Relapsed Or Refractory Multiple Myeloma Research Articles

Evaluation of cytokine release syndrome (CRS) in patients with relapsed or refractory multiple myeloma (RRMM) receiving step-up priming doses and longer dosing intervals of elranatamab: MagnetisMM-9.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

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

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

Ambulatory teclistamab administration in patients with relapsed/refractory multiple myeloma.

11146 Background: Teclistamab (Tec) is the first B-Cell Maturation antigen (BCMA)xCD3 bispecific antibody FDA approved for the treatment of relapsed or refractory multiple myeloma (RRMM) in patients who have received ≥4 prior lines of therapy. The phase 1-2 MajesTec-1 study raised concerns for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS). 48-hour inpatient observation is recommended for step-up dosing, which imposes financial and logistical burdens. We report our institutional experience with ambulatory Tec administration. Methods: Our inpatient/outpatient (IPOP) hybrid nursing unit is staffed with specialized nurses, advanced practice providers, and attending physicians. Our patients treated in IPOP must live within 1 hour of the hospital and have a 24-hour caregiver. Patients were treated with the recommended step-up dosing schedule. CRS grading and ICE scoring were performed daily. Both CRS and ICANS were graded according to the ASTCT grading systems. We collected toxicities until the second full treatment dose, at which point hospitalization is no longer recommended. Results: In total, 25 patients were treated with Tec between January 2023 to December 2023. The median age was 70 years old (range 59-89), with a median of 6 prior lines of therapy. One patient was dialysis dependent prior to starting Tec. All patients were triple class refractory. Thirteen patients (52%) received prior bone marrow transplant. One (4%) patient received prior anti-BCMA CAR-T therapy. Seventeen patients (68%) required admission during the Tec ramp-up period. CRS was observed in 15 (60 %) patients, all of which were grade I/II events. Fourteen of these patients were hospitalized for CRS. They were admitted for median number of 2 hospital days (range 1-6). Tocilizumab was administered for Grade 2 CRS in 3 patients (12%). ICANS was reported in 4 (16%) patients. Two of those patients developed Grade 2 ICANS which completely resolved with dexamethasone. The median number of admitted hospital days for these patients was 3 days (range 2-49). Neutropenia with ANC < 500 was seen in only 1 (4%) patient. Grade 3/4 infections were seen in 3 (12%) patients during the ramp-up period. Conclusions: Tec administration through an inpatient/outpatient hybrid model is safe and feasible. CRS was common but low grade and short lived. ICANS was observed, but remained low grade and may be attributable to our older patient population. As our center gained experience with the Tec management, we noticed lower rates of admission for low grade CRS. Lower incidences of infections and neutropenia demonstrate that these complications emerge in the months after starting therapy. Future studies will help identify patients who are higher risk for CRS and ICANS during ramp-up treatment and may pave the way for prophylactic interventions and outpatient administration.

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

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

BCMA/CD47-directed universal CAR-T cells exhibit excellent antitumor activity in multiple myeloma

BackgroundBCMA-directed autologous chimeric antigen receptor T (CAR-T) cells have shown excellent clinical efficacy in relapsed or refractory multiple myeloma (RRMM), however, the current preparation process for autologous CAR-T cells is complicated and costly. Moreover, the upregulation of CD47 expression has been observed in multiple myeloma, and anti-CD47 antibodies have shown remarkable results in clinical trials. Therefore, we focus on the development of BCMA/CD47-directed universal CAR-T (UCAR-T) cells to improve these limitations.MethodsIn this study, we employed phage display technology to screen nanobodies against BCMA and CD47 protein, and determined the characterization of nanobodies. Furthermore, we simultaneously disrupted the endogenous TRAC and B2M genes of T cells using CRISPR/Cas9 system to generate TCR and HLA double knock-out T cells, and developed BCMA/CD47-directed UCAR-T cells and detected the antitumor activity in vitro and in vivo.ResultsWe obtained fourteen and one specific nanobodies against BCMA and CD47 protein from the immunized VHH library, respectively. BCMA/CD47-directed UCAR-T cells exhibited superior CAR expression (89.13-98.03%), and effectively killing primary human MM cells and MM cell lines. BCMA/CD47-directed UCAR-T cells demonstrated excellent antitumor activity against MM and prolonged the survival of tumor-engrafted NCG mice in vivo.ConclusionsThis work demonstrated that BCMA/CD47-directed UCAR-T cells exhibited potent antitumor activity against MM in vitro and in vivo, which provides a potential strategy for the development of a novel “off-the-shelf” cellular immunotherapies for the treatment of multiple myeloma.Graphic

The role of proliferating stem-like plasma cells in relapsed or refractory multiple myeloma: Insights from single-cell RNA sequencing and proteomic analysis.

The management and comprehension of relapsed or refractory multiple myeloma (RRMM) continues to pose a significant challenge. By integrating single-cell RNA sequencing (scRNA-seq) data of 15 patients with plasma cell disorders (PCDs) and proteomic data obtained from mass spectrometry-based analysis of CD138+ plasma cells (PCs) from 144 PCDs patients, we identified a state of malignant PCs characterized by high stemness score and increased proliferation originating from RRMM. This state has been designated as proliferating stem-like plasma cells (PSPCs). NUCKS1 was identified as the gene marker representing the stemness of PSPCs. Comparison of differentially expressed genes among various PC states revealed a significant elevation in LGALS1 expression in PSPCs. Survival analysis on the MMRF CoMMpass dataset and GSE24080 dataset established LGALS1 as a gene associated with unfavourable prognostic implications for multiple myeloma. Ultimately, we discovered three specific ligand-receptor pairs within the midkine (MDK) signalling pathway network that play distinct roles in facilitating efficient cellular communication between PSPCs and the surrounding microenvironment cells. These insights have the potential to contribute to the understanding of molecular mechanism and the development of therapeutic strategies involving the application of stem-like cells in RRMM treatment.

Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.

Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Of 41 enrolled patients, 34 (n=6 part 1, n=28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. gov as NCT03848845.

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects...

Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials.

Bispecific antibody (BsAbs) therapy represents a promising immunotherapeutic approach with manageable toxicity and noteworthy preliminary efficacy in treating patients with relapsed or refractory multiple myeloma (RRMM). The objective of this systematic review and meta-analysis was to compare the efficacy and safety of B-cell maturation antigen (BCMA)-targeted BsAbs and non-BCMA-targeted BsAbs in the treatment of RRMM patients. PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library and meeting libraries were searched from inception to August 16th, 2023. The efficacy evaluation included the complete objective response rate (ORR), complete response (CR) rate, stringent CR (sCR) rate, partial response (PR) rate, and very good PR (VGPR) rate. The efficacy evaluation included any grade adverse events (AEs) and grade ≥ 3 AEs. Fourteen studies with a total of 1473 RRMM patients were included. The pooled ORR of the entire cohort was 61%. The non-BCMA-targeted BsAbs group displayed a higher ORR than the BCMA-targeted BsAbs group (74% vs. 54%, P < 0.01). In terms of hematological AEs, BCMA-targeted BsAbs therapy exhibited higher risks of neutropenia (any grade: 48% vs. 18%, P < 0.01; grade ≥ 3: 43% vs. 15%, P < 0.01) and lymphopenia (any grade: 37% vs. 8%, P < 0.01; grade ≥ 3: 31% vs. 8%, P = 0.07). Regarding non-hematological AEs, there were no significant differences in the risks of cytokine release syndrome (CRS, any grade: 64% vs. 66%, P = 0.84; grade ≥ 3: 1% vs. 1%, P = 0.36) and infections (any grade: 47% vs. 49%, P = 0.86; grade ≥ 3: 24% vs. 20%, P = 0.06) between the two groups. However, non-BCMA-targeted BsAbs therapy was associated with a higher risk of immune effector cell-associated neurotoxicity syndrome (ICANS, any grade: 11% vs. 2%, P < 0.01) and lower risks of fatigue (any grade: 14% vs. 30%, P < 0.01) and pyrexia (any grade: 14% vs. 29%, P < 0.01). This analysis suggest that non-BCMA-targeted BsAbs therapy may offer a more favorable treatment response and tolerability, while BCMA-targeted BsAbs therapy may be associated with diminished neurotoxic effects. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42018090768.

Clinician and Administrator Perspectives on Chimeric Antigen Receptor (CAR) T-Cell Therapy Outpatient Administration in Relapsed or Refractory Multiple Myeloma (RRMM) in the United States

Clinician and Administrator Perspectives on Chimeric Antigen Receptor (CAR) T-Cell Therapy Outpatient Administration in Relapsed or Refractory Multiple Myeloma (RRMM) in the United States

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1–21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39–76) years, a median prior line of therapy of 4 (range, 1–16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44–50.01). The disease control rate was 67.1% (95% CI, 56.02–76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68–7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Patient-reported experiences during and following treatment with belantamab mafodotin for relapsed/refractory multiple myeloma in the DREAMM-2 study.

Patients with relapsed or refractory multiple myeloma (RRMM) are likely to be living with persistent symptoms, especially bone pain and fatigue, and experiencing restrictions in their physical and social functioning, which reduce health-related quality of life. This qualitative interview study evaluated patients' perspectives about living with RRMM and their treatment with belantamab mafodotin, using interviews embedded in the Phase II DREAMM-2 trial (NCT03525678) with belantamab mafodotin. Patients consented to participate in up to 2 recorded telephone interviews (at treatment cycle 4 [C4] and at end of treatment [EOT]) comprising open-ended questions. A total of 142 interviews were conducted with 111 unique patients. At C4, common symptoms included neuropathy, fatigue, and bone or joint pain. Improvements in symptom severity were reported by patients who responded to belantamab mafodotin. Symptoms associated with visual impairment, eye irritation, and eye pain reported during the trial were reported to be at- or near-resolution by the EOT interview. Regarding impacts of underlying MM, patients most commonly expressed concerns about changes in daily performance and lifestyle for both responders (67.5% of all impact expressions) and non-responders (63.2%). Overall, interview participants reported being satisfied with belantamab mafodotin treatment. This qualitative patient interview study provides valuable insight into patients' symptomatic experience with belantamab mafodotin for their RRMM treatment and may help healthcare providers better anticipate their patients' real-world experience and needs when prescribing this novel agent in the clinic.

Integrating Immune Therapies for the Treatment of Multiple Myeloma.

Patients with relapsed or refractory multiple myeloma (RRMM) that is refractory to a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 antibody (triple-class refractory MM) have poor outcomes. Recently, 2 classes of T-cell engaging therapies-CAR T-cell therapy and bispecific T-cell engaging antibodies (BsAbs)-have resulted in unprecedented response rates and survival outcomes in these heavily pretreated patients. The most common targets are BCMA and GPRC5D, with other targets in development. The main classes of adverse effects include cytokine release syndrome, neurotoxicity, infections, and cytopenias, as well as adverse effects unique to specific products. As of September 2023, 2 BCMA-targeting CAR-T cell products, 2 BCMA-targeting BsAbs, and 1 GPRC5D-targeting BsAb, are FDA-approved for standard-of-care use in patients with RRMM who received at least 4 prior lines of therapy, including prior treatment with a proteasome inhibitor, an IMiD, and an anti-CD38 antibody. Earlier-line use is under investigation and has shown promising results. Several other investigational CAR-T constructs and bispecific antibodies are in clinical development. As these therapies become more widely used, including in earlier-line setting, efforts to understand optimal sequencing and mitigate toxicities remain critical.

HPR9 Value Criteria for Outcomes Based Managed Entry Agreement of CAR-T in Relapsed or Refractory Multiple Myeloma (RRMM) through MCDA

HPR9 Value Criteria for Outcomes Based Managed Entry Agreement of CAR-T in Relapsed or Refractory Multiple Myeloma (RRMM) through MCDA

Cost per Responder Analysis of Patients with Lenalidomide-Refractory Multiple Myeloma Who Received Cilta-Cel from the Cartitude-4 Trial

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor-T cell (CAR-T) immunotherapy approved for patients with relapsed or refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated better efficacy than physician's choice (daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with an overall response rate (ORR) of 84.6% versus 67.3% and ≥complete response (CR) of 73.1% versus 21.8% (San-Miguel et al. New Engl J Med. 2023). The present analysis assessed the value of cilta-cel and physician's choice treatments within the CARTITUDE-4 trial from a US combined commercial and Medicare payer perspective using a novel cost per responder (CPR) model that incorporates efficacy and total treatment costs. Methods: A CPR analysis was conducted from a mixed payer perspective (67.7% commercial, 23.3% Medicare), comparing the direct medical cost per patient receiving cilta-cel versus physician's choice (87% DPd and 13% PVd, per distribution in the trial) over 25.4 months, the maximum observed period for the physician's choice arm in the CARTITUDE-4 trial. The model was developed using progression-free survival (PFS), overall survival (OS), time to next treatment, CR, stringent CR (sCR), and ORR endpoints from the CARTITUDE-4 trial to inform health status. A standard parametric approach was taken to extrapolate the PFS and OS beyond the trial period for each arm for analysis scenarios with longer follow-up. Resource use and costs associated with the administration process for each treatment were included: apheresis, bridging therapy, pre-conditioning treatment, infusion, drug acquisition, other medications (infection prophylaxis, antihistamine, and antipyretic), and monitoring (eg, labs, vital sign assessment, hematologist visit) for CAR-T; drug acquisition, administration, other medications, and monitoring for physician's choice. The base case assumed CAR-T infusion was entirely administered in the inpatient setting, and an additional scenario was included that considered the outpatient infusion setting (70% inpatient and 30% outpatient). Costs of managing grade 3 to 4 AEs and grade 1 to 4 AEs for cytokine release syndrome (CRS) and neurotoxicity were included. Costs of subsequent therapies were assigned following disease progression, and costs of terminal care were also considered upon death events. Model outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS compared between cilta-cel and physician's choice of therapy. All costs were adjusted to 2023 US dollars based on the consumer price index for medical care. Results: The total cost (PFS and post-progression survival [PPS] combined) per treated patient was estimated as $693,009 for cilta-cel and $1,028,444 for physician's choice over 25.4 months. Total estimated costs per treated patient were lower for cilta-cel than physician's choice during PFS and PPS separately ($581,108 vs $765,169 and $111,901 vs $263,275, respectively). Treatment acquisition and subsequent treatment costs are key drivers of the total costs during PFS and PPS, respectively ($451,318 and $103,101 for cilta-cel; $726,356 and $249,005 for physician's choice). Total cost per complete responder was estimated to be lower for cilta-cel compared with physician's choice ($948,029 vs $4,717,634) (Figure). Total estimated cost per month in PFS was $30,814 for cilta-cel versus $58,113 for physician's choice (Figure). Scenario analysis with a lower percentage of patients receiving CAR-T infusion in inpatient settings led to lower cost per complete responder and lower cost per month in PFS for cilta-cel (70% inpatient and 30% outpatient, $940,431 and $30,520, respectively). Conclusions: Overall, cilta-cel offers substantial clinical and economic benefit for patients with RRMM. The CPR analysis of data from CARTITUDE-4 estimated that, for patients with RRMM, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower compared to physician's choice (DPd or PVd). Treatment acquisition and subsequent treatment costs appear to be key drivers for total direct medical costs.

Multicenter Open Label Phase 2 Study of Quadruplet-Based Regimen Iskpd (isatuximab plus pomalidomide and dexamethasone with carfilzomib) in Early Relapsed or Refractory Multiple Myeloma - IFM2018-03

Background. RRMM (relapsed or refractory multiple myeloma) is associated to shortened OS (survival) with subsequent relapses and needs optimized treatment approaches. The current treatment paradigm is based on triplet-based association of antiCD38 immunotherapy (antiCD38 IT) with either Imids (Pomalidomide) and dexamethasone or proteasome inhibitors (PI) such as Carfilzomib and dexamethasone. However, quadruplet-based regimens (antiCD38 immunotherapy +Imids +PI +dexamethasone) have transformed the treatment landscape in the upfront setting, improving MRD (minimal residual disease) and survival. We hypothesized that a quadruplet-based regimens (antiCD38 immunotherapy +Imids +PI +dexamethasone) would further improved MRD and survival in early RRMM. We describe a phase II multicentric, open-label study, of isatuximab, pomalidomide and dexamethasone plus carfilzomib (IsKPd/ IFM2018-03, NCT04287855) for patients with early RRMM. Study design and Methods. Approximately 90 patients will receive the association of isatuximab, pomalidomide and dexamethasone with carfilzomib (IsKPd), and the study has fully enrolled 82 patients as of January 2023. Eligible patients are adults aged ≥18 years old with RRMM previously treated with 1 or 2 lines of therapy, including lenalidomide, prior to the study entry. Patients were excluded if they were refractory to any anti-CD38 monoclonal antibody or to carfilzomib, or if they were previously exposed to pomalidomide. Isatuximab will be given by IV route at 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, on days 1 and 15 from cycle 2 to 12 and on day 1 only from cycle 13, 28-day cycles. Carfilzomib will be given by IV route at 20/27 mg/m² on days 1-2, 8-9, 15-16 during cycle 1, at 56mg/m² on days 1, 8, 15 from cycle 2 to 13 and at 56mg/m² on days 1 and 15 after cycle 13. Pomalidomide will be administered by oral route at 3 mg daily on days 1 to 21 in cycle 1 and at 4 mg daily from cycle 12. Dexamethasone will be given by oral route at 40/20 mg daily on days 1, 8, 15 and 22. The primary objective is to evaluate the MRD rate at 10-5 in patients with RRMM treated with IsKPd. Patients will pursue Isa-KPd until progression or unacceptable toxicity. Key secondary objectives include the survival analysis (OS, PFS, EFS, TTNT), response rates and duration of response and evaluation of the safety profile. The study is expected to read out in January 2024 with sustained MRD reported.

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

Introduction: Several BCMA CAR T-cell products have been approved for relapsed or refractory multiple myeloma (RRMM), but long-term response has not been established. There is growing interest in the use of next-generation CAR T-cell therapy in RRMM. CBG002 is an armored BCMA CAR T-cell product engineered to constitutively express CD27, which binds CD70 to promote T-cell proliferation and differentiation. In vitro, CBG-002 cells exhibited enhanced proliferation, greater cytotoxicity and a higher proportion of memory T cells compared to control BCMA-CAR T cells; in animal models, CBG-002 infusion also resulted in improved tumor control and prolonged survival in MM xenograft mice. Based on the preclinical data, we conducted a phase I clinical trial to evaluate its safety and efficacy in patients with RRMM. Methods: This is a single-arm, open-label, phase I study (NCT04706936). Key eligibility criteria were RRMM patients who had received at least 3 prior regimens, including a proteasome inhibitor and an immunomodulatory drug; the percentage of BCMA expression ≥50% on myeloma cells, detected by either flow cytometry and immunohistochemistry. Patients received 3 days of fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) followed by a single dose of CBG-002 infusion. The dose-escalation study follows a “3+3” design with 1×10 6/kg, 2×10 6/kg and 3×10 6/kg CAR-T cell cohorts. The primary endpoint was safety, including grade 3 or 4 treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs); The secondary endpoints were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of June 25, 2023, 12 patients were enrolled and 1 patient was later excluded due to &amp;lt;50% BCMA expression. Among the evaluable 11 patients, there were 9 males and 2 females; median age was 52 years (range 36-66), 5/11 (45.5%) patients had high-risk cytogenetics including complex karyotype, t(4;14),1q21 amplification and del(17p), 4 (36.4%) had extramedullary disease (EMD). The median number of prior treatments was 5 (range 3-7); 7/11 pts were triple-agent exposed and refractory; 5/11 underwent ASCT. The most common TEAEs were neutropenia (G3/4 63.6%), thrombocytopenia (G3/4 36.4%) and anemia (G3/4 45.5%). Nine patients developed G1/2 CRS, which resolved spontaneously except for 2 patients who required steroids and tocilizumab, and no patients developed G3/4 CRS or ICANS. The median time to onset of CRS was 7 days (range 5-21) and the median duration was 6 days (range 5-8). At a median follow-up of 9 months, the ORR was 81.8%, including sCR/CR of 63.6%, VGPR 9.1% and PR 9.1%. After infusion, 8 pts were MRD negative in bone marrow by flow cytometry at day 28, 5 pts continued at month 3. The median OS was 14 months and the OS rate was 100%. The median PFS was 9 months and the PFS rate was 60%. The CBG-002 kinetics paralleled peripheral blood sCD27 levels with a median time to peak of 15 days (range 7-14). The fold increase in sCD27 levels was significantly higher in responders (12.1, range 1.2-83.8) than in non-responders (1.68, range 0.81-9.45). Conclusions: In this phase I study, CBG-002, a CD27-armored BCMA-CAR T therapy has demonstrated remarkable safety and clinical activity in RRMM patients.

Elranatamab Exposure-Efficacy Analysis in Patients with Relapsed or Refractory Multiple Myeloma: Insights from Pooled Magnetismm Studies

BACKGROUND Elranatamab (ELRA) is a heterodimeric humanized full-length bispecific antibody comprised of one B-cell Maturation Antigen (BCMA) binding arm and one cluster of differentiation 3 (CD3) binding arm paired through hinge mutation technology. Results from the MagnetisMM-3 (NCT04649359) study indicated deep and durable responses in patients with relapsed or refractory multiple myeloma (RRMM). The current analysis was conducted a) to characterize the relationship between free (ie, unbound) and total (ie, unbound and bound to soluble BCMA - sBCMA) ELRA exposure and objective response rate (ORR), b) to evaluate the effect of potential covariates in the ELRA exposure-response (E-R) relationship with ORR, and c) to characterize the relationship between ELRA exposure and duration of response (DOR). METHODS Data from ELRA monotherapy from the MagnetisMM-1 (first-in-human Ph1, NCT03269136), MagnetisMM-2 (Japan Ph1, NCT04798586), MagnetisMM-3 (Ph2 with pivotal Cohort A in BCMA-naïve patients and Cohort B with BCMA-exposed patients), and MagnetisMM-9 (Ph1/2, NCT05014412) studies were pooled for analyses. The dataset included a wide dose range from 0.1 µg/kg IV to 1000 µg/kg / 76 mg SC weekly (QW) dosing. Free and total exposure metrics (C ave,Day28, ie, average ELRA concentration on Day 28) and (C ave,Event, ie, average ELRA concentration up to the time of first response or progression/end of treatment) were obtained using the individual post-hoc pharmacokinetic (PK) parameters from the population PK model 1. The E-R relationship for the efficacy endpoint ORR by Investigator and the effects of various baseline demographic and disease risk factors (eg, age, sex, baseline sBCMA level, cytogenetics, extramedullary disease [EMD], and number of prior lines of therapy) were characterized using binomial logistic regression method. A Cox proportional hazard model was used to quantify the effects of C ave,Day28 and C ave,Event and the reduction of the dosing intensity from QW to once every two weeks (Q2W) on DOR. The relationship between tertiles and DOR was also explored using Kaplan-Meier (KM) analysis. The analyses were performed with R software. RESULTS A significant E-R relationship was identified between both total and free ELRA C ave,Day28 and C ave,Event and ORR. Higher ELRA exposure was associated with higher ORR. For the total ELRA PK analysis, lower baseline sBCMA level was associated with higher ORR. For both total and free ELRA E-R relationships, number of prior lines of therapy ≤ 5 and absence of baseline EMD were associated with higher ORR. None of the other covariates were significant predictors of ORR. The models developed using either C ave,Day28 or C ave,Event identified same set of significant covariates. Figure 1 shows the results of free ELRA C ave,Day28 E-R analysis. The Cox proportional hazard analysis and KM plots of DOR by tertiles of exposure revealed no significant association between ELRA exposure, Q2W switch, and DOR. CONCLUSION The efficacy endpoint ORR demonstrated E-R relationships with total and free ELRA exposures. Patients with higher ELRA exposure, lower number of prior lines of therapy, , were more likely to achieve objective responses. Lower sBCMA was also a significant predictor of ORR in the total PK analysis. The findings supported the 76 mg QW ELRA, which is the highest tested dose in the MagnetisMM-1 study. This regimen is projected to provide meaningful clinical benefit in the majority of RRMM patients, including those with relatively high baseline sBCMA levels. The identified covariates are known prognostic factors for RRMM, yet the ORR achieved in these subgroups is clinically meaningful. There was no significant association between total or free ELRA exposures, Q2W switch and DOR, which further supports the maintenance of responses with Q2W switch for the RRMM population.

Tolerability, Incidence of Second Primary Skin Malignancies and Diarrhea in Patients with Relapsed Refractory Multiple Myeloma Treated with Isatuximab: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Multiple myeloma, which accounts for 1% of all cancers, is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Isatuximab is a human, CD38-targeting, IgG1 monoclonal antibody with direct antitumor effects, and an immunomodulatory component, resulting in apoptosis of myeloma cells. Over the recent years, it has shown that the addition of isatuximab to proteasome inhibitors and immunomodulatory drugs has improved outcomes in patients with relapsed or refractory multiple myeloma (RRMM). However, there are considerable safety concerns. The purpose of our study is to determine the risks of second primary skin malignancy, diarrhea, treatment emergent serious adverse events (SAE) and treatment discontinuation due to treatment emergent adverse events (TEAE) in patients with RRMM treated with isatuximab. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma that mention second primary skin malignancy, diarrhea, treatment emergent serious adverse events and treatment discontinuation were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results A total of 600 patients with RRMM from 2 phase III RCTs (ICARIA-MM and IKEMA were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. Second primary skin malignancy was reported in 16 of patients (4.9%) treated with isatuximab based combination treatment compared to 7 (2.6%) but RR was not statistically significant at 1.79 (95% CI: 0.74 - 4.31; P = 0.19). More events of any-grade diarrhea were noted in study arm (36.2%) compared to 26.9% in control arm with RR of 1.31 (95% CI: 1.03 - 1.67; P=0.03) but RR for high-grade diarrhea was not statistically significant at 1.26 (95% CI: 0.42 - 3.82; P = 0.68). TD due to TEAE was noted in 40 patients (12.2%) in study group vs 43 (15.9%) in control group with RR of 0.76 (95% CI: 0.51 -1.13; P = 0.17). Treatment emergent SAEs were reported in 71.4% vs 60.1 % in control group (RR, 1.19; 95% CI: 1.06-1.34; P = 0.004). Conclusions Our meta-analysis showed that there was no significant difference in the treatment discontinuation due to adverse events in patients with RRMM treated with isatuximab combination regimen, compared to control arm although rate of treatment emergent SAEs and any-grade diarrhea were slightly higher in the isatuximab-treated arm than the control arm. Furthermore, differences in the risks of second primary skin malignancy and high-grade diarrhea were found to be statistically not significant between study and control arms. Further studies and longer follow up are required to determine the actual relationship of second primary skin malignancies. In addition, close observation and supportive care is essential to improve treatment-emergent SAEs.

Clinician and Administrator Perspectives on Chimeric Antigen Receptor (CAR) T-Cell Therapy Outpatient Administration in Relapsed or Refractory Multiple Myeloma (RRMM) in the United States (US): A Qualitative Study

Background: The use of CAR-T cell therapy has transformed treatment paradigms in B-cell malignancies. Ciltacabtagene autoleucel (cilta-cel) was approved for use in RRMM after four or more prior lines of therapy in 2022. While the pivotal studies exclusively treated patients in an inpatient setting, robust infrastructure planning at some centers across US has fostered outpatient administration of the commercially available product. Outpatient administration of CAR-T is more desirable due to superior financial sustainability, lower healthcare resource utilization, and greater patient autonomy during the treatment. Hence, we conducted a qualitative study to evaluate clinical and administrative perspectives and trends in outpatient administration of commercialized cilta-cel with an aim to understand best practices from certified CAR-T centers in the USA. Methods: A targeted literature review was conducted to better understand current practices around outpatient administration of CAR-T, and inform the development of primary research materials for designing subsequent interviews. Next, two 60-minute exploratory interviews were conducted with multi-stakeholder participants (n=5) from two certified cilta-cel centers, each with significant volume of outpatient administration of cilta-cel. Following the qualitative analysis of interviews, two 90-minute panels were conducted with multi-stakeholder participants (n=14) from six certified cilta-cel centers, including centers from exploratory interviews, focusing on clinical and administrative topics across the patient journey. Results: Each center in the study treated approximately 15-30 patients with cilta-cel in the outpatient setting. Using Likert scales, participants from all centers ranked space/capacity as the most important factor in decision-making process for outpatient cilta-cel administration, and ranked reimbursement incentives as a highly (67% of participants) or a moderately (33%) important factor. All participants agreed that having a dedicated outpatient infrastructure (dedicated space such as bed availability and internal processes including standard operating procedures (SOPs)), 24/7 support, outpatient bone marrow transplant (BMT) or cell therapy experience, and robust multidisciplinary teams were key to setting-up successful outpatient centers for cilta-cel therapy. The participants agreed that cilta-cel can be administered safely in an outpatient setting due to generally predictable, delayed onset of potential AEs, except in patients with significant comorbidities or organ dysfunction. Participants also considered caregiver support and lodging availability as factors of importance for outpatient administration. Institutionally established AE monitoring protocols are critical for safe use of cilta-cel in an outpatient setting. Over 50% of the centers interviewed have recently started to administer tocilizumab to treat mild grade 1 cytokine release syndrome (CRS) in an outpatient setting. Based on the findings across the phases of research, the patient journey for outpatient administration of cilta-cel was updated (Figure 1). While patients may be admitted for toxicity events, 100% of centers interviewed had 24-hour coverage and bed availability for these patients if needed. Conclusions: Overall, this study further supports the notion that centers can safely administer cilta-cel in an outpatient setting, if appropriate infrastructure is in place. Additional best practices for new outpatient sites include adequate infrastructure, SOPs, a well-trained and multidisciplinary team, and education of patients and caregivers (Table 1). Outpatient management and earlier intervention for low-grade AEs is currently evolving, with more real-world research required. Continued expert sharing of best practices can aid centers in implementing outpatient administration of CAR-T therapies. Funding: This analysis was supported by Janssen Research &amp; Development, LLC and Legend Biotech USA, Inc