Relapsed/refractory Multiple Myeloma Research Articles

Therapeutic progress in relapsed/refractory multiple myeloma.

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.

Unscheduled healthcare interactions in multiple myeloma patients receiving T cell redirection therapies

Outcomes for relapsed/refractory multiple myeloma (RRMM) patients have dramatically improved following the development and now growing utilization of B cell maturation antigen targeted chimeric antigen receptor (CAR) T cell therapy and bispecific antibody (BsAb) therapy. However, healthcare utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled healthcare interactions (UHIs) among RRMM patients responding to B-cell maturation antigen targeted BsAbs and CAR T cell therapies (N = 46). This included analysis of remote UHIs including calls to physicians’ offices and messages sent through an online patient portal. Our results showed that nearly all (89%) RRMM patients receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. RRMM patients responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase, p = 0.038) or visit an urgent care center (>3-fold increase, p = 0.012) than RRMM patients responding to CAR T cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that RRMM patients experience while receiving CAR T cell or BsAb therapies. This preemptive management may significantly reduce unnecessary healthcare utilization in this vulnerable patient population.

Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives

Patients with relapsed/refractory multiple myeloma (RRMM) that are refractory to the five most active anti-MM drugs, so-called penta-refractory MM, have historically had dismal outcomes with subsequent therapies. Progressive immune dysfunction, particularly of the T-cell repertoire, is implicated in the development of disease progression and refractory disease. However, the advent of novel immunotherapies such as bispecific antibodies are rapidly changing the treatment landscape and improving the survival outcomes of patients with RRMM. Bispecific antibodies are antibodies that are engineered to simultaneously engage cytotoxic immune effector cells (T cells or NK cells) and malignant plasma cells via binding to immune effector cell antigens and extracellular plasma cell antigens leading to immune effector cell activation and malignant plasma cell destruction. Currently, bispecific antibodies that bind CD3 on T cells and plasma cell epitopes such as B-cell maturation antigen (BCMA), G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5) are the most advanced in clinical development and are showing unprecedented response rates in patients with RRMM, including patients with penta-refractory disease. In this review article, we explore the available clinical data of bispecific antibodies in RRMM and summarize the efficacy, safety, toxicity, clinical outcomes, mechanisms of resistance, and future directions of these therapies in patients with RRMM.

Abstract CT071: Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy

Abstract Introduction: Despite therapeutic advances, multiple myeloma remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T provide high response rates, but relapses are common. Autologous CAR-T are logistically challenging due to the need for apheresis, prolonged manufacturing and occasional manufacturing failures. Importantly, pts who have progressed after a prior BCMA targeting immunotherapy are an emerging area of high unmet need. Emerging data indicate that autologous CAR-T have lower clinical activity in pts ho have progressed on TCE. Methods: P-BCMA-ALLO1 is an allogeneic CAR-T therapy manufactured from healthy donor T-cells available “off-the-shelf” and being evaluated in a phase 1 clinical trial (P-BCMA-ALLO1-001) in RRMM pts. This primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1, and the key secondary objective is to investigate the anti-myeloma activity. The pts must have progressed on a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. The study allows enrollment of pts who have received prior BCMA targeting therapy. The study is exploring escalating P-BCMA-ALLO1 doses and several different lymphodepletion chemotherapy (LD) regimens. Here we report the safety and early efficacy results for the 5 pts who were treated with P-BCMA-ALLO1 after having progressed on BCMA targeting CAR-T, TCE or both. These pts were treated in arms P1 (LD: cyclophosphamide (cy) 500 mg/m2 + fludarabine (flu) 30 mg/m2 X 3 days) or arm P2 (LD: cy 1000 mg/m2 + flu 30 mg/m2 X 3 days) at a P-BCMA-ALLO1 dose of > 2 X 106 to <6 X 106 cells/kg. Results: The median pt age was 62 years and median prior lines of therapy was 10. Three pts were treated in arm P2 and 2 in arm P1. Two pts had received prior teclistamab, 2 had received prior CAR-T and 1 had received prior teclistamab and CAR-T. P-BCMA-ALLO1 was well tolerated with no dose limiting toxicities or graft vs. host disease. Three of the five pts developed cytokine release syndrome (all grade (G) 2) and one developed G2 immune effector cell neurotoxicity syndrome. Three of the five pts (60%) achieved clinical responses with all three achieving the best response of very good partial response. The two non-responders had previously received and failed to achieve clinical response with teclistamab. One pt who had previously received both teclistamab and CAR-T achieved VGPR. Conclusion: In conclusion, P-BCMA-ALLO1 is an allogeneic CAR-T that is available “on-demand” with activity in RRMM pts who have progressed following prior BCMA targeted CAR-T and TCE. We believe this is the first such report of an allogeneic CAR-T showing clinical activity in such a pt population with high unmet need. Enrollment is continuing and updated data will be presented at the meeting. Citation Format: Bhagirathbhai Dholaria, Leyla Shune, Andrew Kin, Katherine McArthur, Jeff D. Eskew, Christopher E. Martin, Sabrina Haag, Joanne McCaigue, Hamid Namini, Sam DePrimo, Stacey Cranert, Julia Coronella, Devon Shedlock, Rajesh Belani. Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT071.

Abstract CT001: Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups

Abstract Background We report pivotal results from the registrational filing data cut-off (DCO) of the 200 mg dose used in the LINKER-MM1 (NCT03761108) clinical trial, testing the safety and efficacy of linvoseltamab (a B-cell maturation antigen × CD3 antibody [Ab]) as treatment for relapsed/refractory multiple myeloma (RRMM). Methods Eligible patients had RRMM that either progressed on/after ≥3 lines of therapy that included a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 Ab or that was ≥double- (Phase 1) or triple- (Phase 2) class (PI/IMiD/anti-CD38 Ab) refractory. Phase 2 patients received intravenous linvoseltamab once a week through week 14, then once every 2 weeks (Q2W). Phase 2 patients achieving ≥very good partial response (VGPR) who have received treatment for ≥24 weeks transitioned to Q4W dosing. Primary endpoint was objective response rate (ORR) per Independent Review Committee (IRC). Secondary endpoints included duration of response (DOR), progression free survival (PFS), overall survival (OS), and safety. Results At DCO of Sep 8, 2023, median duration of follow-up for the 117 patients enrolled into the 200 mg dosing cohorts (phase 1+2) was 11.1 months (interquartile range 2.9-14.1). Median age was 70 years (26% ≥75), 17% were African American, 18% had International Staging System (ISS) stage III disease, 16% had extramedullary (excluding paramedullary) plasmacytomas (EMPs) ≥2 cm, 39% had high-risk cytogenetics, and 82% were ≥triple-class refractory. Linvoseltamab induced high rates of deep responses with an ORR of 71% including ≥complete response (CR) rate of 46%. Among all patients with ≥CR, 39% were documented minimal residual disease negative. These frequent and deep responses were observed across prespecified high-risk subgroups including patients with ISS stage III (ORR 62%; ≥CR 43%), and EMPs (ORR 53%; ≥CR 26%). Kaplan-Meier (KM) estimated median DOR was not reached (NR); estimated probability of ongoing response at 12 months was 78% (95% confidence interval [CI] 65-86). KM estimated PFS and OS were NR; and probability of PFS and OS at 12 months were 69% (95% CI 58-77) and 75% (65-82), respectively. The most common treatment emergent adverse event (TEAE) was cytokine release syndrome (CRS; any grade [Gr] 46%, Gr2 10%, Gr3 1%, Gr≥4 0%), which occurred mostly during step-up dosing of linvoseltamab with a median time to onset of 11 hours. Other common TEAEs were neutropenia (any Gr 41%, Gr 3-4 40%), anemia (39%, 31%), cough (36%, 0%), and diarrhea (35%, 2%). Infections occurred in 73% (Gr 3-4 34%) of patients. The frequency and severity of infections decreased after 6 months coincident with Q4W dosing. Conclusions Linvoseltamab induced high rates of deep and durable responses in patients with RRMM including those in high-risk subgroups. Linvoseltamab is associated with a generally predictable timing of CRS, and the Q4W response adapted schedule in patients with ≥VGPR may provide a substantial benefit for patient convenience and is associated with a reduced infection rate. Citation Format: Sundar Jagannath, Joshua Richter, Madhav V. Dhodapkar, James E. Hoffman, Hans C. Lee, Attaya Suvannasankha, Mansi R. Shah, Suzanne Lentzsch, Jeffrey A. Zonder, Rachid Baz, Joseph J. Maly, Swathi Namburi, Ka Lung Wu, Matthew Pianko, Rebecca Silbermann, Chang-Ki Min, Marie-Christiane Vekemans, Markus Munder, Ja Min Byun, Joaquín Martínez Lopez, Michelle DeVeaux, Dhruti Chokshi, Anita Boyapati, Anasuya Hazra, Karen Rodriguez Lorenc, Glenn S. Kroog, Yariv Houvras, Naresh Bumma. Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT001.

An open-label phase 2 study treating patients with first or second relapse of multiple myeloma with carfilzomib, pomalidomide, and dexamethasone (KPd): SELECT study

Once-weekly carfilzomib at 56 mg/m2 plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10−5) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory.

Sequence not salvage.

Chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR-T products, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti), have been FDA- and EMA-approved for the treatment of relapsed/refractory MM (RRMM); both target B-cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR-T therapy, most patients will need subsequent treatment, and the optimal next-line therapy is presently unclear. Commentary on: Liu etal. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA-specific CAR-T therapy: A retrospective analysis of LEGEND-2. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19340.

A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Abstract 3617: Expansion and persistence of anti-BCMA CAR T cells correlates with durability of responses in multiple myeloma patients

Abstract Background: Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) can induce >70% response rates in patients with relapsed/refractory multiple myeloma (RRMM). However, most patients ultimately relapse. There are two FDA-approved CAR T products: ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), the former having much more durable responses. The mechanisms that mediate more durable responses with these CAR T cells is unknown. Previous studies have shown that specific cell states in the apheresis and infusion products are associated with long-term efficacy of anti-BCMA CAR therapy in MM and the relationship between durability of response and CAR T cell persistence remains unclear. Methods: We analyzed serial bone marrow and PBMC samples from 20 MM patients who received BCMA CAR T therapy, including cilta-cel, ide-cel, and JCARH125. Flow cytometry and single-cell RNAseq were used to evaluate the features of CAR T cells that are associated with durable clinical responses. Results: While CAR T cells were detectable but variable among patients at 1-month post infusion, the frequency of CAR T cells in bone marrow at 1-month post-infusion is positively correlated with progression free survival (PFS) in all MM patients (p=0.009). This association was also evident in patients just treated with cilta-cel (p= 0.008). By 6 months, CAR T cells could still be detected by high-throughput flowcytometry in the cilta-cel-treated patients, but CAR T cells were not detectable in most of the patients receiving the other 2 products. Cilta-cel CAR T cells predominantly possessed an effector-like surface phenotype at 1-moth post infusion in both CD8+ and CD4+ compartments in bone marrow. These CAR T cells shifted to effector memory and central memory T cell states by 6 months, respectively. For ide-cel and JCARH125, patients with more durable responses (>6mos) there was a significantly higher proportion of CAR T cells with CD8+ effector memory-like state at 1-month post infusion. Conclusions: Our data demonstrate that distinct anti-BCMA CAR T cell treatments lead to very different cellular outcomes: Cilta-cel CAR T cell treatment leads to greater expansion and persistence compared to other anti-BCMA CAR T cells. Cilta-cel CAR T cells also shift from the initial effector state to a memory phenotype. These results provide insights into features of more efficacious anti-BCMA CAR T cells that can help guide the future development of more durable treatments for MM. Citation Format: Kai Wu, Karen Law, Guy Ledergor, Chang Liu, Zenghua Fan, Vibha Gurunathan, Averey Lea, Matthew Clark, Serena Kwek, Alexander Cheung, Jeffrey Wolf, Ajai Chari, Anupuma Kumar, Justin Eyquem, Thomas Martin, Lawrence Fong. Expansion and persistence of anti-BCMA CAR T cells correlates with durability of responses in multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3617.

Abstract 1691: p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma

Abstract Multiple myeloma (MM), an incurable plasma cell malignancy, is addicted to oncogenic transcription factor (TF) IRF4 signaling. Lineage TFs like IRF4 are difficult to drug but represent high value oncology targets owing to the depth and context selectivity of their genetic dependency. Using a transcription regulatory network (TRN) based approach to integrate a high dimensional multi-platform dataset, we defined the key regulatory activity of IRF4 and its druggable co-factors. This unbiased analysis identified p300 lysine acetyl transferase (KAT) function as the nearest selective neighbor for therapeutic intervention, with more potent and selective effects than historically observed with p300/CBP bromodomain inhibitors. To further probe this biology, we developed a highly selective inhibitor of the KAT domain of p300 and its close homolog CBP. p300 KAT inhibition led to selective downregulation of IRF4 at the mRNA and protein level as well as reduction in acetylation at highly specific sites co-localized with IRF4, in contrast to more general agents like BET inhibitors. Gene expression reduction was most pronounced at IRF4/p300 co-bound genes, in particular IRF4 itself and MYC. IRF4 and p300 also directly bind to each other and other key MM nodes regulating them at the chromatin, mRNA, and protein levels. p300 KAT inhibition exhibits strong antiproliferative activity across in vitro MM models regardless of cytogenetics or resistance to other therapies. Moreover, this relationship is mediated by the KAT domain and not its acetyl-lysine recognizing bromodomain. Comparative pharmacology studies found that a p300 KAT inhibitor downregulated the IRF4 TRN and induced apoptosis in MM cells more effectively than existing standard of care agents, including IMiDs and glucocorticoid receptor agonists, or p300/CBP bromodomain inhibitors. Combinations of a p300 KAT inhibitor with clinically active molecules such as IMiDs and glucocorticoid agonists showed synergistic impacts on reducing key MM TFs and cell line viability. Ex vivo treatment of primary patient samples demonstrated broad anti-proliferative activity with loss of IRF4 and induction of apoptosis in relapsed-refractory MM patient samples, independent of prior lines of therapy. Importantly, the induction of MM cell apoptosis occurs in the milieu of CD138 negative bone marrow stromal cells while also sparing them from toxicity, supporting a potential therapeutic index. Finally, p300 KAT inhibition demonstrated activity in in vivo MM models with robust tumor growth inhibition at tolerated doses and exposures correlated to reduced p300-dependent substrate acetylation. IRF4 dependency is a hallmark of MM that has been challenging to target with existing therapies, motivating further development of p300 KAT targeting therapeutics. Citation Format: Michael R. McKeown, Giulia Giorgetti, Walter F. Lenoir, Marek J. Kobylarz, Tamara D. Hopkins, Wayne L. Glore, Michelle G. Shum, Yare Calderon, Kameron R. Mori, Hua Gao, Luis A. Carvajal, Nikolaus D. Obholzer, Benjamin W. Trotter, Christopher D. Dinsmore, Nikhil C. Munshi, Peter B. Rahl, Mariateresa Fulciniti, Charles Y. Lin. p300 catalytic inhibition selectively targets IRF4 oncogenic activity in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1691.

Treatment pattern and outcomes of re-induction therapy prior to stem cell transplantation in patients with relapsed/refractory multiple myeloma in Germany.

There are limited data guiding choice of re-induction therapies for patients with relapsed/refractory multiple myeloma (RRMM) prior to stem cell transplantation (SCT). We performed a retrospective medical chart review of 171 patients with RRMM in Germany who received re-induction therapy in second line (78%; n = 134) or third line (22%; n = 37) prior to re-SCT. Index therapy was defined as first completed re-induction therapy for planned myeloablative conditioning and SCT in second/third line within the eligibility period (1/2016-12/2019). Most common pre-index first line and maintenance therapy used were bortezomib-based combinations (91%; n = 155/171) and lenalidomide (55%; n = 29/53), respectively. Median duration of index therapy line was 9 months; carfilzomib-based combinations were the most widely used in second/third line re-induction therapy (49%; n = 83/171), followed by daratumumab-based combinations (21%; n = 36/171). Overall response rates in second/third line were 87% after re-induction and 96% after SCT; median time to next treatment line after start of index therapy was 31 months; median progression-free survival (PFS) was 29 months; and median overall survival after index date was not reached. Based on these data, re-induction therapy with salvage SCT appears to be beneficial in selected patients with RRMM in clinical practice in Germany, translating into deep responses, long PFS and prolonged time to next treatment.

Efficacy of Selinexor in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with del17p and Other High-Risk Abnormalities (A Retrospective Single-Center Study).

Selinexor (Seli) is a first-in-class, oral selective inhibitor of the nuclear export protein, exportin-1 (XPO1). Seli exhibits its antitumor effect through the blockage of XPO1, which increases nuclear retention of tumor suppressor proteins (TSPs), including p53, thereby limiting the translation of oncogenes, triggering cell cycle arrest and the death of malignant cells. Multiple Myeloma (MM) patients with del17p are deficient in TP53 and have a particularly poor prognosis. Given its unique mechanism of action, we investigated whether Seli has increased efficacy in RRMM patients with del17p compared to other high-risk cytogenetics (OHRC). This is an IRB-approved observational study of RRMM patients with high-risk cytogenetics (del17p, t (4;14), t (14;16) or gain 1q) or standard-risk cytogenetics treated at the Levine Cancer Institute (LCI) with a Seli-based regimen between January 2019 and December 2022. Time-to-event endpoints (PFS, OS) were evaluated using Kaplan-Meier (KM) methods. Log-rank tests compared time-to-event endpoints between cohorts [del17p vs. OHRC vs. standard risk]. We identified 40 RRMM patients with high-risk cytogenetics, including 16 patients with del17p and 24 patients with OHRC, as well as 20 with standard-risk cytogenetics. The median age was 62.5 vs. 69 vs. 65.5 years (del17p group vs. OHRC vs. standard risk). The median prior line of therapies was five (range: 3-16) with similar rates of prior autologous stem cell transplant in all arms (68.8% vs. 62.5% vs. 70.0%). The most frequently used regimens were Seli-Pomalidomide-dexamethasone(dex) or Seli-Carfilzomib-dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. The median time to start the Seli-based regimen after initial MM diagnosis was 5.6 years for the del17p group, 4.1 years in OHRC, and 4.8 years in the standard-risk group. The median follow-up time after the start of the Seli-based regimen was 10.5 months (mos) in the del17p group, 8.4 mos in OHRC, and 10.3 mos in the standard-risk group. In the del17p group, 50% had an objective response, 41.7% in the OHRC, and 35% in the standard-risk group (p = 0.71). Depth of response was also similar across the arms (12.5% vs. 12.5% vs. 10.0% VGPR p = 0.99). The median OS was 10.9 mos in the del17p group, 10.3 mos in the OHRC, and 10.3 mos in the standard-risk group (p = 0.92). The median OS was 15.5 mos for patients who received Seli as a bridging therapy versus 9 mos for Seli use for other reasons rather than as a bridge. Overall, Seli-based regimens showed promising responses even in this heavily pretreated population. Our analysis suggests that Seli-based regimens lead to similar outcomes among RRMM patients with del17p, OHRC, and standard-risk cytogenetics. This contrasts with previously reported outcomes using combinations of novel therapies in this population, where the del17p patients often have a poorer prognosis. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response.

The role of pentraxin 3 and oxidative status in the prognosis of multiple myeloma.

Multiple myeloma (MM) is a bone marrow malignancy characterized by plasma cell proliferation. It was aimed to investigate pentraxin 3 (PTX3) levels, oxidative/antioxidative status, and their correlation in MM. In the study, four groups were established, including newly diagnosed MM (NDMM), MM in remission (Rem-MM), relapsed/refractory MM (RRMM) patients, and a healthy control group. PTX3 levels were measured using enzyme-linked immunosorbent assay, and the total antioxidant status (TAS) and total oxidant status (TOS) were assessed with an autoanalyzer. The oxidative stress index (OSI) was calculated using the formula: OSI (arbitrary unit) = TOS (µmol H2O2 Eq/L)/TAS (mmol Trolox Eq/L) × 100. The study involved comparing PTX3, TAS, TOS, and OSI levels among these four groups. PTX3 levels were significantly elevated in NDMM and RRMM groups compared to controls and the Rem-MM group (NDMM vs control; p < 0.001, NDMM vs Rem-MM; p < 0.001, RRMM vs control; p < 0.001, and RRMM vs Rem-MM; p = 0.006). TAS was higher in NDMM and RRMM groups versus controls (p = 0.009 and p < 0.001, respectively), and TOS was higher in rem-MM group versus NDMM and control groups (p < 0.001 and p = 0.016, respectively). OSI was higher in the Rem-MM group than in NDMM and RRMM groups (p < 0.001 and p = 0.009, respectively). Multivariate analysis confirmed associations between MM groups and PTX3 levels. Receiver operating characteristic analysis revealed high specificity (90%) and sensitivity (79%) for PTX3 in NDMM at a >0.56 ng/mL cut-off value. This study suggests that PTX3 levels may have diagnostic and prognostic potential in MM and its relationship with oxidative stress requires further exploration.

CAR T therapies in multiple myeloma: unleashing the future.

In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with potent complement-dependent cytotoxic effects. Despite the challenges and obstacles associated with these treatments, the recent approval of the second FDA multiple myeloma CAR T-cell therapy has sparked immense promise in the field. Thus far, the results indicate its potential as a highly effective therapeutic solution. Moreover, ongoing preclinical and clinical trials are exploring the capabilities of CAR T-cells in targeting specific antigens on myeloma cells, offering hope for patients with relapsed/refractory MM (RRMM). These advancements have shown the potential for CAR T cell-based medicines or combination therapies to elicit greater treatment responses and minimize side effects. In this context, it is crucial to delve into the history and functions of CAR T-cells while acknowledging their limitations. We can strategize and develop innovative approaches to overcome these barriers by understanding their challenges. This article aims to provide insights into the application of CAR T-cells in treating MM, shedding light on their potential, limitations, and strategies employed to enhance their efficacy.

CtDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone

AbstractIt remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis–associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma

AbstractFor patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA–directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

Practical Aspects of Immunotherapy: A Report from the 20th International Myeloma Society (IMS) Annual Meeting

Immunotherapeutic strategies, specifically T-cell redirected therapies have been transformative in the context of multiple myeloma (MM). With the approval of two chimeric antigen receptor T-cell (CAR-T) drug products and three bispecific antibodies/T-cell engagers (bsAbs/TCEs) in relapsed/refractory MM (RRMM), the 20th annual IMS meeting dedicated a session to the practical aspects of these therapies. Here, we highlight the discussion during this session including the role of CAR-T and bsAb therapies in frontline MM treatment, management of acute toxicities, prevention and management of infections, and finally treatment sequencing of T-cell redirected therapies.

Management of Adverse Events Associated with Pomalidomide-Based Combinations in Patients with Relapsed/Refractory Multiple Myeloma.

Multi-agent regimens incorporating immunomodulatory (IMiD®) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Currently, there are three IMiD agents approved for the treatment of MM: thalidomide, lenalidomide, and pomalidomide. Lenalidomide is commonly used to treat patients with newly diagnosed MM and as maintenance therapy following stem cell transplant or after disease relapse. Pomalidomide, the focus of this review, is approved in patients with relapsed/refractory MM (RRMM). Despite survival benefits, IMiD agents each have different safety profiles requiring consideration both prior to starting therapy and during treatment. Adverse event (AE) management is essential, not only to ensure treatment adherence and thus ensure optimal efficacy but also to maintain patient quality of life. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).

Cost-effectiveness and budget impact analysis of Daratumumab, Lenalidomide and dexamethasone for relapsed-refractory multiple myeloma

BackgroundThe prominent efficacy in terms of increasing progression-free survival (PFS) of Daratumumab, Lenalidomide and dexamethasone (DRd) triplet therapy versus Carfilzomib, Lenalidomide and dexamethasone (KRd) was proven previously in relapsed-refractory multiple myeloma (RRMM). However, the cost effectiveness of DRd versus KRd is unknown.MethodsWe developed a Markov model by using an Iranian payer perspective and a 10-year time horizon to estimate the healthcare cost, Quality-adjusted life years (QALYs) and life years gain (LYG) for DRd and KRd triplet therapies. Clinical data were obtained from meta-analyses and randomized clinical trials (RCTs). One-way and probabilistic sensitivity analysis were performed to assess model uncertainty. Budget impact analysis of 5 years of treatment under the DRd triplet therapy was also analysed.ResultsDRd was estimated to be more effective compared to KRd, providing 0.28 QALY gain over the modelled horizon. DRd-treated patients incurred $264 in total additional costs. The incremental cost utility ratio (ICUR) and cost effectiveness ratio (ICER) were $956/QALY and $472/LYG respectively.The budget impact analysis indicates that adding Daratumumab to Lenalidomide and dexamethasone regimen, in the first 5 years, will increase the healthcare system’s expenses by $6.170.582.ConclusionDRd triplet therapy compared to KRd is a cost-effective regimen for RRMM under Iran willingness-to-pay threshold.

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2months in 1q21+ patients and 38.2 versus 16.2months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.