Penta-refractory Multiple Myeloma Research Articles

BCMA x CD3 T-cell engager in a patient with penta-refractory multiple myeloma and HIV: a clinical and immunological report.

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HTA236 A Systematic Review of Clinical Efficacy and Safety Data in Penta-Refractory Multiple Myeloma: Findings Indicate the Challenges for HTA Submission

HTA236 A Systematic Review of Clinical Efficacy and Safety Data in Penta-Refractory Multiple Myeloma: Findings Indicate the Challenges for HTA Submission

Functional Characterization of GPRC5D alteration and Its Impact on Talquetamab Resistance in Relapsed/ Refractory Multiple Myeloma

Background T-cell engaging (TCE) antibodies show unprecedented efficacy in heavily pretreated penta-refractory multiple myeloma (MM). Responses however are often not durable as resistance mechanisms can arise despite the initial absence of resistance-conferring mutations. Biallelic loss of GPRC5D on chr.12p is a rare, yet well-established mechanism of acquired resistance to the first-in-class anti-GPRC5D directed TCE talquetamab (Lee et al., 2022). At the same time, monoallelic GPRC5D frameshift and missense mutations are much more common and occur in up to 15% of MM patients (Truger et al., 2021). In this study, we investigated the functional relevance of monoallelic GPRC5D alterations and their impact on talquetamab resistance. Methods GPRC5D alterations were modeled in vitro by using CRISPR-Cas9 editing in the OPM-2 MM cell line. The bioluminescence-based cytotoxic assay was performed using PBMCs as effector cells to measure the resistance to talquetamab. Quantitative PCR (qPCR), immunohistochemistry, bulk whole genome sequencing (WGS), and whole genome bisulfite sequencing (WGBS) were performed for molecular, genomic, and epigenetic characterization in a patient with acquired talquetamab resistance. Results Using CRISPR-Cas9, we generated cell line models with mono- vs. biallelic deletions in the GPRC5D gene. Clones with biallelic alterations (OPM-2 Del/Del) displayed a 96.4%, reduced expression of GPRC5D ( p < .0001), leading to in vitro resistance to talquetamab. GPRC5D expression levels in monoallelic models (OPM-2 Wt/Del) decreased by 57.4% ( p = .0004) compared to the wild type. Sensitivity to talquetamab in these clones was equally impaired, however, less pronounced than in the biallelic knock-outs. To assess the impact of monoallelic GPRC5D deletions in the clinic, we next investigated the case of a heavily pretreated 58-year-old patient with lambda light-chain MM treated at our institution with talquetamab in his 7th line of therapy. qPCR was used to measure GPRC5D expression in CD138+ MM cells from the bone marrow of this patient before and at the time of relapse to talquetamab after 15 months of treatment (best response: CR). At the time of relapse, we observed a 94.0% ( p < .0001) decrease in GPRC5D expression upon qPCR assessment as compared to the pre-treatment time point which was confirmed by immunohistochemistry. WGS revealed a novel monoallelic loss of chr.12p encompassing GPRC5D in talquetamab-resistant CD138+ MM cells. Since monoallelic alterations seem unlikely as the sole drivers of resistance, we hypothesized that epigenetic modifications may have contributed to talquetamab resistance in this patient. To this end, WGBS was performed and uncovered a significant shift towards hypermethylation of two regulatory regions of GPRC5D, most likely resulting in the silencing of the second GPRC5D allele. Time-course experiments are currently ongoing to explore the methylation landscape of our CRISPR-Cas9-generated clones with monoallelic GPRC5D deletions. Data for these validation experiments will be presented at the meeting. Conclusions Our study provides the first evidence of the functional impact of monoallelic GPRC5D alterations resulting in relative resistance to talquetamab in vitro. We further report on epigenetic regulation as a potential second-hit mechanism conferring clinical resistance to anti-GPRC5D-directed TCE therapy. This data suggests that patients with monoallelic GPRC5D deletions may be at particular risk for developing resistance to talquetamab.

Characterizing outcomes in severe cytopenias by 3 months in BCMA and CD19 CAR-T cell therapies: A single institution experience.

e19504 Background: Chimeric antigen receptor (CAR) T-cell therapy is approved for treatment in relapsed/refractory diffuse large B cell lymphoma, penta-refractory multiple myeloma (MM), and acute lymphoblastic leukemia. We evaluated relapse and survival rates by 3 months (mo) in patients (pts) who received BCMA and CD19 CAR-T cell therapies. Methods: We performed a retrospective analysis of pts with RRMM and R/R Non-Hodgkin lymphoma (NHL) who received CAR-T cell therapy from 2012-2023 at the Winship Cancer Institute at Emory University. Pts who relapsed prior to 3mo were excluded. SAS was used for statistical analysis with alpha of 0.05. Grades 3/4 cytopenias were compared at day 0, 1mo, and 3mo per CTCAE criteria with each pt counted once if > 1 cytopenia. Hematological recovery was defined as sustained Hgb > 8, Plt > 50,000, and ANC > 1000 without transfusion support. Group differences were evaluated using Chi-Square or Fisher’s exact tests for categorical and ANOVA or Kruskal-Wallis for numerical variables. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method from CAR-T receipt to progression or death, or last known contact for those censored. Univariable and multivariable cox regression were performed. Results: Of 126 pts, 60 had MM and 66 had NHL. Median age at CAR-T receipt was 64yrs (range: 25-85). Fifteen pts had ECOG ≥2. Most pts were male (52.4%) and of white race (61.9%). For R/R NHL, 39.4% received tisa-cel, 33.3% axi-cel, 13.6% brexu-cel, 3.0% liso-cel and 10.6% clinical trial. For RRMM, 91.7% received ide-cel and cilta-cel (8.3%). Bridging therapy, CRS, and ICANS were not associated with severe cytopenias. Overall, 89.7% had grade 3/4 cytopenias at day 0, 54.0% at 1mo, and 34.1% at 3mo. Cytopenia rates, hematological recovery, transfusions, and infectious complications were comparable between groups. Overall, 36.5% required GCSF, 34.9% red cells, 23.0% platelets, and 2.4% TPO. In MM pts, decreased OS was seen with persistence of severe cytopenias (p = 0.009) and decreased PFS with GCSF use ≥2wks (p = 0.007). Time to ANC recovery (days) was more prolonged in MM compared to NHL pts (p = 0.039). Overall median time to recovery (days) was 8, 19, 22.5 for Hgb, ANC, and Plt respectively. On MVA for overall cohort, grade 3/4 cytopenias at 3mo were associated with decreased OS [HR 2.28, 95%CI: (1.22-4.29), p = 0.010) and PFS [HR 1.8, 95%CI: (1.09-2.98), p = 0.022]. On MVA for NHL, decreased OS [HR 2.38, 95%CI: (1.03-5.48), p = 0.043] and PFS [HR 2.11, 95%CI: (1.01-4.41), p = 0.047] were associated with 3mo grade 3/4 cytopenias but not seen in MM pts. Conclusions: We report significant rates of severe cytopenias at 3 months and a potential association with higher relapse and decreased survival rates in pts receiving BCMA and CD19 CAR-T cell therapies. These results are hypothesis generating, and more prospective studies are needed for further confirmation.

Effectiveness of anti-B-cell maturation antigen (BCMA)-targeting therapy after selinexor treatment.

e20034 Background: Multiple myeloma (MM) remains incurable, with the disease typically becoming refractory to three main classes of standard therapies: immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (αCD38 mAbs). Treatments with novel mechanisms of action, including the XPO1 inhibitor selinexor and T-cell engaging anti-B-cell maturation antigen (αBCMA)-agents (antibody drug conjugates [ADC], bi-specific antibodies [BiS]), are increasingly used for treatment of relapsed and/or refractory MM (RRMM) after standard therapies have failed. Emerging data suggests a deleterious impact on T cell function with certain MM treatments, including alkylators and PIs, leading to inferior clinical outcomes. The influence of selinexor-based treatment on T cell function, which may alter the efficacy of αBCMA agents following selinexor treatment, is unknown. Methods: We analyzed the effectiveness of non-cellular αBCMA (NCA) therapies in pts with MM treated in 4 clinical studies (STORM [NCT02336815]; STOMP [NCT02343042]; BOSTON [NCT03110562], XPORT-MM-028 [NCT04414475]) with selinexor + dexamethasone (Xd), with or without PIs, IMiDs, or αCD38 mAbs, followed by therapy with NCA. After end of treatment with selinexor, survival follow-up data was collected every 3 months for 1 (STORM, STOMP, XPORT-MM-028) to 5 years (BOSTON). Results: Across the 4 clinical studies, 724 pts received selinexor, 404 of which had therapy post-selinexor documented. Thirty-seven pts (median age: 68, range: 40-87) received NCA therapy at any time following a selinexor regimen (Xd, n = 12; Xd + bortezomib, n = 9; Xd + pomalidomide, n = 6; Xd + daratumumab, n = 3; Xd + carfilzomib, n = 5; Xd + ixazomib, n = 2). NCAs included the ADC belantamab mafodotin (n = 28), the BiS teclistamab (n = 2), SEA-BCMA (n = 2), AMG 701 (n = 1), elranatamab (n = 1), MEDI2228 (n = 1), and investigational (n = 3; 2 had αBCMA bispecific antibodies and 1 had αBCMA BITE) (1 pt received 2 NCAs, belantamab and teclistamab). For the selinexor-based regimens, the median number of previous lines of therapy was 5 (range: 2-11) and 21 (56.8%) pts had triple-class refractory MM including 8 (21.6%) with penta-refractory MM. Median time from last dose of selinexor to NCA was 8 weeks (range: 2-117). Median time to treatment discontinuation with NCA was 4.4 months (95% CI: 2.1, NE). The median overall survival from initiation of NCA was 12.0 months (95% CI: 9.4, NE) with a median follow-up of 7.8 months. Conclusions: In this cohort of heavily-pretreated pts with MM who received a selinexor regimen prior to NCA, overall survival was in the range of 1 year, akin to historical results seen with ADCs. The 8-week median time between administration of selinexor and NCAs suggests that selinexor, with various partner agents, did not negatively impact overall survival with subsequent NCA therapy.

Outcomes of Penta-Refractory Multiple Myeloma Patients Treated with or without BCMA-Directed Therapy.

Despite advances in treatment, outcomes remain poor for patients with penta-relapsed refractory multiple myeloma (RRMM). In this retrospective analysis, we evaluated the survival outcomes of penta-RRMM patients treated with (BCMA)- directed therapy (BDT). We identified 78 patients with penta-RRMM. Median age was 65 years, 29 (37%) had R-ISS stage III disease, 63 (81%) had high-risk cytogenetics, and 45 (58%) had extra-medullary disease. Median LOT prior to penta-refractory state was 5 (3-12). Amongst penta-RRMM, 43 (55%) were treated with BDT, 35 (45%) were not treated with BDT. Type of BDT received included belantamab mafadotin 15 (35%), Chimeric Antigen Receptor T-cell therapy 9 (21%), BCMA monoclonal antibody 6 (14%), and Bispecific T-cell engager 2 (5%). Eleven (25%) patients received more than one BDT. No significant differences were identified between baseline characteristics for the two groups. Patients treated with a BDT had better median overall survival, 17 vs. 6 months, HR 0.3 p-value < 0.001. Poor performance status, white race, and high-risk cytogenetics were associated with worse outcomes, whereas using a BDT was associated with better outcomes. Patients with penta-refractory MM have poor outcomes. Our retrospective analysis showed a significant survival benefit using BDT when compared to non-BDT for patients with penta-RRMM.

Nivolumab-Based Salvage Therapy to Restore T Cell Fitness in Penta-Refractory Multiple Myeloma with Relapse to Anti-BCMA CAR T Cell Therapy

Background: Idecabtagene Vicleucel (ide-cel) is the first FDA-approved BCMA-directed CAR T cell therapy for the treatment of relapsed/refractory multiple myeloma (RRMM). Despite remarkable activity of 85% objective response rate and a progression-free survival (PFS) of 11.8 months reported in the CRB-401 trial (NCT02658929), most responses to ide-cel are not durable, and nearly all patients (pts) eventually relapse, even those achieving MRD-negative complete remission (CR). Factors associated with clinical relapse to ide-cel include BCMA loss, lack of CAR T persistence, T-cell exhaustion and PD-1/ PD-L1 impaired T-cell fitness. Here, we report clinical data and correlative findings for 4 pts who were salvaged with a nivolumab (anti-PD1)- based triplet therapy at the time of clinical relapse to first or second ide-cel infusion. Methods: Four pts with penta-refractory RRMM were treated as part of the CRB-401 phase 1 study as previously reported (Raje et al.N Engl J Med.2019;380:1726-37). All pts received nivolumab along with lenalidomide-dexamethasone (Nivo-Rd) or pomalidomide-dexamethasone (Nivo-Pd) at the time of relapse to ide-cel. CD3+ T cells (n=1,047) were isolated from the peripheral blood of 2 of these pts and full-length single-cell RNA sequencing (scRNA-seq) was conducted before and upon treatment with Nivo-Rd/-Pd. Response rates were assessed as per IMWG criteria. Results: The median age of pts was 48.5 years (range 37-56). Two out of 4 pts had cytogenetic high-risk MM and all pts were penta-refractory at the time of CRB-401 study inclusion. The median PFS and OS after first ide-cel infusion were 10.4 (range 3.0-13.8) months and 21.5 (range 16.0-34.6) months, respectively. Three pts received a second ide-cel infusion, whereof only 1 pt achieved a partial response (PR) at a PFS of 5.2 months. Two pts each were treated with Nivo-Rd and Nivo-Pd respectively at the time of progression to ide-cel. Responses to anti-PD1- based therapy varied markedly with 1 PR, 1 stable disease (SD) and 2 progressive disease (PD) as per IMWG criteria. The median PFS to nivolumab-based salvage therapy was 3.6 (range 0.4-8.1) months. Interestingly, pts MM1 and MM2 both had a CR to first ide-cel infusion (PFS 13.8 and 11.9 months, respectively), but while both pts did not respond to second CAR T cell infusion, the benefit from anti-PD1 treatment differed markedly in both pts. MM1 reached a PR and PFS of 105 days. In contrast, MM2 experienced immediate PD and succumbed to his disease 3.0 months later. Profiling of CD3+ T cells from MM1 and MM2 by scRNA-seq revealed rapid cellular state changes in response to PD1 inhibition. PAGODA2 clustering and t-Stochastic Neighbor Embedding (t-SNE) visualization revealed 3 distinct clusters, segregating to an individual pre-anti-PD1 cluster for MM1 and MM2 each and a shared post-anti-PD1 cluster comprising CD3+ T cells from both pts. The pre-anti-PD1 cluster for MM1 contained CD3+ T-cells with a memory T cell- like phenotype (IL7Rhigh, CD62Lhigh) and decreased expression of markers correlating with T-cell fitness (GNLY, PRF1, NKG7, GZMH,LY6C, KLRG1). This phenotype could be rescued, and T-cell fitness could be restored by Nivo-Pd treatment, potentially contributing to the clinical response observed in MM1. Opposingly, the pre-anti-PD1 cluster for MM2 showed intact T-cell fitness with low expression of T-cell exhaustion markers. No clinical benefit to Nivo-Rd was noted in this pt. Conclusions: Checkpoint inhibition and IMiD therapy can induce clinical responses at the time of relapse to first or second CAR T infusion. Efficacy however seems to depend on impaired T-cell fitness as premise for PD1 inhibition to re-induce clinical responses in selected pts.

Real-World Analysis of Cytopenias after Chimeric Antigen Receptor T-Cell Therapy: A Comparison of BCMA and CD19 Based Outcomes

Introduction: Chimeric Antigen Receptor (CAR) T-cell therapy is now approved as a second-line treatment for relapsed/refractory diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and acute lymphoblastic leukemia. B-cell maturation antigen (BCMA) and CD19 CAR-T therapies are associated with substantial hematological toxicity, potentially causing complications in the post-CAR-T setting. It is unclear if cytopenia rates differ between CAR-T therapies. We evaluated differences in cytopenia, transfusion support, and associated outcomes in patients receiving CAR-T therapy for MM and non-Hodgkin's lymphoma (NHL) at our institution. Methods: We performed a retrospective analysis of patients diagnosed with MM and NHL from 2012-2022 who subsequently relapsed and received CAR-T-cell therapy at the Winship Cancer Institute at Emory University. Patients were excluded if they underwent apheresis but had not received infusion or had manufacturing failure. We compared rates of grade 3/4 cytopenias based on CIBMTR criteria and supportive care at day 0, 3mo, 6mo, and 1 year as well as date of hematological recovery. Day 0 was defined as onset of grade 3/4 cytopenia after CAR-T therapy. Hematological recovery was defined as sustained hemoglobin >8g/dL, platelets >50,000/µL, and ANC >1000/mm3 without need for support. Differences between groups were determined using Fisher's exact test and Kruskal-Wallis Test where appropriate. PFS and overall survival (OS) were estimated using the Kaplan-Meier method from CAR-T infusion to progression or death for those events and last contact for those censored. Statistical analysis was performed using SAS with significance at the 0.05 level. Results: Of 35 patients, 24 received BCMA and 11 received CD19 CAR-T therapy. Median age at CAR-T infusion for all patients was 58 years (36-78). Most patients were male (66.7%) and of white race (57.1%) [Table 1]. Overall, 4 patients (11.4%) had an initial ECOG ≥2. Twenty-one patients (87.5%) had penta-refractory MM disease with extramedullary involvement in 25%. All patients with NHL had stage 4 disease with bone marrow involvement in 33.3%. Eight patients had DLBCL (72.7%), 1 double hit lymphoma (18.2%), and 2 mantle cell lymphoma (9.1%). Six patients received tisa-cel, 2 axi-cel, 2 brexu-cel, and 1 liso-cel. The MM cohort underwent significantly more autologous transplantations as a prior line of therapy (p<0.001). Patients with NHL received CAR-T at a later median age (p=0.006). Median follow-up for the MM and NHL cohort was 2.38 years and 0.2 years respectively. There was no difference in time from last therapy to CAR-T infusion (p=0.171) nor days of hospitalization (p=0.681). Almost all patients (95.8%) achieved hematological recovery after infusion with similar recovery rates between groups (p=0.536). Median time to grade 3/4 anemia recovery was 6 days (1-90), neutropenia recovery at 15 days (1-336), and thrombocytopenia recovery at 28 days (14-277). Time to grade 3/4 anemia, neutropenia, and thrombocytopenia was 1 day (0-11), 2 days (0-11) and 2 days (0-15) respectively. Most patients required supportive care with growth factors (34.6%), packed red cells (57.7%), and platelets (23.1%) without significant group differences [Table 2]. One patient with MM received TPO. Prolonged grade 3/4 cytopenia rates were significant with 17.1% at 3mo, 22.9% at 6mo and 8.7% at 1 year. Both groups had similar rates of grade 3/4 cytopenia at day 0, 3mo, 6mo, and 1 year. The MM cohort had higher rates of infection (p<0.001). Rates of CRS (p=0.226) and neurotoxicity (p=0.063) were similar. Fourteen patients with MM (58.3%) and 3 patients with NHL (27.3%) progressed post-CAR-T. Median PFS overall was 1.7 years, 2 years (95%CI: 1, 3) in the MM group, and not reached (NR) (0.2, NA) in the NHL group. Median OS overall was NR, NR in MM (2.5, NA) and NR in NHL (0.3, NA). Grade 3/4 neutropenia and thrombocytopenia were not associated with survival at any time interval. Onset of grade 3/4 cytopenia were not associated with histopathological characteristics, inflammatory markers, or CRS/ICANS. Conclusions: This real-world study demonstrates comparable rates of upfront and prolonged cytopenia in patients receiving BCMA and CD19 CAR-T therapies. Over 20% of patients had prolonged, ongoing grade 3/4 cytopenias requiring supportive care at the 3-6mo mark. Further follow-up and larger prospective studies are needed to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma Receiving Salvage Cytotoxic Therapy with Supportive Stem Cell Boost

Background Autologous hematopoietic stem cell transplant (ASCT) remains a cornerstone of therapy for eligible patients with multiple myeloma (MM) and can be incorporated as part of the initial therapy (early ASCT) or at the time of first relapse (delayed ASCT) [1]. Current guidelines recommend that adequate hematopoietic stem cells (HSC should be collected for a potential second ASCT, with a minimum goal of 2 million CD34+ cells/kg per transplant [2]. The stored HSC may be used for either a planned tandem transplant or future salvage ASCT. Less commonly, the previously stored HSC may be used for stem cell "boosts” following either dose intensive, non-myeloablative chemotherapy or for patients with "burned out” bone marrows secondary to extensive prior therapies. [3]. To our knowledge, there is a paucity of data on the effectiveness and survival outcome of patients with multiple relapsed MM who receive a stem cell boost following dose intensive chemotherapy. This study analyzes the clinical outcomes of multiply relapsed MM patients receiving multi-agent chemotherapy followed by a stem cell boost. Outcomes evaluated were overall response rate, proportion of patients who received a subsequent line of therapy, and overall survival. Methods This is a retrospective chart review performed at 2 institutions (Hackensack University Medical Center and MedStar Georgetown University Hospital). Fifty-nine (59) patients with MM aged ≥18 years old who underwent first ASCT from 1999 to 2021 and who collected sufficient s to allow for either tandem or salvage transplant or potential future stem cell boost were included in this study. Response to therapy was defined as stable disease or better on evaluation 1 month following stem cell boost. Patients who received another line of therapy less than 1 month post boost but did not have evidence of disease progression at that time, were excluded from ORR analysis. Overall survival (OS) was defined as the time from stem cell boost to date of death or last follow up. Statistical analysis was performed using STATA v16.0 (Stata Corp, TX, USA). Survival analysis was carried out using the Kaplan-Meier method and the log-rank test was used to compare survival curves. Results The patient characteristics who received a stem cell boost are shown in Table 1 (n=59): male gender (61 %), median age at diagnosis was 60 (range 37-81), median number of lines of therapy 6.3 5 Range 1-16). The patient who received only 1 prior line of therapy had aggressive relapse less than 100 days post melphalan-conditioned ASCT which necessitated use of urgent dose intensive chemotherapy. The stem cell dose used for the boost ASCT ranged from 0.4 to 9.8 X 10^6 CD34+ cells/kg (median 2.3). 1.6. Of the 49 evaluable patients, 28 (57.1%) had response to therapy 1 month post stem cell boost. Overall, 37 (62.7%) patients successfully received a subsequent line of therapy post stem cell boost. The median overall survival for the entire cohort was 129 days (range 1 - 1462 days) (Figure 1). OS was significantly longer in responding patients compared to those who did not respond (182 days vs 82 days, p=0.0081). Conclusions Dose intensive, non-myeloablative chemotherapy can improve survival in heavily pretreated, usually penta-refractory MM that require disease for refractory relapse. The administration of a stem cell boost utilizing previously collected HSCs may assist with hematopoietic recovery following dose intensive chemotherapy and in this subset of patients who have poor marrow reserve from prior therapy. This study serves to demonstrate the clinical outcomes of patients treated with multiagent chemotherapy followed by a stem cell boost. With an ORR of 57.1%, this approach can be effective in the appropriate clinical setting and significantly improves OS in patients who do respond to therapy (Figure 2). The goal of such therapy is to achieve disease control, and often serves as a "bridge” for patients to receive subsequent myeloma-directed therapy that may not be readily available at the time of relapse, such as clinical trial or chimeric antigen receptor T-cell (CAR-T) therapy. This data allows for treating oncologists to appropriately implement and inform patients of the therapeutic uses and clinical outcomes of treating such patients with dose intensive multiagent chemotherapy followed by a stem cell boost.

T-cell redirected bispecific antibodies in relapsed and refractory multiple myeloma: A systematic review and meta-analysis.

e20014 Background: Multiple myeloma (MM) is a malignant plasma cell disorder which remains incurable, and in relapsed and refractory treatment, chimeric antigen receptor therapy shows promise. Bispecific antibodies (bsAbs) utilize the exact mechanism by engaging BCMA and other potential tumor-associated antigens on myeloma cells and T-cells. We have conducted a systematic review and meta-analysis to evaluate the efficacy and safety of bsAbs in heavily pretreated MM cohorts. Methods: We searched PubMed, Clinicaltrials.gov, Cochrane, Google Scholar, Embase, and major conferences (oral and poster presentation), with MeSH terms and keywords for “multiple myeloma” or “relapsed refractory multiple myeloma,” AND “bispecific antibody” or “BiTE”. We included all original studies reported in the English language published from inception until January 2022. After primary and secondary screening, eleven clinical trials were included. Pooled analysis was done with the help of random effects model (Freeman-Tukey Double Arcsine Transformation) in OpenMetaAnalyst software. Results: We identified nine phase I and two phase II trials (n=837), with a mean age of 64.5 years. Most cohorts being triple-, quad- or penta-refractory MM. Complete response (CR) or stringent CR (sCR) reported is 12% (95% CI 9-15.3%, I² 16.54%, n=66), very good partial response (VGPR) 14.8% (95% CI 8.3-22.7%, I² 80.57%, n=93) and partial response (PR) 11.8% (95% CI 0.2-3.41%, I² 93.21%, n=26). The overall response rate (ORR) reported is 59.5% (95% CI 44.7-73.5%, I² 90.71%, n=307). Among the most common adverse events anemia is seen in 44.2% (95% CI 38.1-50.4%, I² 17.86%, n=152), neutropenia in 33.8% (95% CI 18.4-51.2%, I² 93.27%, n=179), thrombocytopenia in 32% (95% CI 21.4-43.6%, I² 75.96%, n=113) and cytokine release syndrome in 57.1% (95% CI 45.5-68.4%, I² 85.63%, n=315). Conclusions: Bispecific antibodies have shown promising efficacy in relapsed and refractory MM cohorts with a very well safety profile. Upcoming phase II/III trials are much awaited, along with combination studies of bsAbs with other agents to gauge response.[Table: see text]

Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials

Background: Selinexor (SEL) is an orally bioavailable, highly-selective, and slowly-reversible small molecule that inhibits Exportin 1. Preclinical studies showed that SEL had synergistic antimyeloma activity with glucocorticoids, proteasome inhibitors (PIs) and immunomodulators. The combination of selinexor and dexamethasone (DEX) has been approved in the United States for patients with penta-refractory multiple myeloma in July 2019. This meta-analysis aimed to investigate the safety and efficacy of selinexor based treatment in Multiple myeloma. Methods: We systematically searched the Medline (PubMed), Embase, Web of Science, Cochrane Central Register of Controlled Trials Library databases and ClinicalTrials.gov. Outcome measures of efficacy included overall response rate (ORR), clinical benefit rate (CBR), stringent complete response rate (sCR), complete response rate (CR), very good partial response (VGPR), partial response rate (PR), minimal response (MR), rate of stable disease (SDR), rate of progressive disease (PDR) and median progression-free survival (mPFS). Safety was evaluated by the incidences of all grade adverse events and Grade≥3 adverse events. The subgroup analysis was conducted to analyze the difference in different combination treatment regimens (SEL + DEX + PIs vs SEL + DEX). Results: We included six studies with 477 patients. The pooled ORR, CBR, sCR, CR, VGPR, PR, MR, SDR, and PDR were 43% (18–67%), 55% (32–78%), 5% (−2–13%), 7% (4–11%), 14% (5–24%), 23% (15–31%), 11% (8–14%), 26% (14–38%) and 14% (4–23%), respectively. SEL + DEX + PIs treatment had higher ORR (54 vs 24%, p = 0.01), CBR (66 vs 37%, p = 0.01), sCR (10 vs 2%, p = 0.0008), and VGPR (23 vs 5%, p < 0.00001) compared to SEL + DEX treatment, and lower PDR (4 vs 23%, p < 0.00001) and SDR (17 vs 37%, p = 0.0006). The pooled incidences of any grade and grade≥3 were 45 and 30% in hematological AEs, and in non-hematological AEs were 40 and 30%, respectively. The most common all grade (68%) and grade≥3 (54%) hematological AE were both thrombocytopenia. Fatigue was the most common all grade (62%) and grade≥3 (16%) non-hematological AE. Compared to SEL + DEX treatment, SEL + DEX + PIs treatment had lower incidences of hyponatremia (39 vs 12%, p < 0.00001), nausea (72 vs 52%, p < 0.00001), vomiting (41 vs 23%, p < 0.0001), and weight loss (42 vs 17%, p = 0.03) in all grade AEs. Meanwhile, SEL + DEX + PIs treatment had lower incidences of anemia (36 vs 16%, p = 0.02), fatigue (20 vs 13%, p = 0.04), hyponatremia (22 vs 5%, p < 0.0001) than SEL + DEX treatment in grade≥3 AEs. Conclusion: Our meta-analysis revealed that selinexor-based regimens could offer reasonable efficacy and tolerable adverse events in patients with multiple myeloma. SEL + DEX + PIs treatments had higher efficacy and lower toxicities than SEL + DEX.

Single Cell RNA Sequencing in Patients Enrolled in a Selinexor Clinical Trial Reveals Overexpression of Alternative Nuclear Export Pathways Associated with Resistance to Selinexor in Refractory Multiple Myeloma

Selinexor is a novel, first-in-class oral selective inhibitor of nuclear export which blocks Exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. Selinexor has been approved for the treatment of patients with penta-refractory multiple myeloma (MM) who have received at least 4 prior therapies. We previously reported the discovery of a novel transcriptional signature and therapeutic targets for therapy resistant MM by comprehensive single cell RNA-seq analysis (scRNA-seq) of plasma cells (PCs) in patients with primary refractory MM (PRMM) enrolled in the KYDAR clinical trial (NCT04065789, carfilzomib Lenalidomide dexamethasone daratumumab for PRMM [Cohen YC, Nature Med, 2021]).Here we report scRNA-seq analysis of PCs from patients with advanced refractory MM (aRRMM) (n=21) enrolled in an ancillary sub-study of a prospective clinical trial (XPORT-MM-028, NCT04414475), treated with selinexor combined with dexamethasone (Xd, in penta-refractory MM n=7), or with bortezomib, dexamethasone (XVd, in triple-class refractory [TCR] MM n=9), 5 patients participated in the ancillary study only. Median age was 75 years (range: 60-87), 50% were male, median time since active MM diagnosis was 4.8 years (range: 1.3-11.1). All treated patients (N=16) had TCR MM and 7/16 treated patients had penta-refractory MM. Single cell clustering analysis showed a unique molecular signature for each myeloma patient's PCs (Fig 1A), while patient-level analyses revealed a distinct transcriptional signature in aRRMM compared with PRMM (Fig 1B). aRRMM was characterized by upregulation of several pathways, including heparin growth factor (HDGF), Rho-GTPases activator (ARHGEF2), H3.3 histone variant and Prothymosin Alpha (PTMA) (Fig 1C-D). PPIA expression, which we previously identified as a biomarker and synergistic target for carfilzomib resistance, was low among healthy donors' PCs, progressively increased along with malignant evolution of plasma cell dyscrasia, from newly diagnosed MM, through PRMM, and was the highest in aRRMM (Fig 1C). We observed strong down-regulation of CD38 likely a consequence of daratumumab treatment and relapse in earlier lines.Finally, we discovered differential expression of several genes between patients with MM refractory to versus non-refractory (achieving at least partial response by IMWG criteria or a progression free survival greater than 4 months) to a selinexor-regimen (Fig 1E), including up-regulation of XPOT, a tRNA exportin, and KPNB1 a nucleocytoplasmic transporter (Fig 1F-G). Protein-protein interaction enrichment analyses revealed mRNA splicing and capping as well as nucleocytoplasmic transport as up-regulated modules in the refractory patients potentially serving as a resistance mechanism for blockade of XPO1 mediated nuclear export by selinexor.In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials to stratify patients according to their level of anti-MM drug resistance, to define new biomarkers for drug resistance that may support personalized therapeutic decisions and reveal potential novel targets. [Display omitted] DisclosuresCohen: Karyopharm: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stemer: AbbVie: Consultancy. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Amit: Neogene therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; CELLINK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Maruho Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck KGaA: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Immunology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karophram: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Inferior Outcomes of Patients with Quad and Penta-Refractory Multiple Myeloma (MM) Compared to Those of Patients Who Have Been Quad and Penta Exposed

Background: Despite significant advancements in MM therapies, patients with quad-refractoriness (refractory to proteasome inhibitors: bortezomib and carfilzomib, and immunomodulatory drugs: lenalidomide and pomalidomide) and penta-refractoriness (additional refractoriness to CD-38+ monoclonal antibody daratumumab) have a poor prognosis in terms of short progression-free survival (PFS) and overall survival (OS).This is a retrospective, single institutional study comparing the outcomes of patients with quad and penta-refractory MM to patients who were quad and penta-exposed, but not refractory.Methods: Consecutive patients from the John Theurer Cancer Center at Hackensack Meridian School of Medicine who were quad and penta-exposed and/or refractory between the dates of 1/1/2015 and 3/1/2021 were identified. Quad-exposed was defined as having had prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide. Penta-exposed was defined as having prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide and daratumumab. Penta or quad refractory was defined as having stable disease (as best response) or progressive disease while on all of the above drugs, per International Myeloma Working Group (IMWG) definition of refractory. Patients were excluded if they had missing data or if they did not meet the above definitions. Baseline characteristics, high-risk status, ISS, treatment history, treatment response, drugs at first relapse and survival outcomes were obtained retrospectively from the electronic medical record and entered into database. High-risk cytogenetics were defined as the presence of t(4;14), t(14;16) or del 17p; 1q21 gain or amplification; 1p del; t(6;14); t(14;20). Baseline patients' characteristics were summarized descriptively by quad and penta-exposed groups. PFS and OS were estimated using the Kaplan-Meier method. Univariate and multivariable adjusted Cox proportional hazard regression models examined factors affecting OS.Results: A total of 162 patients met the inclusion criteria: 18/162 (11%) were quad or penta-exposed, 32/162 (20%) were quad-refractory, and 112/162 (69%) were penta-refractory. Median age was 62 (55-69), IgG subtype (59%), and 62/162 (38.5%) had high-risk cytogenetics. The median number of lines prior was 6 (range 4-8) among all patients, and 7 (range 5-9) in the penta-refractory group. 133/162 (82.1%) had prior autologous-stem cell transplant (ASCT). Extramedullary disease was present in 40/162 (25.2%). Plasma cell leukemia was present in 14/162 (8.8%). For those who were penta-refractory, the median time from quad to penta-refractory status was 10.2 months (95% confidence interval (CI), 3.57-16.57). See Table 1.Figure 1 shows PFS and OS from the time of becoming quad or penta-exposed or refractory (T0 ). The median PFS after T0 was 11.86 months (95% CI, 6.5-26.6) for combined quad and penta-exposed, compared to 3.88 months (95% CI, 2.99-5.17) for quad and penta-refractory patients. With a median follow-up of 5.14 months (Range, 0-52.4), the median OS for all patients was 7.43 months (95% CI, 5.8- 12.94). (Figure 1A). With a median follow-up time of 4.45 months (Range, 0-52.38), the median OS for patients who were quad or penta-refractory was 5.97 months [95% CI. 4.44-8.23], compared to OS not reached (NR) for quad or penta-exposed, with a median follow-up of 11.86 months. (Figure 1B). At least one subsequent treatment regimen was employed after T0 in 85% of the patients. (Figure 1C).Multivariable adjusted analysis (Table 2) revealed that patients ≥62 had inferior OS compared to those < 62 (p -value=0.046). Furthermore, patients who had ≤10 months between becoming quad- and penta-refractory had inferior OS compared to patients with >10 months (p=0.031). OS was not significantly affected by high risk versus standard cytogenetics or drugs used at first relapse.Conclusion: MM patients with quad and penta-refractory disease have significantly worse outcomes compared to patients with quad and penta-exposed MM: older age (> 62 years) and a short interval (< 10 months) between becoming quad and penta-refractory confer an adverse prognosis. Prospective studies are required to confirm these findings. Penta and quad-refractory multiple myeloma continues to represent a vulnerable population with an unmet need for therapeutic approaches. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Dose Fractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (mHyperCVAD) Is an Active Regimen in Heavily Pretreated Relapsed/Refractory Multiple Myeloma, Enabling Access to Experimental Therapies

BackgroundTherapeutic advancements and deeper understanding of disease biology have helped improve the outcomes of multiple myeloma (MM). However, there is no consensus regarding the optimal management of patients whose disease becomes refractory to the three main class of drugs [proteasome inhibitors (PI), immunomodulatory drug (IMiD), and monoclonal antibodies (mab)] or among those presenting with complications secondary to rapidly progressive disease. While chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engagers have yielded high rates of durable responses, access to these therapies in clinical trials is often hindered by high disease burden compromising eligibility. We evaluated the use of a combination of cytotoxic agents (cyclophosphamide, doxorubicin, vincristine, and dexamethasone; mHyperCVAD) in this challenging population.MethodsThis is a retrospective, single center study evaluating the safety/tolerability and efficacy of mHyperCVAD in relapsed and refractory MM (RRMM). The regimen consists of cyclophosphamide 300 mg/m2 IV every 12 hours on D1-4 (total 2400 mg/m2), vincristine 0.4 mg/day IV continuous infusion D1-4 (total 1.6 mg), doxorubicin 9 mg/m2/day IV continuous infusion D1-4 hours (total 36 mg/m2) and dexamethasone 40 mg PO daily D1-4. Adult patients with RRMM were included if they received ≥1 cycle of mHyperCVAD between 2019-2021. Patients with primary plasma cell leukemia were excluded. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Patients were censored for progression free survival (PFS) at the last follow-up date if neither progression nor death occurred. All patients received growth factors, and infectious disease prophylaxis per institutional standard. Toxicities were graded using CTCAE v5.0 up to 30 days post therapy.ResultsBetween 1/2019 and 7/2021, 39 patients met the inclusion criteria and received 44 courses of mHyperCVAD (four patients received mHyperCVAD at more than one timepoint). The median age was 54 years (range 32-71), 56% male. 36% patient had ISS stage III disease and 56% had high risk disease [t(4;14), t(14;16), del17p, +1q]. The median lines of therapy prior to mHyperCVAD were 3 (range 1-12) with 93% triple class refractory (refractory to PI, IMID and mab) and 64% penta-refractory (refractory to 2 PI, 2 IMiDs and mab) and 76% had received a prior autologous transplant. The median number of mHyperCVAD cycles per course was 1 (range 1-8). Baseline characteristics are summarized in Table. Eleven courses (25%) were administered as bridge after lymphocyte collection for the manufacture of CAR-T cells and prior to lymphodepletion chemotherapy (100% triple class refractory and 91% penta-refractory) with ORR 18% and DCR 72%. Thirty-three courses (75%) were used as salvage for rapid disease control. The most common toxicities with mHyperCVAD were hematologic (65% grade 3/4 toxicities) with 20% incidence of febrile neutropenia. Four patients died during mHyperCVAD therapy due to rapidly progressive disease and one patient died due to sepsis.For the entire cohort, the ORR is 50% (≥VGPR 30%) with a DCR 82%. Additionally, 39% could proceed with experimental CAR-T cells and/or bispecific T cell engagers. The median progression free survival is 3.6 months, and the median overall survival is 8 months from start of mHyperCVAD with 10.5 months median follow up. The most common cause of death was progressive disease (39%).ConclusionmHyperCVAD is an efficacious cytotoxic chemotherapy regimen which can achieve rapid disease control allowing patients an opportunity to proceed with additional therapies, including investigational agents on clinical trials. It can also be used as an effective bridging strategy among heavily treated, triple class and penta-refractory MM awaiting manufacturing of CAR-T cells with manageable and expected toxicities. [Display omitted] DisclosuresGiri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Costa: Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau.

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

ATG-010 Plus Low-Dose Dexamethasone (Sd) in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Received Chimeric Antigen Receptor T-Cell (CAR-T)

Background:There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy.Methods:The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received lymphodepleting conditioning followed by CAR-T cell therapy before study screening. ATG-010 (80mg) plus dexamethasone (20mg) was administered orally twice weekly. Response was assessed by an independent review committee.Results:Among 10 pts, 8 were male and 2 were female. Median age was 58.5 years. Median duration from MM initial diagnosis was 5.2 years. A total of 6 pts (60.0%) had high-risk cytogenetic abnormalities, including 4 pts (40.0%) with del (17p). Three pts had baseline plasmacytoma. Five pts (50%) experienced very rapid disease progression as indicated by a median of 46.2% increase of tumor burden from screening to Cycle 1 Day 1. Patients were heavily pre-treated with a median of 9.5 prior regimens (range: 5-12), with 8 receiving more than 6 regimens. Four pts were exposed to daratumumab (triple-class exposure). ORR was 50% including 1 very good partial response and 4 partial responses. Disease control rate defined as SD and above was 70%. Median duration of response was 1.4 months (mo) (95% CI: 0.96, NE). Median progression free survival was 1.9 mo (95% CI: 0.93, 3.74). xx pts (xx%) pts died; median overall survival was not reached, and estimated 12-mo OS rate was 68.6%.Adverse events were consistent with those events previously reported with Sd regimen in RRMM patients. The most common grade≥3 treatment emergent adverse events (TEAEs) included anemia, thrombocytopenia, neutropenia and nausea. Most events were manageable with appropriate supportive care or dose modification. Four pts (40%) experienced TESAEs, including anemia, pneumonia, neutropenia, and upper gastrointestinal hemorrhage. There were no TEAEs leading to treatment discontinuation or death.Conclusions:Sd was able to induce an encouraging response with a manageable safety profile for a group of Chinese RRMM patients desperately needing treatment after failing CAR-T therapy. With the small sample size, further investigation is warranted, including using ATG-010 in combination with other anti-MM therapies to potentially enhance and prolong therapeutic benefit. DisclosuresYu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Efficacy of Treatments for Patients with Triple-Class Refractory (TCR) Multiple Myeloma (MM): Benchmark for New Agents Utilizing Real-World Data (RWD)

Efficacy of Treatments for Patients with Triple-Class Refractory (TCR) Multiple Myeloma (MM): Benchmark for New Agents Utilizing Real-World Data (RWD)

P-201: Triple-class refractory disease as a modern therapeutic benchmark for clinical trials testing new agents for relapsed refractory Multiple Myeloma

P-201: Triple-class refractory disease as a modern therapeutic benchmark for clinical trials testing new agents for relapsed refractory Multiple Myeloma

P-211: Phase 2 MARCH study: ATG-010 plus Dexamethasone in Chinese relapsed/refractory Multiple Myeloma (RRMM) patients previously treated with an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI)

<h3>Background</h3> ATG-010 (selinexor), a novel, oral selective inhibitor of nuclear export, inhibits exportin1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) has been approved by US FDA for treatment of patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. <h3>Methods</h3> Enrolled Chinese pts were previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd was administered in 4-week cycles. The primary endpoint was overall response rate (ORR) per independent review committee. The total planned 82 pts provide -80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract includes data from the first 60 treated pts. <h3>Results</h3> As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with the following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed'). ORR was 26.7% (95% CI: 16.1, 39.7). Median duration of response (DOR) was 4.6 mo (95% CI: 1.42, NE). Median progression free survival was 3.7 mo (95% CI: 1.92, 4.66). Median overall survival (OS) was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts. Nine pts had prior CAR-T therapy with a median of 9 prior regimens (range 5-12). Among them, ORR was 44.4%, and median DOR was 3 mo (95% CI; 0.96, 4.63). Common treatment emergent adverse events (TEAEs) of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), and pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (>3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), and hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (>2%): thrombocytopenia (5%) and pneumonia (3%). There were three fatal TEAEs: pneumonia, intracranial hemorrhage, and sudden death (1 each). <h3>Conclusions</h3> MM pts refractory to both IMiD and PI remain a high unmet medical need. The MARCH study confirms the efficacy of Sd in Chinese patients with a manageable safety profile. These data are consistent with the STORM trial and offer a new, oral therapeutic option for MM patients.

P-090: BRAF V600E multiple myeloma patient salvaged with triple MAPK inhibition after CAR T relapse

<h3>Background</h3> Despite a growing arsenal of treatment choices, patient relapse post-BCMA-targeted CART therapy remains a challenge and the therapeutic path is still undefined. Among the most frequently observed actionable mutations, BRAF V600E, is present in ~7% of multiple myeloma (MM) patients. The availability of selective inhibitors of BRAF V600E makes this a valuable therapeutic target. However, the clinical efficacy of these inhibitors has been limited and short-lived, frequently due to feedback-induction of BRAF dimers. Novel studies revealed that the multi-kinase inhibitor regorafenib is a potent and selective inhibitor of dimeric BRAF. They have further demonstrated relief of these negative outcomes by inhibiting BRAF in both its monomeric and dimeric form in combination with MEK inhibition leading to more efficacious and tolerable treatment. (Adamopoulos C. et al. Cancer Discov. 21). We present a case of a MM patient with BRAF V600E mutation salvaged with a triple therapy inhibition strategy after relapsing following anti-BCMA CART therapy. <h3>Method</h3> A 61-year-old male with penta-refractory MM (IgA lambda), ISS stage 3 with hyperdiploidy, gain of 1q21 and del13 was treated with anti-BCMA CART therapy, achieving a best response of VGPR, and disease progression after 6 months. He was temporarily salvaged with BCNU/Mel ASCT and achieved a best response of PR until progression with extramedullary disease (subcutaneous skin lesions in lower extremities) and elevated lambda free light chains (FLC, 126.4mg/l) at 6 months. <h3>Results</h3> Targeted sequencing showed a BRAF V600E mutation was present prior to CART therapy in his bone marrow and persisted in his bone marrow and a plasmacytoma with a VAF of 41% at this current relapse. A western blot analysis of bone marrow aspirate confirmed BRAF V600E with a specific antibody, and showed phosphorylation of ERK, which was diminished with trametinib. Longer exposure to trametinib confirmed a feedback loop activating MAPK which was abrogated with the BRAF dimer inhibitor regorafenib. With these findings the patient was started on targeted therapy based on combination of a BRAF monomer-inhibitor, dabrafenib (100mg, orally twice daily), a MEK-inhibitor, trametinib (1.5mg, orally for 21/28 days daily), and a BRAF dimer inhibitor, regorafenib (40mg, orally once daily). Within 3 months of treatment initiation, prompt reduction in subcutaneous skin lesions and 80% reduction in free lambda FLC (27.5 mg/l) was observed. Furthermore, the patient had good tolerance to all three medications with minimal side effects (grade 1 fatigue) and continues treatment. The treatment regimen allowed the patient to carry out activities of daily living and return to work. <h3>Conclusion</h3> Post-CART failure treatment is a challenging and unmet need. NGS may identify targeted therapy that would be able to salvage patients with a tolerable side effect profile.