ABBV-383 therapeutic dose due to its predicted better therapeutic benefit/risk profile (high response rates, improved/equivalent ≥G3 neutropenia, and lower CRS events) and extended dosing interval. ABBV-383 at 60 mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM.

Bridging therapies used in trials testing CAR-T therapies.

e19011 Background: Chimeric Antigen Receptor T-cell (CAR-T) therapy can induce durable remission in some patients but requires time for a patient’s own cells to be reengineered to produce CAR proteins that can bind to and destroy cancer cells. During this time, bridging therapy is often used in debulking to reduce treatment toxicities and to control the disease while waiting for the manufacturing of CAR-T cells. Because bridging therapy often involves systemic treatment, the bridging therapies can induce responses, in and of themselves, in clinical trials testing CAR-T therapies. As such, we sought to assess bridging therapies used in CAR-T trials. Methods: Using the FDA labels (labels.fda.gov) to identify the indications and the pivotal clinical trials that led to the approval of each CAR-T cell therapy, we looked at which bridging therapies were used, whether multiple therapies were combined, response rates, and the reported adverse events associated with bridging therapy. We took note of all relevant comments regarding bridging therapy in the main paper and supplemental results. Results: Of the 11 studies testing CAR-T therapies, 10 reported the bridging therapies that were used in the study. Notably, only three of 11 studies provided clear information about which combinations of bridging therapy treatments were used during the trials. Of those that reported the types of bridging therapies (n=10), the most commonly used bridging therapy was dexamethasone, which was used in every study (10/10). The next three most commonly used treatments include rituximab (6/10), gemcitabine (5/10), and etoposide (5/10). Of the trials, 2/11 clearly reported whether patients had a complete response (CR), partial response (PR), or very good partial response (VGPR) to bridging therapy. 5/11 vaguely reported responses, using terminology outside of CR, PR, VGPR. 4/11 trials did not report or mention any response information in regards to bridging therapy. Of all the trials, 1/11 clearly reported adverse events associated with bridging therapy in the supplement, while 10/11 of the trials listed adverse events associated with the treatment groups, without clarifying those associated with bridging. Conclusions: Although patients are often refractory to first-line therapies, which share considerable overlap with the bridging therapies used, these therapies may still induce responses. Despite this possibility, the reporting of bridging therapy combinations and their subsequent response rates and adverse event rates, is highly variable. Of 11 pivotal clinical trials that led to the approval of a CAR-T cell therapy, none clearly reported bridging therapy data that encompassed all three categories (combinations used, response rates, adverse events). What is more, these data were often omitted completely. These findings highlight the need for greater transparency in the reporting of bridging therapy in order to more reliably assess the efficacy of CAR-T therapies.

Unveiling consistency: A large-scale analysis of conference proceedings and subsequent publications in oncology clinical trials using large language models.

7568 Background: Conference abstracts serve as pivotal sources for sharing initial clinical trial findings, and influencing clinical decisions.Yet, concerns persist regarding the impact of unpublished conference abstracts on ultimate conclusions and the potential for inconsistency in result reporting. We aim to assess the feasibility of large-scale analysis, examining the consistency between initial conference results and subsequent reporting in published articles, specifically focusing on treatment efficacy and safety in oncology clinical trials using a large language model (LLM) pipeline. Methods: We collected clinical trial abstracts (2012-2023) from the American Society of Clinical Oncology conference (ASCO) conference and PubMed, encompassing both solid and hematopoietic cancer treatments. Utilizing a GPT-4-based LLM model, we extracted study details, treatment safety, and efficacy outcomes. Performance evaluation was conducted on manually annotated gold standards, including 100 multiple myelomas, 25 leukemia, 25 lymphomas, 30 breast cancer, and 35 lung cancer studies. To assess the consistency between reported outcome values in earlier conference abstracts and final published articles, we conducted a two-proportional Z-test. The test factored in cohort size and outcome values at each time point for selected efficacy outcomes, with p-values exceeding 0.05 suggesting a consistent pattern. Results: Our LLM pipeline achieved high performance with precision, recall (sensitivity), and F1 scores in the ranges of 0.958-0.986, 0.944-0.969, and 0.951-0.976, respectively, across diverse cancer types. While challenges arose in comparing outcomes between initial and final reporting in phase 1 dose-escalation studies due to variations in reported dosage groups, consistency prevailed when focusing on the recommended phase 2 dosage (RP2D) cohort in phases 1/2 and 2 studies. As part of the feasibility test, we analyzed outcomes from conference abstracts and final published data (with 1-2y differences) for the most common efficacy-safety measures in multiple myeloma studies. Results showed consistency with p-values ranging for Overall Response Rate (0.618-1), Complete Response (0.072-0.844), Very Good Partial Response (0.525), Minimal Residual Disease Negative (0.074), Neutropenia (0.212), Thrombocytopenia (0.372-0.422), Cytokine Release Syndrome (0.113-1), and Neurotoxicity (0.308-1). Conclusions: Our LLM model enables large-scale dataset analysis and facilitates effective outcome comparison among diverse sources and time points. The analysis of frequently appearing treatment outcomes showed no significant differences between earlier and final time points in the fixed dosage studies across therapies, despite variations in cohort sizes and follow-up times.

Assessment of health-related quality of life (HRQoL) in triple-class–exposed patients with relapsed or refractory multiple myeloma (RRMM) treated with linvoseltamab in the LINKER-MM1 trial.

e23185 Background: Linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, is being evaluated in LINKER-MM1, a Phase 1/2 study in patients with RRMM (NCT03761108). Early results over 36 weeks of treatment showed promising efficacy and a generally manageable safety profile (Jagannath et al., ASH 2023), and improvement or stability in patient-reported outcomes (PROs) including pain and fatigue (Hoffman et al., ASH 2023). We now report PRO data over a treatment period of 76 weeks. Methods: We evaluated patients in LINKER-MM1 who received the 5-25-200 mg dosing regimen in Phases 1 and 2 (n = 117). Patients ≥18 years old with triple-class exposed RRMM were administered linvoseltamab at Weeks 1 (5 mg), 2 (25 mg), and 3 (200 mg), followed by 200 mg once weekly through Weeks 14 (Phase 2) or 16 (Phase 1), then every 2 weeks until progression. Patients with a very good partial response by Week 24 in Phase 2 transitioned to dosing every 4 weeks. The EORTC QLQ-C30 was administered at baseline, Week 4, and then every 4 weeks. Least squares (LS) mean change from baseline and 95% confidence interval (CI) were estimated at each timepoint and overall on all scales using a mixed effects model for repeated measures. A 10-point change from baseline was considered clinically meaningful. Results were stratified by objective response status (at least partial response). No adjustment for multiplicity was performed; statistical significance is nominal, with LS mean change from baseline considered statistically significant if 95% CI did not cross 0. Results: PRO completion rates were generally ≥80% through Week 44 and dropped slightly after Week 44. LS mean change showed improvement in Global Health Status/QoL at Week 12, reaching the clinically meaningful threshold at Week 44; clinically meaningful improvements were observed on role and social functioning scales at Weeks 24 and 28, respectively. Pain and fatigue significantly improved and reached the clinically meaningful threshold at Weeks 20 and 44, respectively; the clinically meaningful improvement in pain was generally maintained through Week 76. Overall LS mean change in pain was clinically meaningful (-10.2; 95% CI -13.7, -6.7). Among treatment responders, statistically significant improvements were observed on all scales, including clinically meaningful improvement in pain (-11.2; 95% CI -14.7, -7.6). Non-responders had statistically significant worsening in fatigue (9.9; 95% CI 0.8, 19.1); overall change from baseline was not significant on other scales. Conclusions: Over 76 weeks of treatment, improvements in measures of HRQoL including pain and fatigue were reported in patients with triple-class exposed RRMM receiving linvoseltamab; responders showed significant improvements on all scales. These PRO results support a favorable benefit–risk profile of linvoseltamab. Clinical trial information: NCT03761108 .

Real-world analysis of belantamab mafodotin (belamaf): Care patterns in relapsed/refractory multiple myeloma.

e19507 Background: Belamaf is an anti-B cell maturation antigen immunoconjugate for relapsed/refractory multiple myeloma that has shown efficacy and safety in the DREAMM clinical trials. Additional long-term real-world data on its use patterns, efficacy, and tolerability are needed. Methods: This retrospective review (NCT05986682) analyzed adults with multiple myeloma receiving ongoing care at Duke Cancer Institute who began belamaf monotherapy (not in a clinical trial) between 8/5/2020 and 11/22/2022. We abstracted data for 30 patients through 9/18/2023. We described baseline clinical characteristics, disease response (per International Myeloma Working Group [IMWG] criteria, as possible given available marrow biopsy data), belamaf use patterns, and ocular adverse events (AEs) (per the Keratopathy Visual Acuity [KVA] scale). Results: Our sample was 53% (n=16) female, 47% (14) White, and 47% (14) Black; median age was 68 years at the beginning of belamaf therapy. 67% (20) had ≥4 prior lines of therapy (median: 4, min-max: 2-19), 87% (26) were triple-/quad-/penta-refractory, and 23% (7) had high-risk cytogenetics (per IMWG). Overall response rate (ORR) was 67% (11 very good partial response, 9 partial response). Median (min-max) time to best response was 1.5 (0.7-9.9) months. Median (min-max) response duration was 9.8 (1.1-20.2) months. Progression occurred in 73% (22) of patients; median progression-free survival (PFS) was 8.4 months (95% CI 6.6-12.7). Median overall survival was not reached. Median (min-max) number of cycles was 6.5 (2-13). 63% of patients (19) had a dose reduction from 2.5 to 1.9 mg/kg; 65% (13) were due to corneal AEs and 30% (6) due to hematologic AEs. 93% (28) had ≥1 cycle delay, and the median (min-max) number of delays was 5 (1-14); 85% of delays (n=153) were due to corneal AEs. Cycle length changed for 33% (10) from every 3 weeks to every 4 (1) or 6 (9) weeks; 91% (n=10) of cases were due to corneal AEs. 93% (28) had keratopathy (any grade); among all events (n=323), 2% were grade ≥3. Median (min-max) time to resolution of grade ≥2 keratopathies was 6 (2-22) weeks. 90% (27) experienced a visual acuity change; among all events (n=244), 3.3% were grade ≥3. Median (min-max) time to resolution of grade ≥2 visual acuity events was 6 (2.9-53) weeks. The most common ocular symptoms were blurry vision (53% of symptoms), dry eyes (17%), and photophobia (14%). Belamaf was discontinued in 13% (4) due to ocular AEs and 20% (6) to patient/physician choice or other reason. Median (min-max) time to last dose/discontinuation was 9.3 (0.7-21.6) months. Conclusions: In our study, ORR and median PFS were greater than other real-world studies. Corneal AEs were also more common, but severity was consistent with these and DREAMM-3 findings. Despite a higher rate of dose reductions and delays than other real-world studies, our study adds promise to the benefit of belamaf over an extended time with dose modifications.

Association of patient (pt) factors and pharmacodynamic biomarkers with progression-free survival (PFS) after idecabtagene vicleucel (ide-cel) in pts from KarMMa-3.

7527 Background: Ide-cel, a B-cell maturation antigen (BCMA) CAR T cell therapy (tx), significantly improved PFS vs standard regimens in pts with triple-class–exposed relapsed or refractory MM (13.8 vs 4.4 mo, P<0.001) in KarMMa-3. Median PFS in the ide-cel treated population (pop; n=225) was 15.7 (95% CI, 12.5–18.9) mo (Rodríguez-Otero ASH 2023). PFS benefit of ide-cel was consistent across high-risk pt subgroups. Previous analyses indicated that lower levels of baseline soluble BCMA (sBCMA; measure of tumor burden) and lower basal inflammatory markers were positively associated with response to ide-cel. This analysis identified pre- and post-tx pt factors and pharmacodynamic biomarkers associated with longer PFS with ide-cel in the treated pop. Methods: Median PFS (15.7 mo) of the treated KarMMa-3 pop was used to divide pts into 2 groups: longer PFS (>15.7 mo; n=106) or shorter PFS (≤15.7 mo; n=110). Censored pts (n=9) who had a PFS <15.7 mo were excluded. Pre- and post-tx values for laboratory parameters, MM assessments, sBCMA, inflammatory cytokines, ide-cel transgene persistence, and minimal residual disease (MRD; 10−5 sensitivity) were evaluated. Serum free light chains (sFLCs) were evaluated as biomarkers of plasma cell clearance; clearance was defined as level below limit of detection of both involved and heterotypic sFLC. Analyses were post hoc and exploratory; statistical tests were used to identify relationships of interest. Results: In total,94% of pts with longer PFS achieved a best overall response of ≥very good partial response and had lower levels of β-2 microglobulin ( P<0.01), lactate dehydrogenase ( P<0.01), and sBCMA ( P<0.01) at baseline. Inflammatory markers (eg, tumor necrosis factor, ferritin, C-reactive protein) were significantly higher ( P<0.05) in pts with shorter vs longer PFS at baseline. All pts with longer PFS (100%) achieved sFLC clearance after ide-cel infusion. Among pts who achieved initial clearance, pts with longer PFS had a longer duration of sFLC clearance than shorter PFS ( P<0.001), suggesting more durable engraftment of ide-cel and tumor control. Within MRD-evaluable pts, those with longer PFS achieved higher MRD negativity vs shorter PFS (87% vs 41%) at 6 mo post infusion with sustained MRD negativity (53% vs 4%) lasting 8–12+ mo. No apparent relationship was observed between PFS and ide-cel persistence at 6-, 9- and 12-mo post-infusion. Conclusions: Pts with longer PFS after ide-cel infusion had relatively lower tumor burden and lower levels of peripheral inflammatory markers before tx, highlighting the importance of managing baseline tumor burden before CAR T cell infusion to achieve optimal response. Complete and sustained clearance of sFLCs within the first few mo post infusion was associated with longer PFS. MRD negativity at 6 mo and sustained MRD negativity were enriched in pts with longer PFS. Clinical trial information: NCT03651128 .

Real-world outcomes of teclistamab for the treatment of relapsed/refractory multiple myeloma at UC San Diego Health: A single-institution experience.

e19504 Background: Bispecific antibodies (BsAb) are emerging as a promising class of cancer immunotherapy. Teclistamab, a BsAb targeting B-cell maturation antigen (BCMA) expressed on plasma cells, received FDA approval for the treatment of relapsed/refractory (R/R) multiple myeloma (MM) in 2022. Here we describe the real-world experience of teclistamab at a single institution. Methods: We retrospectively reviewed patients with R/R MM who received teclistamab at University of California San Diego and had at least 6 months of follow up. Baseline characteristics, efficacy outcomes, and safety outcomes were collected. Kaplan-Meier method was used to describe survival. Results: A total of 18 patients who received teclistamab between 01/01/2023 and 06/15/2023 were included in this analysis. The median age was 67 years old (range 50-83). Median prior lines of therapy was 6.5 (range 3-11). All patients had triple-refractory disease; all but one had penta-refractory disease. Approximately 44% of patients had extramedullary plasmacytomas at time of BsAb initiation; 39% had received prior BCMA therapy (2 belantamab, 5 ide-cel) before teclistamab. High-risk cytogenetics (t(4;14), t(14;16), t(14;20), Del17p, Gain1q) were characterized for 13 patients with data available. 6 had a single high-risk mutation, 4 had two, and 1 had three. Incidence of cytokine release syndrome (CRS) was 12 (67%); (4 (33%) grade 2, no grade 3-5). 6 (50%) received tocilizumab to treat CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was 2 (11%); (1 (50%) grade 2, no grade 3-5). Pain crisis occurred in 11% of patients. The incidence of infection was 67%; the majority were grade ≥ 3. The overall response rate (ORR) by IMWG criteria was 50%. All patients who responded had a very good partial response (VGPR) or better; further response data was not available due to the lack of restaging bone marrow biopsies during treatment. Median duration of response for the entire cohort was not reached. Median progression-free survival (PFS) was 12.5 months (95% CI 1.0 – not reached); median overall survival (OS) was not reached (95% CI 7.8 – not reached).Univariate analyses showed no statistically significant relationship between response and prior BCMA therapy (p=.91), response and presence of extramedullary disease (p=.31), or response and mSMART risk stratification (p=.13). Conclusions: Overall, the incidence and grades of CRS, ICANS, and infection in our cohort were similar to those observed in the phase I/II MajesTEC-1 trial. In contrast, the ORR and PFS in this study were lower compared to the MajesTEC-1 study. This difference may be due to a greater proportion of patients with high-risk cytogenetics and more aggressive disease, as depicted by the higher median prior lines of therapy and higher rates of extra-medullary plasmacytomas and triple-/penta-class refractory disease.

Efficacy and safety of GPRC5D-based monotherapies for relapsed/refractory multiple myeloma: A systematic review and meta-analysis.

e19503 Background: G protein-coupled receptor family C group 5 member D (GPRC5D), a highly expressed receptor in myeloma cells, is one of the novel emerging targets for relapsed/ refractory (R/R) multiple myeloma (MM). Among the GRPC5D therapies, currently one agent talquetamab has been approved while CAR-T therapies are under development. Methods: A literature search using electronic databases Pubmed, Embase, Scopus, Web of Science and Cochrane, including major conference abstracts was conducted from inception to December 31, 2023 focusing on GPRC5D therapies in MM. For multiple reports of the same study, the latest available report of the study describing the efficacy or safety was selected. Only GPRC5D based monotherapies were included, and combination regimens were excluded for this review. Data on safety and efficacy were extracted, evaluated and systematically analyzed using Comprehensive Meta-analysis 3.3. The study protocol was registered with PROSPERO (CRD42024497933). Results: After screening 562 articles, and removing duplicates, total seven studies with 581 patients were included (5 GPRC5D-CAR T studies with 137 patients and 2 GPRC5D-BsAb studies with 444 patients). The pooled overall response rate (ORR) for GRPC5D therapies in this cohort was 77.4%, with best response rate [very good partial response (VGPR) or better] of 59.2%. The pooled incidence rate of cytokine release syndrome (CRS), any grade and Immune effector cell-associated neurotoxicity syndrome (ICANS), any grade, was 78.8% and 9.6% respectively. Grade 3/4 hematological adverse events included neutropenia being the most common (69.6%), followed by thrombocytopenia (36.8%) and anemia (34.2 %). Subgroup analysis was performed for GPRC5D therapies- CAR T and BsAb as shown in the table. Conclusions: GPRC5D based therapies showed high response rates in R/R MM with distinct side effect profile including CRS and cytopenias. Further studies along with follow up of the ongoing trials is needed to understand the long-term outcomes. [Table: see text]

Safety results from the phase 3 MajesTEC-7 study in patients (pts) with transplant ineligible/not intended newly diagnosed multiple myeloma (NDMM).

7506 Background: Despite recent advances in the treatment (tx) of transplant ineligible/not intended NDMM, most pts still relapse and require alternative txs, highlighting a need for new frontline tx options with new mechanisms of action to improve pt outcomes. Teclistamab (tec) demonstrated rapid, deep, and durable responses in the MajesTEC-1 trial (NCT03145181/NCT04557098). Preliminary data from the MajesTEC-2 trial (NCT04722146) demonstrated that tec, daratumumab (dara), and lenalidomide (len) combination (tec + DR) is tolerable, with promising efficacy in pts with relapsed/refractory MM and NDMM. The phase 3 MajesTEC-7 (NCT05552222) study will compare tec + DR vs DR + dexamethasone (dex) in pts with NDMM who are ineligible/not intended for ASCT as initial tx. We report the results of the first safety run-in (SRI) from MajesTEC-7. Methods: Eligible patients were aged ≥18 yrs with NDMM and ineligible/not intended for ASCT as initial tx, with measurable disease and an ECOG performance status (PS) score 0–2. Pts in the SRI received tec (step-up dose [cycle 1], QW [cycle 2], Q2W [cycle 3–6], and Q4W [cycle 7+]) + DR (as SOC) until progression, unacceptable toxicity, or death. Response assessments were based on IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Prophylactic immunoglobulin replacement was highly recommended. Results: As of Nov 27, 2023, 26 pts had received tec + DR (median, 11 cycles; range, 2–14) and 24 pts (92.3%) remained on tx. Median follow-up was 10.2 mo (range, 2–12). At baseline, median age was 72.5 yrs, 11.5% had an ECOG PS score of 2, and 15.4% had ≥1 soft-tissue plasmacytoma. 4 pts (15.4%) deferred transplant. Treatment-emergent AEs (TEAEs) occurred in 100% of pts (grade [gr] 3/4, 22 pts [84.6%]). Infections occurred in 25 pts (96.2%; gr 3/4, 8 pts [30.8%]). CRS occurred in 16 pts (61.5%; all gr 1). ICANS occurred in 1 pt (gr 1). Gr 3/4 TEAEs occurring in ≥3 pts were neutropenia (13 [50%]), febrile neutropenia (5 [19.2%]), thrombocytopenia (4 [15.4%]), COVID-19 (3 [11.5%]), maculo-papular rash (3 [11.5%]), and hypertension (3 [11.5%]). 1 pt discontinued tec + DR due to withdrawal of consent. 2 discontinued len due to TEAEs (gr 3 maculo-papular rash and gr 4 neutropenia). There was 1 death due to a TEAE in cycle 3 (pneumonia influenza). Overall response rate was 92.3% (complete response or better, 73.1%; very good partial response or better, 92.3%). Conclusions: These results from the first SRI of MajesTEC-7 demonstrate a manageable safety profile with early efficacy of tec + DR in NDMM. Two additional SRIs are ongoing investigating tec (less frequent dosing) + DR and talquetamab + DR. Clinical trial information: NCT05552222 .

Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

7500 Background: The first line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts. Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO) and d (20 mg IV/PO). The primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better and overall survival. Adverse events (AEs) and laboratory parameters were graded with NCI CTCAE v4.03. Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667 . [Table: see text]

Quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma (TENDMM): A systematic review and meta-analysis.

e19534 Background: Immunomodulatory drugs, proteasome inhibitors plus dexamethasone are the standard triplet induction regimen for TENDMM. We analyzed the efficacy of adding either anti-CD38 monoclonal antibodies (mAbs) or anti-SLAMF7 antibody to the triplet therapy. Methods: Ovid MEDLINE, EMBASE and published abstracts were systematically searched from each database’s inception through 01-31-2024 to identify II/III trials assessing quadruplet therapy versus triplet therapy in TENDMM patients. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), odds ratios (OR) for overall response rates (ORR), measurable residual disease (MRD) negativity rate (with sensitivity of 10 -5) and grade 3 or higher treatment-related adverse events (G≥3 TRAE) were summarized using random effects meta-analysis via inverse variance approach. Additional subgroup analyses based on the cytogenetic risk were performed. P-value of interaction (Pint ) < 0.1 was pre-specified as statistically significant for the difference between the two groups. Results: 3806 studies were screened and seven trials were included with a total of 3546 patients. Four trials (2303 patients) assessed the addition of anti-CD-38 mAbs and three (1243 patients) assessed anti-SLAMF7 mAb, elotuzumab to the triplet regimen. Quadruplet therapy significantly improved PFS as compared to triplet (HR: 0.63; 95% CI: 0.43-0.92), and the PFS benefit was also observed in standard risk group (HR 0.5; 95% CI 0.2-0.9); however, results were insignificant for high-risk group (HR 0.8; 95% CI 0.62-1.93). No significant OS benefit was observed (HR: 0.79; 95% CI 0.49–1.26); however, data for three trials (CASSIOPEIA, DSMM XVII, PERSEUS) is immature, with longer-term follow-up ongoing. Quadruplet therapy showed significant results for very good partial response or better (OR: 1.7; 95% CI 1.2-2.36), stringent complete response (OR: 1.74; 95% CI 1.27-2.07) and complete response or better (OR: 1.91; 95% CI 1.19-3.06). MRD rate shows benefit with quadruplet therapy (OR: 2.59; 95% CI 2.22-3.01). Improved MRD rate was also observed for high-risk (OR 2.13; 95% CI 1.4-3.2) and standard-risk group (OR 2.58; 95% CI 1.68-3.94). Secondary analysis for efficacy of anti-CD38 mAbs showed benefit for PFS (HR: 0.44; 95% CI: 0.35-0.56), ORR (OR: 1.77;95% CI: 1.02-3.06), and MRD (OR: 2.98; 95% CI 1.8-4.8). G ≥3 TRAE did not significantly differ between the groups (OR: 1.05; 95% CI 0.97-1.12). However, quadruplet therapy showed significant risk of infection (OR: 1.2; 95% 1.05-1.35) and thrombocytopenia (OR: 1.41; 95% CI 1.24-1.59). Conclusions: Quadruplet therapy improved PFS, ORR, and MRD rates compared to triplet regimen and has demonstrated promising benefits to be considered the new standard of care for TENDMM patients.

Long-term follow-up of ARI0002h (cesnicabtagene autoleucel), an academic point-of-care B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell strategy: Activity and safety after fractionated initial therapy and booster dose in 60 patients with relapsed/refractory multiple myeloma (RRMM).

7544 Background: The activity and safety ofARI0002h, an academic autologous CAR T-cell product with a humanized single chain variable fragment targeting BCMA has been reported in a pilot multicenter clinical trial (CARTBCMA-HCB-01) treating 30 patients (pts) with RRMM (NCT04309981) (Oliver-Caldés, Lancet Onc 2023). Here, we describe results of the final cohort of 60 pts with longer follow-up. Methods: Patients aged 18-75 years old with RRMM were eligible if they had measurable disease, were refractory to the last line of treatment and received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. The target dose (3x106/kg CAR+cells) was administered in a fractionated manner (10%/30%/60%). A second dose of up to 3x106 CAR+ cells/kg was planned at least 3 months after the first dose in pts with any kind of response and no limiting side effects. Primary endpoints were overall response rate (ORR) within the first 3 months and rate of cytokine release syndrome (CRS) and/or neurotoxicity in the first 30 days. Bone marrow minimal residual disease (MRD) was analyzed by next-generation flow at a sensitivity of 10-6. Results: As of December 18th 2023, 72 pts with RRMM were screened, 69 underwent apheresis and 61 received LD, with 60 pts finally receiving ARI0002h. The ORR in the first 3 months was 95% (≥ very good partial response (VGPR) in 77%). Median time to first response was one month. Responses deepened over time, achieving 58% complete response (CR) (55% stringent CR). MRD-negative rates on evaluable samples on days 28 and 100 were 98% and 96%, respectively. With a median follow-up of 24 months (95%CI 9.8-39.9), estimated median progression-free survival (PFS) was 20 months (95% CI 13.2-26.8). Median overall survival (OS) was not reached with OS rate at 24 months of 63%. CRS was observed in 90% with 5% grades ≥ 3. Median time to CRS was 7 days (1-14) with a median duration of 4.5 days. Mild acute neurotoxicity was reported in only 2 pts (3%) with no late neurologic events. 6 pts (10%) developed a macrophage activation syndrome (4 grades 1-2, 1 grade 3, 1 grade 5). Seven patients (11.7%) developed second primary malignancies after ARI0002h infusion, including 3 skin cancers (one in situ melanoma), 3 solid tumors and one acute myeloid leukemia. 80% (44 out of 5) eligible pts had already received the booster dose, with no relevant toxicities. Median time after first infusion was 4.4 months. Response was evaluable in 42 pts; 45% (n=19) were already in sCR, 29% (n=12) maintained the response and 26% (n=11) improved the response. Conclusions: Results from 60 pts and a longer follow-up confirm the safety profile and the deep and durable responses obtained after ARI0002h infusion. Clinical trial information: NCT04309981 .

All-oral triplet iberdomide, ixazomib, and dexamethasone in elderly patients with multiple myeloma at first relapse: Results of the IFM phase 2 study I2D.

7507 Background: The triplet combination daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are to date the standard of care for patients with transplant ineligible (TI) newly diagnosed multiple myeloma (MM). Most TI patients therefore present with MM refractory to lenalidomide and daratumumab at first relapse and represent a difficult-to-treat population. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD) that demonstrated promising activity in MM patients refractory to lenalidomide/pomalidomide. Here, we report efficacy and safety results of the oral triplet iberdomide, ixazomib and dexamethasone in elderly patients with MM at first relapse. Methods: The Intergroupe Francophone du Myélome (IFM) prospective, multicenter, phase 2 study I2D enrolled MM patients aged over 70 years at first relapse (NCT04998786).Patients received oral iberdomide (1.6 mg on day 1 to 21), ixazomib (3 mg on day 1,8,15) and dexamethasone (20 mg on day 1,8,15,22 on cycle 1-2 and 10 mg on day 1,8,15,22 on cycle 3-6) (28-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was very good partial response (VGPR) rate. Results: Seventy patients were included from Dec 2021 to May 2023 in 19 IFM centers. Median age was 76. The International Myeloma Working Group (IMWG) frailty score was >2 in 35 (50%) patients. In evaluable patients (54/70), cytogenetic analysis revealed del(17p) in 10 patients (18.5%) and t(4;14) in 8 (15%) patients. Based on inclusion criteria, all patients received 1 prior line of treatment, including lenalidomide in 87% (refractory, 74%) and daratumumab in 40% (refractory, 37%) of patients. Median time from MM diagnosis to study enrolment was 28 months. At data cut-off, 36 (51%) patients discontinued the study due to disease progression (n=30), adverse event (n=4) or death (n=2). After a median follow-up of 12 months, the overall response rate was 64%, including 33% VGPR. The median progression-free survival (PFS) was 13 months and the 12-month overall survival (OS) was 85% (77-95% 95% CI). In patients with MM refractory to both lenalidomide and daratumumab (n=26), the median PFS was 10 months. Overall, the triplet I2D was well tolerated. Most common non-hematologic adverse events (AE) were infection (30% of patients), peripheral neuropathy (20%), diarrhea (19%), and were mostly grade 1 or 2. Most common grade 3-4 treatment related AEs (>5% of patients) were neutropenia (46%), thrombocytopenia (9%) and infection (8%). Four patients discontinued treatment due to a severe AE (cytopenia (n=3), skin rash (n=1). Conclusions: The oral tripletiberdomide, ixazomib and dexamethasone demonstrated a favorable efficacy / safety profile in elderly MM patients at first relapse, including in patients with lenalidomide and daratumumab refractory disease. Clinical trial information: NCT04998786 .

Associations of T-cell fitness prior to B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CART) and bispecific T-cell engager (BiTE) therapies and efficacy/toxicity in relapsed/refractory multiple myeloma (RRMM).

7549 Background: While CART and BiTE have led to unprecedented responses in RRMM, some patients (pts) do not respond or have short-lived responses. Currently no predictive markers exist to identify these pts. This study explored pretreatment T-cell fitness and efficacy/toxicity in RRMM using a novel single-cell secretome analysis. We hypothesized that pretreatment Polyfunctional Strength Index (PSI) may predict efficacy to BCMA-directed T-cell therapies. Methods: We included 14 RRMM pts treated with idecabtagene vicleucel or teclistamab at Yale Cancer Center with ≥6 mos post-treatment follow-up. Peripheral blood prior to treatment was frozen and then PBMC’s thawed for analysis. PSI, a metric for T-cell fitness combining polyfunctional T-cells % with the intensity of secreted cytokines, was obtained using the IsoPlexis’ Single-Cell Secretome Platform. The overall PSI was an average of CD4+ and CD8+ PSIs. Response was assessed by the International Myeloma Working Group criteria and response duration was defined as time from response to disease progression. Responder (R) was defined as ≥very good partial response for ≥6 mos. Non-responder (NR) was defined as stable or progressive disease ≤3 mos. Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation & Cellular Therapy system. Statistics were performed with Mann-Whitney U test using GraphPad PRISM v.9. Results: There were 7 pts in R group (2 BiTE & 5 CART) and 7 pts in NR group (3 BiTE & 4 CART). Median follow-up time was 13.5 mos(range, 7-27). Median age at treatment was 64 yrs in R and 63 yrs in NR. Extramedullary disease (EM) was present in 14.3%(n=1) in R and 71.4%(n=5) in NR. High-risk cytogenetics, defined as del17p, t(4;14), t(14;16), t(14;20), 1q gain/amplification and del1p, were seen in 42.9%(n=3) in R and 85.7%(n=6) in NR. Median prior lines of therapy was 6(range, 4-9) in R and 8(range, 4-10) in NR. CRS/ICANS occurred 85.7%(n=6) in R and 28.6%(n=2) in NR. Overall PSI was 184 in R and 91 in NR(p=0.1649). CD4+ PSI was 160 in R and 75 in NR(p=0.1649). CD8+ PSI was 207 in R and 108 in NR(p=0.1981). Overall PSI was 143 in CRS/ICANS and 130 in no CRS/ICANS(p=0.7546). Conclusions: Overall PSI, CD4+ PSI and CD8+ PSI were 1.9-2.1 times higher in R compared to NR and overall PSI was slightly higher in CRS/ICANS compared to no CRS/ICANS though the difference was not statistically significant. One limitation was a small sample size and thus testing PSI in a larger cohort might yield statistically significant results. The NR group had more high-risk cytogenetics and higher EM. One confounder could be that measuring peripheral T-cell fitness may not be sufficient to predict response in EM where spatial determinants of T-cell influx play a role.

Exploring T cell subsets as predictors of response to BCMA targeting bispecific antibody therapy in multiple myeloma.

7567 Background: BCMA targeting bispecific Antibody (bsAb) therapy has shown unprecedented response and survival rates in patients with relapsed/refractory multiple myeloma (MM). The clinical activity of bsAb therapy has been shown to depend on T-cell function, yet clinical parameters, such as absolute lymphocyte count (ALC) have not been found to be associated with response to bsAbs. The aim of the present study was to elucidate whether distinct T cell subsets, such as CD4 and CD8 counts as well as their proportion within the ALC are associated with outcome of BCMA targeting bsAb therapy. Methods: We retrospectively collected data on 79 patients who had been treated with at least one full dose of a BCMA targeting bsAb. T cell subsets, including ALC, total CD3, CD4 and CD8, were measured from peripheral blood within 7 days prior to bsAb therapy initiation. Statistical analysis was performed with SAS version 9.4 using univariate and multivariate logistic regression models. Results: Median age of the patient cohort was 72 (31-84) years with 40/79 (51%) being male and 15/79 (19%) being African American. Median lines of therapy was 5 (2-12) with 78/79 (99%) patients being triple class refractory and 50/79 (63%) being penta-drug refractory. 59/79 (75%) of patients had at least one prior stem cell transplant (SCT) with 35/79 (44%) having had at least two SCTs. 26/79 (33%) patients had prior exposure to BCMA targeting therapy, with 18/79 (23%) and 8/79 (10%) previously having received belantamab mafodotin or BCMA targeting Car-T cell therapy respectively. Cytokine release syndrome (CRS) occurred in 38/79 (48%) of patients with the majority (92%) being grade 1 with the remainder being grade 2. Median ALC was 1.02 (0.25-5) x103/mL, median CD4 count was 0.27 (0.04-1.13) x103/mL while median CD8 count was 0.5 (0.07-2.97) x103/mL. Overall response (OR) rate of the whole cohort was 82% (69/79) with best responders (³very good partial response) comprising 51% (40/79). While total ALC, CD4 and CD8 counts did not appear to impact response to BCMA targeting bsAb therapy, the ratio of CD4 to ALC proved to be significantly associated with OR (univariate p=0.04) and best response (univariate p= 0.004, multivariate p=0.01) . The CD8 to ALC ratio had no significant impact in this patient population. The only other factor to show a significant association with response was the number of prior lines of therapy with higher numbers being associated with worse response (p=0.046). Conclusions: Our study suggests that an increased proportion of CD4 cells within the ALC is significantly associated with better response to BCMA targeting bsAb. While future studies are needed to elaborate on CD4 function in bsAB therapy, our findings imply that therapeutic strategies to increase the CD4 proportion could lead to improved bsAb therapy effectiveness.

Isatuximab with pomalidomide-dexamethasone in relapsed/refractory multiple myeloma: post-marketing surveillance in Japan

This post-marketing surveillance assessed the safety and effectiveness of isatuximab plus pomalidomide and dexamethasone (Isa-Pd) for relapsed or refractory multiple myeloma (RRMM) during real-world use in Japan. Data from 211 individuals with RRMM treated with Isa-Pd in Japan between October 2020 and October 2021 were collected, with follow-up for up to 12 months after initiation of Isa-Pd or until treatment discontinuation. The incidence of adverse drug reactions (ADRs), ADRs of special interest (infusion reactions, bone marrow suppression, infections, cardiac disorders, other ADRs of Grade ≥ 3), and serious ADRs was assessed. Best overall response and overall response rate (ORR) were determined. In the safety analysis set (n = 120), ADR incidence was 57.5%. Most ADRs were hematologic, and serious ADRs occurred in 28.3%. Bone marrow suppression occurred in 46.7% of participants (19.2% serious), infusion reactions in 18.3% (6.7% serious), infections in 11.7% (8.3% serious), and a serious cardiac disorder in one participant; other Grade ≥ 3 ADRs were reported in 3.3% (1.7% serious). In the effectiveness analysis set (n = 108), the most common best overall response was very good partial response (24.1%), and ORR was 51.9%. These findings support the safety and effectiveness of Isa-Pd for RRMM in real-life settings in Japan.

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA

Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. Merck Sharp & Dohme.

Efficacy and safety of once weekly selinexor 40 mg versus 60 mg with pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.

To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.

Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16

AbstractIn newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).