Multiple myeloma is a malignant disease characterised by the clonal proliferation of plasma cells. Since the last update of the Swiss recommendations for the diagnosis and treatment of multiple myeloma in 2019, the therapeutic landscape has evolved significantly, with the development of new monoclonal antibodies, novel combination therapies, and the introduction of T-cell-redirecting treatments such as bispecific antibodies and CAR T-cell therapy. This article summarises the current diagnostic procedures and therapeutic recommendations in Switzerland.

Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel (n = 162) versus cilta-cel (n = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel (p < 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; p < 0.001), with complete response at Day 30 of 48% versus 26% (p < 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel (p < 0.001 and p = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3-4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; p < 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel (p = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM.

Background: Patient management following a multidisciplinary tumor board (MTB) recommendation has become standard of care in oncology and aims to ensure optimization and personalization of patient care. To assess the impact of MTB recommendations in clinical practice, adherence to the recommended procedures needs to be evaluated. Within this retrospective case series, we examined adherence rates to recommendations formulated at multidisciplinary myeloma tumor boards (MMTB) held at our institution. Specifically, we analyzed how often recommendations involving diagnostic procedures, therapies, and enrollment into clinical trials recommended by the MMTB were implemented. In addition, factors leading to non-adherence were evaluated. Methods: We reviewed all consecutive patient cases discussed at MMTBs held at the University Hospital of Bern, Switzerland, between 1 January and 31 December 2023. Adherence was assessed by systematically comparing all available clinical records with the recommendations formulated at the MMTBs. Results: In total, 218 patients were included in the study. Of all MMTB recommendations, 86% (n = 251) of all MMTB recommendations were followed. Of these, 84% (n = 244) were followed with complete adherence and 2% (n = 7) incompletely. All cases of non-implementation of MMTB recommendations concerning diagnostics or therapy were clinically justified. The main reason for non-adherence was patient decision. Other reasons included lack of cost coverage and relevant changes in the clinical scenario, including patient’s death. In total, 36% (n = 104) of MMTB recommendations included clinical trial enrollment. However, study enrollment occurred only in 32% (n = 33) of the 104 cases. In 41% (n = 29) of the cases, justification for non-enrollment was documented in the clinical records. The most frequent reasons were patient decision, unmet inclusion criteria, delays in recruitment, lack of reimbursement, and changes in the clinical scenario. Conclusions: Our study showed an overall high level of adherence to MMTB recommendations for diagnostic procedures and therapy. However, only one third of recommendations for clinical trial enrollment were implemented, frequently due to patient decisions. Our results highlight the relevance of regular assessments of adherence rates to MTB recommendations and suggest that considering patient preferences in MTB discussions might minimize deviations.

Relapsed/refractory multiple myeloma (RRMM) patients with dialysis-dependent renal impairment face limited therapeutic options due to exclusion from clinical trials, a lack of evidence-based guidelines, and inferior outcomes. Bispecific antibodies targeting B-cell maturation antigen (BCMA) have shown promise in RRMM treatment but remain understudied in this vulnerable population. To illustrate this issue, we introduce the case of a 68-year-old female with triple-class RRMM and end-stage renal disease requiring hemodialysis, treated with elranatamab as a second line treatment following progression after therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone. Despite experiencing grade I cytokine release syndrome during the initial administrations, symptoms were managed effectively with tocilizumab and dexamethasone, allowing treatment continuation. The patient achieved a very good partial remission within 7 weeks. Although hemodialysis dependence persisted, the therapy was well-tolerated with manageable adverse events. According to the literature, BCMA-directed immunotherapies, including teclistamab, belantamab mafodotin, and idecabtagene vicleucel, have shown efficacy in dialysis-dependent RRMM patients, though data remain limited. Pharmacokinetic analyses indicate that mild or moderate renal impairment does not have a significant impact on the pharmacokinetics of elranatamab. Although no retrospective studies or case series have investigated the use of elranatamab in dialysis-dependent patients, a single case report suggests that its administration is both feasible and well-tolerated in this population despite the absence of comprehensive pharmacokinetic data. This review highlights feasibility, safety, and encouraging efficacy of elranatamab in managing RRMM in a dialysis-dependent patient, representing the second case report in the literature. By providing real-world evidence for the use of bispecific antibodies in end stage renal disease patients, this review emphasizes the potential for expanding therapeutic options to this vulnerable population while highlighting the need for vigilant monitoring of infection prevention and management. Prospective studies are warranted to validate these findings and optimize therapeutic strategies for patients with RRMM and severe renal impairment.

Background: BCMA-directed CAR-T therapies and bispecific antibodies (BsAbs) have transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM), yet the optimal sequencing of these therapies remains unclear. Limited access to CAR-T – especially across Europe – and the lack of direct comparative data hinder clinical decision-making. To address this, we conducted a large, real-world, multicenter European study using propensity-weighted analysis to compare the efficacy, safety, and accessibility of CAR-T versus BsAb therapy in RRMM. Methods: We retrospectively analyzed 640 patients with RRMM treated with either a BCMA-directed CAR-T product (n=399; including idecabtagene vicleucel [ide-cel], ciltacabtagene autoleucel [cilta-cel], and academic CAR-T construct [ARI]) or a BsAb (n=241; including teclistamab, talquetamab, and elranatamab). Among BsAb-treated patients, 200 had no access to CAR-T due to regulatory, logistical, or economic barriers. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences in key prognostic covariates: extramedullary disease (EMD), high-risk cytogenetics, International Staging System (ISS), ECOG performance status, penta-refractoriness, and age. The co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS), assessed by Kaplan-Meier analysis and IPTW-adjusted Cox proportional hazards regression. Safety endpoints were immune effector cell associated neurotoxicity (ICANS), cytokine release syndrome (CRS), and non-relapse mortality (NRM). Results: Patients treated with BsAb were generally older (median age 66 vs. 64 years) and exhibited a higher burden of adverse clinical features compared to those receiving CAR-T therapy. Specifically, high-risk cytogenetics (74% vs. 55%), extramedullary disease (EMD, 32% vs. 25%), and ECOG performance status ≥2 (35% vs. 17%) were more prevalent in the BsAb cohort. The ORR was significantly higher among CAR-T recipients (p<0.001), with complete response rates reaching 58% in the CAR-T group versus 15% in BsAb-treated patients. Among CAR-T products, cilta-cel achieved the highest complete response rate (69%), followed by academic CAR-T (ARI, 60%) and ide-cel (48%). In contrast, BsAbs showed markedly lower CR rates: elranatamab (22%), teclistamab (17%), and talquetamab (9%). At a median follow-up of 12 months, PFS consistently favored CAR-T over BsAb treatment. Unadjusted 12-month PFS was 66% in the CAR-T group compared to 47% for BsAbs. This benefit was maintained across subgroups stratified by EMD status: among EMD-negative patients, 12-month PFS was 70% (CAR-T) vs. 54% (BsAb), and for EMD-positive patients, 52% vs. 32%, respectively. Product-level analysis highlighted cilta-cel with the highest PFS at 86%, followed by ARI (69%) and ide-cel (52%). Among BsAbs, teclistamab and elranatamab showed comparable PFS rates of 44% and 46%. In IPTW-adjusted Cox regression, BsAb therapy remained significantly associated with shorter PFS (HR 1.54; 95% CI: 1.13-2.10; p=0.006). EMD (HR 2.03; 95% CI: 1.43-2.87; p<0.001) and ECOG ≥2 (HR range: 2.08-2.66; p<0.02) were identified as strong independent predictors of inferior PFS, while age and high-risk cytogenetics showed attenuated effects after adjustment. Safety profiles differed notably between modalities. BsAbs were generally better tolerated, with lower incidences of CRS and ICANS compared to cilta-cel and ide-cel. ARI showed similarly low toxicity to BsAbs. However, NRM varied significantly across agents (p=0.005): NRM was 5% for ide-cel, 6% for both cilta-cel and ARI, but higher in BsAb recipients – 12% for teclistamab, 11% for talquetamab, and notably 20% for elranatamab Conclusion: This is the first large-scale, real-world comparative analysis of BCMA-targeted CAR-T versus BsAb therapies in RRMM across European countries, adjusted for both access disparities and baseline prognostic factors. Cilta-cel and ARI demonstrated superior PFS compared to BsAbs, while ide-cel performed comparably to BsAb therapies. In settings where access to commercial CAR-Ts is limited or absent, academic CAR-T approaches must match the efficacy of cilta-cel to offer a meaningful advantage over readily available off-the-shelf BsAbs. These data underscore the importance of both innovation and equitable access in determining treatment sequencing strategies in RRMM.

Background Both idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) showed substantial progress in the treatment of triple-class exposed relapsed or refractory multiple myeloma (RRMM). Crude comparisons of prospective trials indicated potential differences in efficacy and safety. However, direct comparative data are lacking. This European comparative study endeavors to bridge this gap, to elucidate relative risks and identify different cellular dynamics of cilta-cel versus ide-cel. Methods This is the first international European study on the comparative efficacy and safety cilta-cel versus ide-cel in RRMM. We included only patients infused after 3 or more lines of therapy according to current approval. CAR-T expansion and persistence was measured at day 7, 14, 30, 90, and last follow-up by PCR or FACS, as per center's practice. Co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS). Secondary endpoints were complete response rate, overall survival (OS), incidence of cytokine release syndrome (CRS) or immune effector cell associated neurotoxicity syndrome (ICANS), and non-relapse mortality. Results The total cohort included 162 with ide-cel and 42 with cilta-cel. Median age at time of CAR-T infusion was 61 years (range, 28 to 82 years) for ide-cel versus 61 years (range, 24 to 84 years) for cilta-cel (P=0.32). Median time between diagnosis and CAR-T infusion was 7.5 years for ide-cel versus 6.8 years for cilta-cel (P=0.53), and median turnaround time between apheresis and CAR-T infusion was 47 days for ide-cel versus 68 days for cilta-cel (P<0.001). Median number of prior lines of therapy was 6 for both groups and 15% in the ide-cel group versus 11% in the cilta-cel group had prior exposure to BCMA-directed therapy. Most patient characteristics were well balanced between both groups. Cilta-cel showed deep and significantly higher ORR of 93% versus 79% for ide-cel (P<0.001). Early response appeared to be deeper for cilta-cel, showing complete response at day 30 after CAR-T infusion of 48% in the cilta-cel group versus 26% in the ide-cel group (P<0.001). After a median follow-up of 9.5 months in the cilta-cel group versus 13.4 months in the ide-cel group (P<0.001), the 10-month PFS was 40% in the ide-cel group versus 75% in the cilta-cel group (P<0.001). The 10-month OS was 86% in the cilta-cel group versus 77% in the ide-cel group (P=0.11). Cilta-cel was independently associated with improved PFS and OS after multivariable adjustment. The incidence of CRS was similar between both treatment groups (P=0.51), with 81% in the cilta-cel group versus 84% in the ide-cel group showing CRS of any grade after CAR-T infusion. Half of the patients in both groups had grade 1 CRS, while 9% in the cilta-cel groups versus 4% in the ide-cel group showed CRS grade 3-4. Onset of CRS appeared to be significantly earlier in the ide-cel group (median, 2 days) versus cilta-cel group (median, 4 days; P<0.001). The incidence of ICANS was similar, with ICANS of any grade occurring in 19%, respectively. However, severe ICANS grade 3-4 was seen in 7% of the cilta-cel group versus 2% of the ide-cel group. Non-relapse mortality was similar (P=0.52), being 6% in the cilta-cel group versus 5% in the ide-cel group. All 7 deaths without relapse/progression were due to infection in both groups. Furthermore, we evaluated possible differences in resource utilization. The median length of the hospital stay was 14 days in the ide-cel group versus 17 days in the cilta-cel group (P=0.002). Use of tocilizumab was similar, while use of corticosteroids appeared to be more likely in the cilta-cel group (P=0.04), being used in 35% versus 26% in the ide-cel group. Last, we evaluated CAR-T dynamics, finding that ide-cel was associated with significantly earlier expansion (P<0.001), peaking at day 7 after infusion. In contrast, cilta-cel expansion peaked at day 14 with significantly increased AUC (P<0.001). CAR-T expansion showed stronger association with ORR and PFS for cilta-cel versus ide-cel (P<0.001). Findings were established with PCR and validated in centers with FACS. Conclusion Our study provides real-world evidence that cilta-cel was associated with superior outcomes versus ide-cel in triple-class exposed RRMM. Despite similar non-relapse mortality in both groups, different toxicity profiles of cilta-cel must be taken into account in clinical practice.

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

In fit patients with newly diagnosed myeloma, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is considered standard of care. For mobilization of CD34+ cells for ASCT, combined cytotoxic chemotherapy and G-CSF is commonly used. However, the importance of cytostatic chemotherapy for reliable mobilization remains unclear. This prospective randomized phase II non-inferiority trial compared G-GSF only (G) compared to standard chemotherapy/G-CSF (CG) for CD34+ mobilization. The primary endpoint was a less than 15% difference in successful stem cell collection ( ≥ 5.0 × 106 CD34+ cells/kg b.w. in a single day collection procedure without additional stimulation with plerixafor) with the G regimen. 136 patients were 1:1 randomized. With an 18% difference in favor of the CG therapy, the non-inferiority margin was not maintained (95% CI 1%, 34%, p = 0.04). The median total CD34+ yield was 9.99 × 106/kg b.w. in CG patients and 7.42 × 106/kg b.w. in patients with G-CSF alone (p < 0.001). Ultimately, 130 (96%) patients proceeded to HDCT with ASCT. There were no differences in adverse events, hematologic engraftment, quality of life, or pain perception between the groups. Our data indicate that G-CSF only is inferior to chemotherapy with G-CSF for peripheral CD34+ stem cell mobilization. Trial registration SNCTP #: SNCTP000002952; Trials.gov #: NCT03442673.

Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of PPM1D gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating PPM1D gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the PPM1D-mutated (PPM1Dmut) subset with median progression-free survival (PFS) of 15 vs. 37 months (p = 0.0002) and median overall survival (OS) of 36 vs. 156 months (p = 0.001) for the PPM1Dmut and PPM1Dwt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.

Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, n = 110; D-RVd, n = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, p = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, p = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 106/L, p = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 106/kg BW, p = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, p = 0.0164; and 16 vs. 14 days, p = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, p = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; p = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT.

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations. Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure. Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure. Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes.

Further line treatment of patients with advanced stage AL amyloidosis with cardiac involvement is challenging. Venetoclax is a promising option, especially in t(11;14) and BCL2 expression. In our multicentre observational study, we report the 3-year follow-up of Venetoclax treatment in 9 patients with advanced, relapsed or refractory AL amyloidosis with t(11;14) and BCL-2 expression in > 50

Cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are significant complications in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy. However, it remains unclear whether CAR-T cell expression itself is clinically relevant. We assessed CAR-T cell mRNA expression and DNA concentration by digital droplet PCR in peripheral blood from 14 sequential CAR-T cell recipients. Patients were grouped according to CAR-T cell peak expression. Patients with high CAR-T cell peak expression (8 patients; 57%) had higher rates of ICANS (p=0.0308) and intensive care unit admission (p=0.0404), longer durations of hospitalization (p=0.0077), and, although not statistically significant, a higher rate of CRS (p=0.0778). There was a correlation of CAR-T cell mRNA expression with DNA concentration, but CAR-T cell expression levels failed to correlate to response or survival. Our data suggest that higher CAR-T cell peak mRNA expression is associated with increased risk for ICANS and possibly CRS, requiring further investigation in larger studies.

Introduction Therapy of relapsed and refractory multiple myeloma (MM) with Ide-Cel is superior to alternative treatments, but availability is lower than the number of patients in need. Treatment slots are distributed by the manufacturer per country. Their allocation to individual patients is a medical, logistical and ethical challenge. Ideally, such allocation should be inclusive, fair, transparent, effective, and base on prospectively confirmed objective outcome criteria. Methods Swiss Blood Stem Cell Transplantation and Cellular Therapy (SBST) has established the national SBST-CAR-T MM board for allocation of Ide-Cel treatment slots. Allocation process and triage criteria were developed by clinical experts in exchange with the ethical board of the Swiss academy for medical sciences and health insurers, approved by all JACIE-accredited national centers for cellular therapies, and agreed that Ide-Cel therapy in Switzerland is only available through this allocation system. Patients are registered in parallel with request for insurance coverage in one key document. Patients had to meet qualifying approval criteria for Ide-Cel in Switzerland (relapsed and refractory MM, >2 prior therapy lines, triple-class-exposed). Reaching CR after Ide-Cel is associated with superior PFS. We therefore developed an algorithm to select patients with high likelihood for CR. Patient factors negatively associated with CR derived from the KarMMa trial were complemented by factors prospectively associated with inferior overall survival after CAR-T in malignant lymphoma. High tumor burden (bone marrow infiltration > 50% or high tumor load by PET-CT), inflammatory activity (increasede ferritin or D-dimers), ECOG patient status and comorbidities were used as negative predictive factors and combined to a sum score of 0-4. All registered patients are presented at the monthly virtual meeting and ranked according to this score. Ranking is refined based on availability of alternative treatment options, resulting in a final national ranking agreed by all board members. Because no patients with severe comorbidities were registered, this dimension was later excluded. Results Between May 2022 and April 2023 all 48 Ide-Cel regular treatment slots in Switzerland were allocated in 12 virtual meetings lasting median 55 minutes (25-70) with the participation of median 7 centers (6-8), 8 physicians (6-15), discussing in total 72 patients (median 5.5 per meeting, range 4-10) to distribute 4 slots monthly. All therapy slots were successfully allocated, including short-notice changes in availability of slots or patients requiring immediate allocation of substituting patients. 74.2% of all patients registered with the SBST CART MM board received Ide-Cel. Patient, treatment and outcome parameters were centrally collected to SBST database from 37 treated patients per April 2023. (1 patient each had cell collection failure, Ide-Cel production failure, missing outcome data). Patients were 65% triple refractory, 65 % penta refractory, 14% received prior BCMA-targeted therapy, 8% prior bispecifc antibodies and 67% had high risk cytogenetics. Best response achieved so far was CR or better in 57% of patients, PR-VGPR 16%, PD 13%, not stated/too early 13%. A low SBST-MM CAR-T Score was prospectively associated with CR (table 1, p=0.048). Each scoring dimension (ECOG, tumor load, inflammation) significantly correlated inversely with CR, while conventional characteristics for poor MM outcomes (HR CG, penta refractory disease) did not correlate. PFS and OS data is pending. Cross cohort comparison with the Real-World Experience from the US Myeloma CAR-T Consortium (Hansen et al., JCO 2023) revealed a strong trend towards higher CR rates (57% vs. 23%, p=0.10). Conclusion This algorithm prospectively selects MM patients for BCMA-CAR-T treatment to maximize CR rate. Also, this national real world cohort demonstrates the feasibility of triaging the allocation of CAR-T therapy slots based on a, fair, objective, transparent, consensual algorithm using predefined criteria. The SBST scoring system prospectively reflects differential likelyhood of CR (100>64>53>33%), and the scoring dimensions (ECOG, tumor load, inflammation) prospectively correlate with a CR rate of 57 %, supporting the selection process. The SBST CAR-T scoring system may be used to allocate CAR-T treatment slots to maximize benefit from this treatment.

(1) Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM) and for a subset of patients with relapsed/refractory disease. For stem cell mobilization, G-CSF alone or in combination with chemotherapy mobilizing agents and/or plerixafor are commonly used. Ixazomib is an oral proteasome inhibitor with less neurotoxic potential, which previously showed the ability to mobilize stem cells in preclinical studies. (2) Methods: Prospective single-center phase 1 study assessing the efficacy and safety of stem cell mobilization with ixazomib and G-CSF in patients with newly diagnosed or relapsed/refractory MM undergoing HDCT and ASCT. Primary endpoint was percentage of patients achieving a yield of at least 6.0 × 106/kg CD34+ cells within the first apheresis. G-CSF (filgrastim) 10 μg/kg/day was administered subcutaneously (s.c.) from day 1 to day 5 (planned apheresis) and ixazomib 4 mg orally at day 4. Plerixafor 24 mg s.c. was administered if the stem cell mobilization with ixazomib and G-CSF was not sufficient. (3) Results: 19 patients were treated within the study between 06/2020 and 02/2021. The primary endpoint was reached in 17 (89%) patients, with a median of 7.1 × 106/kg CD34+ cells collected within the first apheresis, comparable to previously published results, and only 2 (11%) patients required a second apheresis. Median number of circulating CD34+ cells was 14.0 × 106/L (2.0-95.2) before the administration of ixazomib, and 33.0 × 106/L (4.2-177.0) pre-apheresis. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. (4) Conclusions: The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity in patients with MM prior to HDCT and ASCT. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM.

BACKGROUND: Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine. METHODS: Plasma levels of soluble BCMA (sBCMA) and anti-BCMA CAR-T cell copy numbers were monitored in the blood, following CAR-T cell infusion in patients with relapsed multiple myeloma. sBCMA peptide concentration was determined in the plasma, applying a human BCMA/TNFRS17 ELISA. ddPCR was performed using probes targeting the intracellular signaling domains 4-1BB und CD3zeta of the anti-BCMA CAR-T construct. RESULTS: We report responses in the first five patients who received anti-BCMA CAR- T cell therapy at our center. Four patients achieved a complete remission (CR) in the bone marrow one month after CAR-T infusion, with three patients achieving stringent CR, determined by flow cytometry techniques. Anti-BCMA CAR-T cells were detectable in the peripheral blood for up to 300 days, with copy numbers peaking 7 to 14 days post-infusion. sBCMA plasma levels started declining one to ten days post infusion, reaching minimal levels 30 to 60 days post infusion, before rebounding to normal levels. CONCLUSIONS: Our data confirm a favorable response to treatment in four of the first five patients receiving anti-BCMA CAR-T at our hospital. Anti-BCMA CAR-T cell expansion seems to peak in the peripheral blood in a similar pattern compared to the CAR-T cell products already approved for lymphoma treatment. sBCMA plasma level may be a valid biomarker in assessing response to BCMA-targeting therapies in myeloma patients.

Definite cure remains exceptional in myeloma patients even after high-dose chemotherapy (HDCT) with melphalan (Mel) and autologous stem cell transplantation (ASCT). Thus, improving efficacy of HDCT in MM remains an unresolved issue. This randomized phase II trial compared standard 200 mg/m 2 Mel HDCT to experimental HDCT with 200 mg/m 2 bendamustine, given both at days −4 and −3, combined with 100 mg/m 2 melphalan at days −2 and −1 (BenMel) before ASCT as first-line consolidation in myeloma patients. The primary endpoint aimed to identify at least a 15% improvement in the complete remission rate (stringent CR + CR) after HDCT with BenMel compared with Mel alone. A total of 120 MM patients were 1:1 randomized. The rate of sCR/CR after ASCT was higher in BenMel than in Mel treated patients (70.0% vs. 51.7%; p = 0.039). Three patients in the BenMel group (5.0%) had reversible acute renal insufficiency compared with none in Mel patients. Minimal residual disease negativity (<10-5) by flow cytometry was observed in 26 (45.6%) BenMel patients and 22 (37.9%) in the Mel group ( p = 0.375). Our data suggest that BenMel HDCT is safe and improves the sCR/CR rate compared with standard Mel alone.