High WEE1 expression is independently linked to poor survival in multiple myeloma.

Current prognostic scores in multiple myeloma (MM) currently rely on disease burden and a limited set of genomic alterations. Some studies have suggested gene expression panels may predict clinical outcomes, but none are presently utilized in clinical practice. We therefore analyzed the MMRF CoMMpass dataset (N=659) and identified a high-risk group (top tertile) and a low-risk group ( bottom tertile) based on WEE1 expression sorted in descending order. The tyrosine kinase WEE1 is a critical cell cycle regulator during the S-phase and G2M-checkpoint. Abnormal WEE1 expression has been implicated in multiple cancers including breast, ovarian, and gastric cancers, but has not until this time been implicated in MM. PFS was significantly different (p <1e-9) between the groups, which was validated in two independent microarray gene expression profiling (GEP) datasets from the Total Therapy 2 (N=341) and 3 (N=214) trials. Our results show WEE1 expression is prognostic independent of known biomarkers, differentiates outcomes associated with known markers, is upregulated independently of its interacting neighbors, and is associated with dysregulated P53 pathways. This suggests that WEE1 expression levels may have clinical utility in prognosticating outcomes in newly diagnosed MM and may support the application of WEE1 inhibitors to MM preclinical models. Determining the causes of abnormal WEE1 expression may uncover novel therapeutic pathways.

Evaluating serum free light chain ratio as a biomarker in multiple myeloma.

Not available.

Addition of Elotuzumab to Backbone Treatment Regimens for Multiple Myeloma: An Updated Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: The efficacy of elotuzumab, an anti-SLAMF7 monoclonal antibody, in treating relapsed/refractory multiple myeloma (RRMM) and newly-diagnosed multiple myeloma (NDMM) has varied in randomized controlled trials (RCTs). Moreover, there is limited data on its real-world application. PATIENTS AND METHODS: We conducted a systematic review and meta-analysis of RCTs investigating the addition of elotuzumab to backbone antimyeloma regimens. The primary outcome of interest was progression-free survival (PFS). Secondary efficacy outcomes included overall survival (OS), overall response rate (ORR), and rates of very good partial response or better (VGPR). Key toxicities were also evaluated. RESULTS: Three RRMM trials (n = 915) and 5 NDMM trials (n = 1790) were included, with 50% of the 2705 patients receiving elotuzumab-containing triplets or quadruplets. In RRMM settings, elotuzumab use significantly improved PFS (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.60-0.82; P < .001; I² = 0%). This benefit was consistent among patients with high-risk cytogenetics (HR, 0.62; 95% CI, 0.43-0.90; P = .01; I² = 0%) and was particularly evident in those previously treated with proteasome inhibitors (PIs) or immunomodulatory drugs (IMiDs). The RRMM cohort also demonstrated better OS, ORR, and ≥VGPR rate. However, the NDMM cohort showed no significant improvements in any efficacy outcomes. Despite an increase in severe (grade ≥3) infections, elotuzumab use did not adversely affect rates of severe cytopenias, severe cardiac disorders, or second primary malignancies. CONCLUSION: Our results suggest that elotuzumab-containing regimens represent valuable therapeutic options for PI/IMiD-exposed patients with RRMM. In contrast, elotuzumab's role in frontline settings remains limited.

A plain language summary of the final analysis of the GRIFFIN study of daratumumab plus lenalidomide, bortezomib, and dexamethasone for people with newly diagnosed multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the final analysis of the GRIFFIN study. In this study, participants were newly diagnosed with a type of blood and bone marrow cancer called multiple myeloma, had never received any treatment, and were able to undergo an autologous stem cell transplant. The GRIFFIN study looked at adding the drug daratumumab (D) to a combination of standard treatments called RVd (lenalidomide [R], bortezomib [V], and dexamethasone [d]) during the treatment phases induction and consolidation, followed by daratumumab and lenalidomide (D-R) maintenance. Participants also received an autologous stem cell transplant to further help reduce multiple myeloma. The GRIFFIN study looked at whether D-RVd followed by D-R maintenance was better at killing multiple myeloma cells compared with RVd on its own followed by R maintenance on its own, and if treatments were safe. This summary also describes results from 2 other GRIFFIN publications: one that looked at participants with certain multiple myeloma characteristics or demographic factors that are associated with worse outcomes, and another that looked at how treatments impacted the participants' quality of life. WHAT WERE THE RESULTS?: At the time of the final analysis of GRIFFIN, participants who were treated with D-RVd followed by D-R maintenance had very low (undetectable) levels of multiple myeloma cells and multiple myeloma markers (biological signs) and were more likely to be alive without the multiple myeloma getting worse or coming back compared with participants who received standard RVd treatment followed by R maintenance. There was also a pattern of similar benefits achieved by participants who were at risk for worse outcomes. Additionally, participants who received D-RVd treatment followed by D-R maintenance reported less pain, less fatigue (extreme tiredness), and greater improvements in their ability to conduct daily physical activities. While some side effects (unwanted or unexpected effects of treatment) were higher with D-RVd, side effects in both groups were as expected, and adding daratumumab did not reduce a participant's ability to handle treatment. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results of the GRIFFIN study showed that D-RVd treatment followed by D-R maintenance was better at treating multiple myeloma than the standard treatment of RVd followed by R maintenance in adults with a new diagnosis of multiple myeloma who were able to receive an autologous stem cell transplant, with no unexpected side effects of treatment.Clinical Trial Registration: NCT02874742 (GRIFFIN) (ClinicalTrials.gov).

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

Dexamethasone dose intensity does not impact outcomes in newly diagnosed multiple myeloma: a secondary SWOG analysis.

Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM) despite common toxicities including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 milligrams (mg) once weekly was associated with lower mortality than higher doses of dexamethasone. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM have not been fully characterized. We conducted a secondary pooled analysis of the S0777 and S1211 SWOG studies of NDMM, which employed lenalidomide-dexamethasone (Rd) alone with or without bortezomib (VRd) and with or without elotuzumab (Elo-VRd). Planned dexamethasone intensity was 40-60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for Grade 3+ toxicities per both study protocols). Of 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There was no difference in PFS or OS between the FD-DEX or LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in multivariate models were treatment arm, age ≥70, and thrombocytopenia; FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given dexamethasone's many toxicities and unclear benefit in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective study. NCT00644228, NCT01668719.

Cost-per-responder analysis of patients with lenalidomide-refractory multiple myeloma receiving ciltacabtagene autoleucel in CARTITUDE-4.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies.

Teclistamab is a B­cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma. In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or CAR-T cell therapy) were enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated RRMM and prior anti-BCMA treatment. NCT03145181; NCT04557098.

Artificial intelligence enabled interpretation of ECG images to predict hematopoietic cell transplantation toxicity.

ABSTRACT: Artificial intelligence (AI)-enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo] HCT recipients). The median follow-up was 2.9 years. The 3-year cumulative incidence of AF was 9% (95% confidence interval [CI], 7-12) in patients who underwent auto HCT and 13% (10%-16%) in patients who underwent allo HCT. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; P < .001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and greater risk of nonrelapse mortality (NRM; HR, 95% CI, 3.36; 1.39-8.13; P = .007), without increased risk of relapse. Association with mortality was only noted in allo HCT recipients, where the risk of NRM was greater. The use of cyclophosphamide after transplantation resulted in greater 90-day incidence of AF (13% vs 5%; P = .01) compared to calcineurin inhibitor-based graft-versus-host disease prophylaxis, corresponding to temporal changes in AI-ECG AF prediction after HCT. In summary, AI-ECG can inform risk of posttransplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment.

Alliance A061202: ixazomib, pomalidomide, and dexamethasone for patients with lenalidomide-refractory MM in first relapse.

ABSTRACT: Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma in their first relapse remains poorly defined. We therefore undertook a randomized phase 2 study to evaluate the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) in this patient population. The overall response rate (ORR) for POM-DEX was 43.6%, and for IXA-POM-DEX, it was 63.2%. The depth of response, measured by the attainment of at least a very good partial response, favored triplet therapy over doublet therapy (28.9% vs 5.1%; P = .0063). A preplanned interim analysis after 75% of the progression events had occurred demonstrated an improvement in progression-free survival (PFS) that favored IXA-POM-DEX and that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI], 4.8-13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI, 7.7-26.0 months; hazard ratio, 0.437; upper 90% bound = 0.657). The ORR and median PFS for 26 of 30 eligible patients who crossed over from the doublet to the triplet therapy at disease progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the 2 groups. More hematologic toxicities were seen with the triplet therapy, but nonhematologic adverse events were similar between the 2 arms. Our data support further testing of this all-oral triplet therapy in comparison with current standard triplet therapy in the context of phase 3 studies for patients with LEN-refractory disease at first relapse. This trial was registered at www.clinicaltrials.gov as #NCT02004275.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease-negativity (10-5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06-1.48]), with HRCAs (0.38 [0.14-1.01]), and with gain/amp(1q21) (0.42 [0.14-1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35-1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM. Video Abstract.

Colesevelam for Lenalidomide Associated Diarrhea in Patients with Multiple Myeloma.

Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is generally well tolerated; however, lenalidomide associated diarrhea is a common side effect and bile acid malabsorption has been suggested as an underlying mechanism. We conducted a single arm phase 2 trial of colesevelam, a bile acid binder, for lenalidomide-associated diarrhea in multiple myeloma. Patients were treated with colesevelam daily starting at 1250 mg (2 tablets 625 mg) for 12 weeks. The trial included 25 patients, 1 patient with grade 3 diarrhea, 14 with grade 2, and 10 with grade 1 diarrhea. All patients were on treatment with single agent lenalidomide maintenance and no patient progressed during the trial. Colesevelam treatment was highly effective for treatment of lenalidomide-associated diarrhea; 22 (88%) of the 25 patients responded where 17 patients (68%) had complete resolution of diarrhea, and 5 patients (20%) had improvement by 1 grade of diarrhea. The responses to colesevelam were seen within the first two weeks of treatment. These findings support the conclusion that lenalidomide-associated diarrhea is driven by bile acid malabsorption. Five patients reported mild gastrointestinal side effects including constipation. Importantly, the pharmacokinetics of lenalidomide were not affected by concomitant colesevelam treatment. The stool microbiome composition was not significantly different before and after colesevelam treatment. Patients reported improved diarrhea, fewer gastrointestinal symptoms, and less interference with their daily life after starting colesevelam. In summary, colesevelam was safe and highly effective for treatment of lenalidomide-associated diarrhea in multiple myeloma and does not reduce the clinical effect of lenalidomide.

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee.

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

ABSTRACT: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.