Relapsed And Refractory Multiple Myeloma Research Articles

Abstract 4114505: Cardiovascular Adverse Events After Anti-BCMA CAR-T (Ide-Cel and Cilta-Cel) for Relapsed/ Refractory Multiple Myeloma

Introduction: Idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-cel) are novel CAR-T therapies targeting B-cell maturation antigen (BCMA) and approved for relapsed and refractory multiple myeloma (RRMM). While cardiovascular adverse events (CVAE) are relatively common with CD-19 CAR-T, the incidence of CVAE in the real-world setting for anti-BCMA CAR-T in RRMM is largely unknown. This study aims to determine the incidence of CVAE and its associated risk factors in patients treated with ide-cel and cilta-cel. Method: This single-center retrospective cohort study evaluated RRMM patients treated with ide-cel and cilta-cel from May 2021 to December 2023. We assessed baseline cardiac and oncologic characteristics and clinical outcomes post-CAR-T. Cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome (ICANS) grading followed ASTCT consensus guidelines. Result: A total of 164 RRMM patients treated with ide-cel (N=109) or cilta-cel (N=55) with at least 6 months follow-up were included. The average age was 63 years, and 57% were male. Advanced RRMM stage (R-ISS III) was present in 17% with a median of 6 prior lines of therapy. CRS grade equal or greater than 2 occurred in 22%, and ICANS grade equal or greater than 3 in 6.7%. Twenty patients (12.2%) experienced CVAE, including atrial fibrillation (7.9%), non-sustained ventricular arrhythmia (3.0%), heart failure (3.7%), and cardiovascular death (0.6%). R-ISS III was associated with increased CVAE (52.9% vs. 11.5%; P=0.001). Patients with CVAE had higher baseline ferritin and CRP levels and a higher incidence of CRS grade ≥ 2 (60% vs. 16.7%; P<0.001) and ICANS grade ≥ 3 (20% vs 4.9%; P=0.001). Treatment with tocilizumab, steroids, or anakinra was more common in patients with CVAE. Conclusion: CVAE occurred relatively frequently following BCMA CAR-T therapy, with high-grade CRS identified as a consistent risk factor. Most CVAEs were manageable with appropriate supportive care, including careful observation and active treatment of CRS.

CD27-Armored BCMA CAR T Cell Therapy (CBG-002) for Relapsed and Refractory Multiple Myeloma: A Phase I Clinical Trial.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM); however, whether patients have long-term response has yet to be established. We investigated the feasibility of CBG-002, an CD27-armored BCMA CAR T therapy, to improve clinical efficacy in patients with RRMM. We present preclinical data showing the activity of CBG-002 against myeloma and results from a phase I clinical trial (NCT04706936) evaluating its safety and efficacy in patients with RRMM. The primary endpoint was safety, as assessed by grade 3 or 4 adverse events(AEs). Key secondary endpoints were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). A total of 11 patients were enrolled and received CBG-002 therapy. Nine patients developed grade 1 or 2 cytokine release syndrome (CRS), while no patients experienced grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome. Other grade 3 or higher AEs included neutropenia (72.7%), thrombocytopenia (45.5%) and anemia (36.4%). At a median follow-up of 16.7 months, the ORR was 81.8%, including a stringent complete response/complete response rate of 45.5%, very good partial response rate of 18.2%, and partial response rate of 18.2%, with a median DOR of 8.9 (range 1.8-21.9) months. The median OS was not reached, and the median PFS was 8.5 (2.7-22.9) months. In this phase I study, CBG-002, a CD27-armored BCMA CAR T therapy, demonstrated safety and clinical efficacy in patients with RRMM.

The occurrence of cytokine release syndrome and its impact on the prognosis of patients with relapsed and refractory multiple myeloma following chimeric antigen receptor T-cell therapy

Objective: To analyze the incidence of cytokine release syndrome (CRS) and its impact on the prognosis of patients with relapsed and refractory multiple myeloma (RRMM) following treatment with chimeric antigen receptor T-cell (CAR-T) therapy. Methods: A retrospective collection was conducted of the clinical data of 91 patients with RRMM who underwent CAR-T therapy at the Affiliated Hospital of Xuzhou Medical University from January 2020 to October 2022. Before CAR-T cell infusion, the patient underwent pretreatment with the fludarabine plus cyclophosphamide (FC) regimen. On day 0 (d0), the patient received a dose of 1×106 cells/kg of CAR-T. The occurrence of CRS was recorded post-treatment and graded accordingly, with grades 1 to 2 indicating mild CRS and grade≥3 indicating severe CRS. The follow-up cut-off date was February 14, 2023, with a median follow-up time [M (Q1, Q3)] of 14.1 (3.1, 37.7) months. Kaplan-Meier survival curve analysis assessed the progression-free survival (PFS) and overall survival (OS) of Grade 1 and Grade 2 CRS patients. Furthermore, univariate logistic regression analysis was conducted to identify factors associated with the development of severe CRS. Results: In a cohort of 91 patients diagnosed with RRMM, there were 51 male and 40 female individuals, with a median age [M (Q1,Q3)] of 57 (31, 73) years. All 91 cases (100%) experienced CRS, with 82 cases (90%) classified as mild (grades 1-2) CRS and 9 cases (10%) classified as severe (grades 3-5) CRS. In a study involving 9 patients with severe CRS, 8 cases resulted in mortality. The Kaplan-Meier survival curve analysis revealed that among grade 1 CRS patients, neither the median PFS nor the median OS was achieved. For grade 2 CRS patients, the median PFS was 12 months (95%CI: 4-not achieved), and the median OS was 21 months (95%CI: 4-not achieved). The progression-free survival and overall survival rates of grade 2 CRS patients were both lower than those of grade 1 CRS patients (both P<0.05). Single-factor logistic regression analysis revealed that a high tumor burden (OR=1.025, 95%CI: 1.002-1.049, P=0.031), a prolonged duration of CRS onset (OR=0.809, 95%CI: 0.646-0.971, P=0.037) and persistence (OR=1.758, 95%CI: 1.349-2.481, P=0.001) were identified as significant factors associated with severe CRS in patients with RRMM. Conclusions: Patients with RRMM who undergoes CAR-T therapy have a high incidence of CRS, with a higher mortality rate among those experiencing severe CRS. Furthermore, patients with grade 2 CRS exhibit lower rates of progression-free survival and overall survival compared to those with grade 1 CRS. Factors associated with the development of severe CRS in RRMM patients include high tumor burden and prolonged duration and onset of CRS.

Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens (SRs) in Triple-Class–Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): KarMMa-3 Sub-Analysis of Black Patients

Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens (SRs) in Triple-Class–Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): KarMMa-3 Sub-Analysis of Black Patients

Personalized Treatment of Multiple Myeloma in Frail Patients.

As the treatment landscape for multiple myeloma (MM) continues to expand at a rapid pace, management of older adults and frail patients becomes increasingly challenging. As these patients have traditionally been underrepresented on clinical trials, there is limited guidance on the optimal approach to frail patients with newly diagnosed multiple myeloma (NDMM) or relapsed and refractory multiple myeloma (RRMM). Frailty is an independent predictor of tolerability and response to antineoplastic treatment. Stringent eligibility criteria have often excluded these patients, but recently some large trials have included frailty sub-analyses to help guide management. In general, triplet regimens are preferred to doublet regimens in this population and enrollment on a clinical trial should be prioritized when possible. In this review, we summarize the MM frailty scoring tools that have been developed to identify and assess this vulnerable population. We present the clinical trials over the past decade that have enrolled frail patients and/or have included subgroup analyses to help elucidate the response and tolerability of different regimens in this underrepresented group. We provide practical advice regarding assessment and management of frail patients NDMM and RRMM.

Pomalidomide improves the effectiveness of CAR-T treatment in the relapsed and refractory multiple myeloma or B-cell leukemia/lymphoma with extramedullary disease.

Relapsed and refractory multiple myeloma (RRMM) and B-cell leukemia/lymphoma with extramedullary disease (EMD) have poor prognosis and high mortality, lack of effective therapeutic approaches. We reported for the first time that 6 patients with malignant hematological diseases with EMD received chimeric antigen receptor (CAR)-T treatment combined with pomalidomide, and CAR-T cells were treated with pomalidomide in vitro to determine its killing activity and cytokine secretion. Three patients with RRMM were given B cell maturation antigen (BCMA)-CAR-T therapy. All 3 patients with B-cell leukemia/lymphoma received CD19/22-CAR-T sequential infusion. There were no treatment-related deaths. The maximum overall response rate (ORR) was 100%. Median follow-up was 211.5 days (75-407 days). Three patients (50%) experienced cytokine release syndrome, all of which were grade 1, and no neurotoxicity was observed. In vitro experiments showed that the killing activity did not differ significantly between BCMA-CAR-T cells with and without pomalidomide (10, 25, or 50 μg/mL) in 8226/U266 cell cocultures (P > .05). Tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion was significantly higher from 8226 and Raji cells cocultured with BCMA-CAR-T and cluster of differentiation (CD)19-CAR-T cells (P < .05). Based on the cocultures, adding pomalidomide significantly promoted IFN-γ and TNF-α secretion (P < .05). Based on the above clinical and in vitro studies demonstrating the co-administration of pomalidomide with CAR-T cell treatment demonstrated favorable tolerability and therapeutic effectiveness in RRMM or B-cell leukemia/lymphoma.

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

The characteristics and impact on prognosis of cytopenia after anti-BCMA-CAR-T therapy in patients with relapsed and refractory multiple myeloma

Objective: To investigate the characteristics of cytopenia and its impact on prognosis in patients with relapsed and refractory multiple myeloma (RRMM) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) immunotherapy therapy. Methods: Clinical data of 36 RRMM patients received BCMA CAR-T therapy at the First Affiliated Hospital of Nanjing Medical University from April 2017 to March 2023 were retrospectively collected. Among them, there were 17 males and 19 females, with an age [M (Q1, Q3)] of 62 (53, 67) years. The follow-up deadline was August 31, 2023, and the follow-up time [M (Q1, Q3)] was 33 (10, 30) months. The characteristics of cytopenia at different time points before lymphodepleting chemotherapy and after CAR-T cell infusion in all patients were analyzed. Kaplan-Meier method was used to compare the differences in progression-free survival (PFS) and overall survival (OS) in patients with different clinical characteristics. Single-cell sequencing analysis was used to analyze the changes in hematopoietic stem cells in three patients after CAR-T cell therapy. Results: The incidence of cytopenia after BCMA CAR-T cell therapy in 36 RRMM patients reached 100%. The incidence of neutropenia peaked on the 7th and 28th day after cell infusion with a biphasic pattern of change.Patients with all grade neutropenia reached 61.1% (22/36) and grade 3 or higher reached 33.3% (12/36) on the 7th day, while patients with all grade neutropenia reached 67.9% (19/28) and grade 3 or higher reached 28.6% (8/28) on the 28th day (P<0.001),respectively. The occurrence rate of lymphopenia reached a peak on the day of CAR-T cell infusion [97.2% (35/36) patients showed lymphopenia, while 80.6% (29/36) patients showed grade 3 or higher lymphopenia] (P<0.001).The incidence of all grade of thrombocytopenia and severe thrombocytopenia (grade 3 or higher) peaked on the 14th day after cell infusion, with the rates of 69.4% (25/36) and 30.6% (11/36) respectively, which had a prolonged duration(P<0.001). Even after 12 months, 40% (8/20) of patients still experienced thrombocytopenia.The incidence of anemia peaked on the 7th and 14th day after cell infusion, with a rate of 100% (36/36) (P<0.001). 50% (10/20) of patients still had anemia even 12 months after cell infusion. Kaplan-Meier survival analysis showed that patients with thrombocytopenia < grade 3 had undefined OS, while patients with thrombocytopenia ≥grade 3 had shorter OS [17 (95%CI: 2-32) months, χ2=4.154, P=0.042], indicating a poorer prognosis. However, there was no statistically significant difference in the relationship between other cytopenia and survival (all P>0.05). Single-cell sequencing analysis of bone marrow cells revealed decreased proliferation, increased apoptosis, and cell cycle arrest of hematopoietic stem cells after CAR-T cell infusion. Conclusions: All patients experienced varying degrees of cytopenia after receiving BCMA CAR-T cell infusion, and patients with thrombocytopenia ≥grade 3 had shorter OS and poorer prognosis.

Analysis of efficacy and safety of daratumumab-containing regimen in relapsed and refractory multiple myeloma patients

Objective: To investigate the efficacy and safety in relapsed and refractory multiple myeloma (RRMM) patients with combination regimen of daratumumab. Methods: The clinical data of 42 RRMM patients admitted to Qingdao Municipal Hospital from December 2020 to November 2023 were retrospectively analyzed, which included 26 males and 16 females, with a median age of 59 (47, 82) years old. According to the number of courses of treatment with Daratumumab, patients were divided into three groups: long course group (≥9 courses, n=21), medium course group (7-8 courses, n=12), and short course group (≤6 courses, n=9). The deadline for follow-up was November 10, 2023, and the follow-up period was 15.6 (6.0, 34.0) months. After completing at least 2 courses of treatment, patients were evaluated for efficacy, including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD), and progressive disease (PD). Basic clinical characteristics of patients, overall response rate of treatment, and adverse reactions were statistically analyzed. Kaplan-Meier method was used to compare the differences of progression-free survival (PFS) in patients with different courses of treatment. Results: Among the 42 patients, 15 (35.7%) had extramedullary disease or plasmacytic leukemia, 7 (16.6%) had amyloidosis, and 18 (42.9%) had renal insufficiency. In Mayo stage, 25 patients (59.5%) were at high risk of myeloma cytogenetic stratification, 8 patients (19%) were standard risk, 9 patients (21.4%) had no cytogenetic data. There were 16 patients with second-line treatment (38.0%), 13 patients with third-line treatment (31%), and 13 patients with more than fourth-line treatment (31%). All patients received at least 2 courses of treatment, achieving the best degree of disease response in 4 cases of sCR (9.5%), 3 cases of CR (7.1%), 10 cases of VGPR (23.8%), 11 cases of PR (26.2%), and 6 cases of MR (14.2%). The overall response rate (ORR) was 80.9% (34/42). The overall response rate was 100% (21/21) in the long course group, 91.6% (11/12) in the medium course group and 22.2% (2/9) in the short course group. Kaplan-Meier survival analysis showed that the duration of PFS was 5.0 (95%CI: 3.1-6.9) months in the short course group,>8.0 months in the medium course group, and>38.0 months in the long course group, the difference was statistically significant (P<0.05). Grade≥3 adverse reactions were mainly neutropenia (3 cases) and thrombocytopenia (1 case). None of the patients discontinued treatment due to adverse reactions. Conclusion: Treatment of RRMM with a regimen containing Daratumumab requires a longer course of treatment to achieve maximum efficacy and the adverse reactions can be controlled.

Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study.

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression- free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non-hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.

Idecabtagene Vicleucel (ide-cel) Versus Standard Regimens (SRs) in Triple-Class–Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): KarMMa-3 Subanalysis of Black Patients (pts)

Idecabtagene Vicleucel (ide-cel) Versus Standard Regimens (SRs) in Triple-Class–Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): KarMMa-3 Subanalysis of Black Patients (pts)

Real-world analysis of teclistamab in 123 RRMM patients from Germany

Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.

Comparison of Lenalidomide Based Triplets (IRD, KRD and DRD) in Relapsed and Refractory Multiple Myeloma in Routine Practice

Background: Treatment of relapsed and refractory multiple myeloma (RRMM) has become a chalenge with the introduction of combined lenalidomide-based triplets. The addition of proteasome inhibitors (PI) or monoclonal antibodies (MoAb) significantly improved the therapeutic outcomes of previous RD regimen (lenalidomide, dexamethasone). The clinical trials with RD triplets confirmed the outstanding synergistic effects of lenalidomide with PIs or MoAbs. However, the outcomes between individual regimens are not easily comparable as the trials used different cohorts of patients. Moreover, the clinical trials often overestimate the outcomes due to selection bias. Aims: Our aim was to compare the outcomes of lenalidomide-based triplets in an unselected “real-world population”. Patients and methods: We performed a large registry based analysis of RRMM patients treated with daratumumab, lenalidomide and dexamethasone (DRD), carfilzomib, lenalidomide and dexamethasone (KRD), and ixazomib, lenalidomide and dexamethasone (IRD) from the Czech Registry of Monoclonal Gammopathies (RMG) treated within 1st-3rd relapse. We excluded patients treated in clinical trials as well as patients with follow-up shorter than 6 months. For the IRD combination we performed 2 separate analyses: from 2016-2018 (early IRD, e-IRD) and 2019 onwards (late IRD, l-IRD), as the first cohort was treated within a Named Patient Program and had no competitive RD triplet or clinical trial, whereas patients treated after 2019 were those who were generally not eligible for competing KRD or DRD regimens. Altogether we assessed 224 patients with DRD regimen, 143 with KRD, 104 with e-IRD and 67 with l-IRD regimen. Data were described by absolute and relative frequencies of categorical variables and median (min-max and 5 th-95 th percentile) for quantitative variables. Survival analysis for different endpoints - overall survival (OS), progression free survival (PFS), time to next treatment (TNT), and duration of therapy (DOT) - was conducted using the Kaplan-Meier method complemented by the 95% Greenwood confidence interval for estimates of probability survival. Statistical significance of differences in survival among subgroups was assessed using the log-rank test. All statistical tests were performed at a significance level of α = 0.05 (all tests two-sided). Results: There were slight but significant differences within the demographic data: Patients treated with DRD and KRD were younger than patients on both e-IRD and l-IRD (median 65.5 vs 64.4 vs 67.2 vs 69.9 years) and had better overal performance status (PS 0 or 1 in 87.9 vs 92.2 vs 83.5 vs 76.1%). They were also less pretreated (1 previous line in 73.2 vs 70.6 vs 62.5 vs 38.8%). Also, patients on DRD and KRD had slightly lower ISS stage versus e-IRD and l-IRD patients (ISS 1 in 48.4 vs 55.5 vs 42.2 vs 37.5%). Patients on KRD had slightly higher presence of extramedullary and/or paraskeletal disease (45.6% versus 32.5% and 35.0% vs 31.6% in DRD and e-IRD and l-IRD, respectively). The presence of high-risk cytogenetics was higher in KRD and l-IRD (42.7 vs 53.1%) than in the e-IRD and DRD group (32.3% and 24.6%). The overal response rates (ORR) in DRD, KRD, e-IRD and l-IRD were following: 91.4% vs 89.6% vs 79.6% vs 70.8%. The rates of very good partial response or better (VGPR+) were 67.3% vs 62.3% vs 40.8% vs 25%. Median PFS in DRD vs KRD vs e-IRD vs l-IRD was 23.64 vs 16.52 vs 19.97 vs 11.57 months. Due to short follow-up, the median OS was not assessable with an estimate around 40 months for all the cohorts. The toxicity was similar to the data reported from clinical trials with no new safety alerts. Conclusions: We conclude that lenalidomide based triplets (DRD, KRD and IRD) have significant efficacy in RRMM even in the routine clinical practice but as expected, they do not achieve the outcomes reported in clinical trials. DRD regimen seems to be the most efficient regimen even in “real-world” setting but the results are biased by the cohort heterogeneity. The outcome of a regimen in “real-world” depends significantly on other variables including competing regimens or clinical trials, and may have large individual differences as seen in the case of e-IRD (assessed at the time with no competing lenalidomide-based triplets) versus l-IRD (influenced by the choice between several effective modalities). Supported by MH CZ - DRO (FNOL, 00098892).

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Elotuzumab, Isatuximab, and Selinexor-Based Regimens in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

Functional Imaging As a Key Diagnostic Tool in the Follow-up of RRMM Patients after CAR-T-Cell Therapy

Introduction: Anti BCMA CAR T-cell therapy (CART) is establishing itself as a new standard of care for relapsed and refractory multiple myeloma (RRMM). However, the optimal follow-up strategy post CART has yet to be determined. Prior studies of our own and others have emphasized the role of functional imaging in monitoring RRMM patients post traditional chemotherapy, revealing residual disease in up to 50 % of otherwise minimal residual disease (MRD) negative patients (Rasche et al. Leukemia 2019). Whether a similar patchy disease pattern is relevant post CART remains unknown. To address this, we implemented a standardized follow-up program post CART, which includes 18F-FDG PET-CT, diffusion-weighted MRI, and bone marrow aspiration with MRD measurements at our center. Methods: We conducted monthly ambulatory visits and serological testing to monitor patients post CART infusion. Additionally, an extended follow-up visit at three months post CART infusion was performed, encompassing whole body PET-CT, whole body diffusion-weighted MRI, and bone marrow aspiration with MRD testing. Response assessments were based on IMWG criteria. MRI classified focal lesions as vital if they exhibited 1) significant diffusion-restriction, 2) a fat fraction less than 20 %, and 3) homogenous hypointensity on T2-weighted images. MRD measurements were performed with flow cytometry with a sensitivity of at least 10 -5 following the Euroflow recommendations. Results: From December 2021 to July 2023 we treated 37 heavily pretreated patients with idecabtagene vicleucel at our center. These patients had a median of 5 prior lines of therapy. High-risk cytogenetics, extra-medullary disease (EMD), and non-secretory disease were seen in 17, 14 and 6 patients, respectively. At data cut off, the ORR, VGPR and CR rates were 78 %, 27 % and 27 %, respectively. We observed primary refractory disease in 14 % of the patients. Among the 22 patients who underwent extended follow-up examinations at three months, the majority achieved MRD negativity, with only 7/22 (32 %) remaining MRD positive after CART. However, functional imaging revealed a higher number of patients with residual disease, with positive results on PET-CT and DW-MRI in 9/22 (41 %) and 10/22 (45 %) of patients, respectively. Notably, 6 of 22 (27 %) patients displayed active lesions on imaging despite MRD negativity at the iliac crest at this time point. Next, we focused on patients who experienced relapse from CART and sought to determine the necessary technology to detect relapse in this setting. Thirteen patients experienced relapse during the study period, and in 8 (61%) of them, functional imaging was the sole method to detect progressive disease. Only 1 patient transitioned from MRD negative to positive during the follow-up period, while the remaining 4 patients showed a significant M protein increase as defined by the IMWG criteria. Conclusion: In our heavily pretreated RRMM population, functional imaging emerged as a crucial diagnostic tool, detecting relapse alone in more than half of the patients. Our data supports inclusion of cross-sectional imaging in a comprehensive follow-plan after CART.

Healthcare Resource Utilization and Economic Burden of Cytokine Release Syndrome and Neurotoxicity in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) Receiving Idecabtagene Vicleucel in Earlier-Line Settings in the KarMMa-3 Clinical Trial

Introduction: Adverse events (AE), such as cytokine release syndrome (CRS) and neurological toxicity (NT), have been associated with chimeric antigen receptor (CAR) T cell therapies. Idecabtagene vicleucel (ide-cel, bb2121), a B-cell maturation antigen-directed CAR T cell therapy, demonstrated deep and durable responses in triple-class exposed (TCE) patients (pts) with RRMM in the pivotal, single-arm, open-label phase 2 KarMMa (3 prior lines of therapy [LOTs]; NCT03361748) (Munshi NC, et al. NEJM 2021;384:705-716) and superior progression-free survival with ide-cel vs standard regimens in the phase 3 KarMMa-3 trial (2-4 prior LOTS; NCT03651128) (Rodríguez-Otero P, et al. NEJM 2023;388:1002-1014). Healthcare resource utilization (HCRU) and costs associated with CRS/NT management were estimated previously for pts receiving ide-cel in the KarMMa trial (McGarvey N, et al. Value Health 2023;26:S89) and suggested low rates of severe (grade ≥ 3) CRS/NT following ide-cel infusion and higher HCRU and costs with increasing AE severity. To further assess resource and economic burden associated with care of treatment-emergent AEs, this analysis evaluated HCRU and estimated cost of CRS/NT management among pts treated with ide-cel in earlier-line settings in the KarMMa-3 study. Methods: In this retrospective study, case report forms from the KarMMa-3 clinical trial database among pts experiencing a CRS and/or NT event that initiated within 90 days post ide-cel infusion were assessed. Pt-level HCRU data, including hospitalizations and length of hospital stay (LOS) (standard inpatient [IP], intensive care unit [ICU] days), diagnostics (eg, lab work, imaging), procedures (eg, dialysis, intubation), and medications (eg, oncology supportive care, prophylactics, other AE management) were identified from CRS/NT onset through resolution. AE management costs were estimated using a micro-costing methodology in which unit costs sourced from public databases or literature (eg, United States Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, IBM ® Micromedex ® RED BOOK ®) were adjusted to 2022 US dollars (USD) using the Consumer Price Index and applied to each HCRU identified. Results: Of 225 pts treated with ide-cel in the KarMMa-3 trial, 203 (90.2%) experienced any grade CRS and/or NT event. Pts experiencing a CRS/NT event had a mean (standard deviation [SD]) age of 61.9 (8.9) years and most were male (123/203 [60.6%]), White (138/203 [68.0%]), and non-Hispanic or Latino (138/203 [68.0%]). The majority (187/203 [92.1%]) of pts experienced less severe CRS/NT events (grade ≤ 2), which resolved quicker and relatively few pts (16/203 [7.9%]) had a more severe (grade ≥ 3) event, which took longer to resolve. Among pts who received ide-cel, the estimated median cost of AE management ranged from USD 17,124 (CRS only grade 1) to USD 181,552 (nonconcurrent CRS or NT grade ≥ 3) (Figure 1). Additional median costs for a pt with a grade ≥ 3 CRS/NT event was USD 31,045 higher than a grade ≤ 2 CRS/NT event. Across AE categories, the main contributors to CRS/NT management were facility costs, namely standard IP hospitalizations and ICU stays. Almost all pts (202/203 [99.5%]) had a standard IP hospitalization; 3.9% (8/203) had an ICU stay (Table 1). The trial protocol required a stay of ≥ 15 days post infusion unless admitted to the ICU; some hospitalization days recorded during the AE overlapped with the protocol-required stay. ICU admissions were more common among pts with CRS/NT grade ≥ 3 (7/16 [43.8%]) than those with grade ≤ 2 (1/187 [0.5%]). Median (range) total LOS was 10 days longer among pts with grade ≥ 3 (14.5 [2-84] days) than those with grade ≤ 2 (4 [1-34] days) CRS/NT. Pts with grade ≥ 3 CRS/NT had higher rates of HCRU than those with grade ≤ 2 for several interventions, such as medications (eg, tocilizumab + corticosteroids: 13/16 [81.3%] vs 63/187 [33.7%]), diagnostics (eg, imaging: 14/16 [87.5%] vs 48/187 [25.7%]), and procedures (eg, dialysis:3/16 [18.8%] vs 0/187 [0%]). Conclusions: Most pts with RRMM treated with ide-cel in the KarMMa-3 trial experienced a CRS and/or NT event, however, few were of high severity (grade ≥ 3). HCRU and costs for CRS/NT increased with AE severity and management. CAR T cell therapies associated with lower-severity AEs and planned interventions to prevent higher-grade AEs may provide an opportunity to better manage HCRU and costs.

Active STAT3 Prevents Selinexor-Induced Caspase-Independent Apoptosis in Multiple Myeloma

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that typically develops late in life with a median age at diagnosis of 69 years and results in approximately 12,000 deaths per year. Currently, the standard treatment strategy for MM is a combination of 3 drugs with different mechanisms: dexamethasone, a proteasome inhibitor, and an immunomodulatory agent. Many MM patients acquire a “double-hit” of their TP53 on Chromosome 17p region after multple rounds of treatment and become resistant to these conventional therapeutics. Thus, novel effective treatments for high-risk and relapsed and refractory (RR)-MM are urgently needed to overcome drug-resistance, especially in TP53 null patients. In many cancers, nuclear exporter protein XPO1 overexpression is induced by c-Myc and/or loss of p53. Previous studies have demonstrated that many RR-MM patients show increased expression/activity of XPO1, which is associated with aberrant cytosolic localization of its protein and RNA cargoes. Selective XPO1 inhibitor Selinexor (Sel) has been approved by FDA to treat relapsed and refractory multiple myeloma (RR-MM) in combination with a bortezomib + DEX regimen. Addition of Sel to this regiment significantly improves the overall response rate (~75% vs. ~60%) and progress free survival (13.9 months vs 9.5 months), regardless of risk factors including TP53 status. However, only ~50% of RR-MM patients benefit from Sel treatment. In addition, Sel has significant dose dependent side effects. It is important to determine the mechanism of Sel-resistance in order to identify biomarker(s) to predict Sel-resistance and develop novel effective combination therapies. . In this study, we compared the response of 10 human MM cell lines to Sel treatment and identified Sel sensitive and resistant cell lines. Based on EC50, we divided the cell lines into Sel-sensitive group with EC 50 values between 80.4 nM to 211.8 nM, and Sel-resistant groups with EC 50 values &amp;gt;741.4 nM. We found that Sel sensitivity was notably independent of TP53 mutation status, as well as other genetic mutations and chromosomal translocations. In resistant cells, high dose of Sel induces an off-target Caspase-mediated apoptosis because it could not be influenced by XPO1-knockdown but could be prevented using a pan-caspase inhibitor Z-VAD. In sensitive cell lines, low dose of Sel induces a Caspase-independent type of cell death because it could not prevented by pre-treated with Z-VAD. To investigate which programmed cell death pathways Sel works through, sensitive cells were treated using with Sel + inhibitors for necroptosis, ferroptosis, pyroptosis, and parthanatos. We found only parthanatos inhibitor could significantly prevent Sel-induced cell death. The parthanatos death pathway functions via DNA-damage/poly (ADP-ribose) polymerase-1 (PARP-1) activation. While proper PARP-1 levels are required for DNA damage repair, over-activation results in the release of apoptosis-inducing factor (AIF) from mitochondria to cytoplasm which then trans-localize to the nucleus where it functions with macrophage migration inhibitory factor (MIF) to induce DNA fragmentation and cell death. We show via Western blotting and immunofluorescence imaging that upon Sel treatment, AIF shifts from the cytosol into the nucleus. Sel treatment was further assessed in combination with with Dex, where it showed a low synergistic effect with Dex in the sensitive cells but not in resistant cells, specifically when used sequentially. When assessing mechanisms of Sel resistance, phosphorylated STAT3 was uniquely observed in the resistant cell lines. To determine if STAT3 mediates resistance, resistant cell lines were pre-treated with a STAT3-PROTAC (SD36). Our study suggested that p-STAT3 predicts Sel-resistance, and Sel + STAT3 inhibitor combination is a novel effective regimen for MM, especially for these Sel-resistant cases.

Real-World Analysis of Teclistamab in 115 RRMM Patients from Germany

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patients (pts) with Triple-Class-Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Analysis of Cytopenias and Infections in Pts from KarMMa-3

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P &amp;lt; 0.001) and overall response rate (71% vs 42%, P &amp;lt; 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at &amp;lt; 3 mo, 52 [24.1%] pts at 3−&amp;lt; 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at &amp;lt; 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at &amp;lt; 3 mo, 18 [8.3%] pts at 3−&amp;lt; 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at &amp;lt; 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at &amp;lt; 3 mo, 0 pts at 3−&amp;lt; 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at &amp;lt; 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−&amp;lt; 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.