Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.

BACKGROUND:A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone. METHODS:This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting. FINDINGS:Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression. INTERPRETATION:Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need. FUNDING:Bristol Myers Squibb.

Multiple myeloma (MM) remains an incurable cancer and is characterized by a remitting-relapsing pattern. The choice of next line of therapy depends on patient-, disease-, and treatment-related factors. The Canadian Myeloma Research Group database (CMRG-DB) hosts information in ≥10 000 individuals with plasma cell disorders across major Canadian institutions. In this retrospective study, we evaluated therapy choices and outcomes of patients with MM undergoing third-line (3L) therapy using the CMRG-DB platform. All patients with relapsed MM in the CMRG-DB who started 3L therapy between January 2015 and December 2020 were potentially eligible. A total of 1125 patients were included. The most common 3L therapies included immunomodulatory agents (702 [62.4%]), proteasome inhibitors (PIs; 491 [43.6%]), and anti-CD38 monoclonal antibodies (CD38 mAb; 277 [24.6%]). Combinations of daratumumab plus lenalidomide with or without corticosteroid produced the best responses, with a median progression-free survival (mPFS) of 25.6 months (95% confidence interval [CI], 20-35.7). An anti-CD38 mAb plus pomalidomide with or without steroid and other PI-based regimens had a much shorter mPFS, between 6 and 9 months. Adverse prognosticators were high-risk fluorescence in situ hybridization, shorter time from myeloma diagnosis to 3L, triple-class exposure, previous PI exposure, and refractoriness to lenalidomide. The median overall survival was 29.7 months (95% CI, 26.4-32.8). Our findings highlight the role of anti-CD38 mAb combined with lenalidomide for improvement of 3L outcomes. The results of combinations selected for 3L therapy by Canadian hematologists provide information on resource use and benchmark outcomes, which, in turn, will be useful for multiple stakeholders in the rapidly evolving myeloma therapeutic landscape.

BACKGROUND:Severe renal insufficiency requiring dialysis in newly diagnosed multiple myeloma (NDMM) patients has been independently associated with poor survival outcomes. However, there is a paucity of data on factors predicting renal recovery and survival outcomes of these patients. METHODS:We retrospectively analyzed outcomes in NDMM patients presenting with severe dialysis-requiring RI from 01/2010 to 12/2022. RESULTS:Seventy patients were identified; all receiving novel agent-based induction (bortezomib-based 96%; lenalidomide-based 3%)-73% (n = 51) underwent ASCT. Thirty-three (48%) patients became dialysis independent; early achievement of VGPR in < 4.4 months from treatment initiation was identified as the only factor predicting renal recovery and dialysis withdrawal on univariate analysis (Hazard ratio [HR] of 4.172; p-value = 0.0014). At median follow-up of 39 months, the median overall survival (OS) of dialysis-requiring NDMM patients was 98.3 months with 2- and 5-year OS rates of 84% and 67%, respectively; 2- and 5-year progression-free survival (PFS) rates were 66.9% and 43.7%, respectively. On multivariable analysis, low LDH at diagnosis (HR: 1.003, p = 0.0092), undergoing ASCT (HR: 0.213; p-value = 0.0016), and dialysis independence (HR: 0.311; p-value = 0.0112) independently predicted improved OS. CONCLUSIONS:Early VGPR and hemodialysis independence translated to improved survival, providing a benchmark for future comparison as anti-CD38 monoclonal antibodies enter first line therapy.

Plasma cell dyscrasias (PCD) are a group of hematological disorders associated with immune dysfunction from underlying disease and/or treatment. With continued circulation of SARS-CoV-2, optimizing and maintaining durable protection in this vulnerable population through vaccination remains important. A prospective cohort study was conducted between August 2021 and January 2023 across 12 sites in Canada to evaluate humoral immunity to COVID-19 vaccination in participants with hematological malignancies. Participants were monitored longitudinally, and finger-prick dried blood spot (DBS) cards were obtained at specific intervals based on vaccination. Serum antibodies against SARS-CoV-2 proteins after the 3rd, 4th and 5th dose were measured by high-throughput ELISA. Differences in anti-spike seropositivity by vaccine dose number and clinical risk factors were analyzed by logistic regression. A total of 262 unique participants with 983 samples were included for analysis, among which 66% were diagnosed with PCD. Analysis of the predicted probability of immunity showed consistently higher proportions of PCD participants with vaccine (anti-S) immunity compared to those with infection-derived (anti-N) immunity throughout the study. While vaccine responses appeared to wane 6 months after dose 3 and, to a lesser extent, dose 4, subsequent doses cumulatively increased anti-S immunity. Seropositivity decreased with anti-CD38 therapy and older age, although receipt of additional vaccine doses significantly improved anti-S immunity. Overall, this study demonstrated that the third and subsequent COVID-19 vaccine doses could safely improve humoral immunity in PCD participants. While anti-CD38 therapy and age reduced seropositivity, antibody responses could still be enhanced with vaccine doses beyond the primary three-dose series.

Teclistamab is the first approved B-cell maturation antigen×CD3 bispecific antibody with weight-based dosing for triple-class-exposed relapsed/refractory multiple myeloma (RRMM). We evaluated the safety and efficacy of teclistamab combined with the anti-CD38 monoclonal antibody daratumumab in the phase 1b TRIMM-2 study. Eligible patients had RRMM (≥3 prior lines of therapy [LOT] or were double-refractory to a proteasome inhibitor and immunomodulatory drug); prior anti-CD38 exposure was permitted. Patients received subcutaneous daratumumab per approved schedule plus weight-based or fixed-dose subcutaneous teclistamab. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and duration of response (DOR). Progression-free survival (PFS) was an exploratory endpoint. Sixty-one patients received the weight-based recommended phase 2 doses (RP2D; teclistamab 1.5 mg/kg QW or 3.0 mg/kg Q2W); median number of prior LOTs was 5 (range, 1-14). Median follow-up was 12.0-months. The most common treatment-emergent adverse events (TEAEs) were infections, cytokine release syndrome, neutropenia, and anemia; grade 3/4 TEAEs occurred in 93.4% and 7 died from TEAEs. No dose-limiting toxicities occurred. ORR was 68.9% (complete response or better, 44.3%); median DOR was not reached. Median PFS was 26.3 months. A cohort exploring fixed-dose teclistamab (100-300 mg) ended prematurely after a safety signal for fatal infections was identified; out of an abundance of caution, all patients were switched to weight-based dosing. In conclusion, the fully immune-based combination of weight-based RP2D teclistamab plus daratumumab demonstrated deep and durable responses, with a well-characterized safety profile. Results highlight the importance of infection management, including early immunoglobulin replacement. Registered at ClinicalTrials.gov: NCT04108195.

Hypersensitivity reactions (HSRs) can be a significant barrier to a patient's cancer treatment journey. HSRs caused by immunomodulating agents, specifically lenalidomide (LEN) can be overwhelmingly distressful, paradoxically depriving patients of access to a clinically meaningful drug. Based on our historical clinical experiences, we have learned that the rapid desensitization protocol (RDP), when executed precisely, can enable patients to successfully resume LEN treatment. This served as the impetus for initiating our prospective study. We consecutively enrolled 10 patients diagnosed with plasma cell disease who had experienced a previous HSR specifically with LEN. After fully recovering from their initial reactions, patients underwent a controlled 10-12 steps incremental increase in drug dosage administration, followed by daily resumption of LEN over a 90-day period. All 10 (100%) patients successfully completed the protocol and continued on further LEN treatment cycles, although 1 patient voluntarily chose to withdraw from the study due to recurrent symptoms after receiving 2 doses of LEN. Three (30%) patients remained symptom-free throughout the follow-up period. Six (60%) patients experienced mild and short-lived HSR reactivation; however, all had the ability to take LEN for the majority of the study period. RDP enables patients to continue taking LEN and maintains the health-related quality of life (HR-QoL) by reducing the occurrence of HSR. RDP empowers patients to participate in future clinical trialsinvolving novel treatments that contain LEN as a backbone therapy, opportunities they would have otherwise been ineligible for.

BACKGROUND:Salvage autologous stem cell transplantation (ASCT2) remains a treatment option for selected patients with relapsed multiple myeloma (MM). In this multicenter study, we conducted a retrospective analysis using the Canadian Myeloma Research Group (CMRG) database to evaluate real-world outcomes of ASCT2 in the maintenance era. PATIENTS AND METHODS:Three hundred and fifty-two patients underwent ASCT2 following progression after ASCT1 between 2012 and 2021. Progression-free survival (PFS), overall survival (OS), depth of response, and the impact of maintenance therapy after ASCT2 were assessed, with further stratification based on maintenance use after ASCT1. RESULTS:Our analysis demonstrated that post-ASCT2 maintenance therapy was associated with improved outcomes, particularly in patients who had also received maintenance after ASCT1 (25.2 months (95% CI, 20.8-39.6) versus 11.6 months (95% CI, 8.51-18.8)). In patients receiving lenalidomide maintenance after ASCT1, a remission lasting less than 3 years represented a high risk group with poor outcomes with an ASCT2. CONCLUSION:While novel agents continue to expand treatment options, ASCT2 remains a viable therapeutic strategy in appropriately selected patients, especially those with durable responses to prior therapy.

Background We have previously reported that current frailty tools have limited ability to predict treatment-related toxicity in transplant-eligible (TE) patients with multiple myeloma (MM) (Devasia, ASH 2022). Although clonal hematopoiesis of indeterminate potential (CHIP) mutations has been associated with more frailty and treatment-related toxicities in patients with newly diagnosed MM (Gelli, Scientific Reports 2024), their clinical relevance specifically in TE patients has yet to be elucidated. Therefore, we aimed to evaluate whether the presence of CHIP mutations predicts frailty and toxicity in patients preparing for autologous stem cell transplant (ASCT). Method We have two ongoing prospective trials in TE-MM patients at our centre. The “Frailty” study evaluates the utility of various frailty assessments prior to ASCT in predicting transplant-related toxicity and outcomes (Shih, IMS 2025). The ARCH-001 study evaluates the prevalence and evolution of CHIP mutations at different time points relevant to their ASCT (Khan, ASH 2024). Patients enrolled in both studies were selected for this correlative analysis. The presence of CHIP mutations prior to ASCT (ARCH-001) served as the predictor variable. The following variables extracted from Frailty study served as the outcome variables: 1) subjective measures of function (Rockwood Frailty, Karnofsky Performance [KPS], ECOG), 2) objective measures of fitness [hand grip strength, 6-min walk test, Timed Up and Go, 3) comorbidity indices (Charlson and HCT-CI), 4) organ function (eGFR, serum albumin, BNP, PFT, ECHO), 5) Post-ASCT acute grade ≥3 organ toxicities and mortality to Day 100, ICU use, time to engraftment, transfusion requirements and length of stay (LOS). Chi2or Fisher's exact test was used as appropriate for categorical variables. T-test was used for continuous variables. All P values were 2 sided and statistically significant at P < 0.05. Statistical analysis was performed using STATA version 19. Results We identified 101 participants who were enrolled in both studies and had evaluable data. Of these, 38 (37.6%) had at least one CHIP mutation and 5 (5.0%) had two CHIP mutations. DNMT3A, ASXL1 and TET2 mutations were most common, with 30 (29.7%) patients having at least one of these. Pre-ASCT There was a greater proportion of patients with CHIP mutation in those age ≥65 than those age <65 (76.3% vs 23.7% respectively, P=0.025), but no difference in other demographics (sex, BMI), or pre-transplant parameters (first vs salvage transplant, melphalan dose or stem cell dose). The presence of CHIP mutations was not associated with increased all-grade anemia, leukopenia or thrombocytopenia prior to ASCT (P = 0.443, P = 0.204 and P = 0.259, respectively), or any of the frailty parameters (data will be presented). Post-ASCT There was no correlation between the presence of CHIP mutations and any of the acute grade ≥3 transplant-related toxicities. There were only 2 ICU admissions and 0 deaths by day+100. There was a trend towards more cardiac-related adverse events in patients with CHIP mutations compared to those without (21.1% vs 9.5% respectively), but this was not statistically significant (P = 0.057). There was also a trend towards more cumulative toxicity (defined as ≥2 toxicity events) in those with CHIP mutations compared to those without (50.0% vs.31.8% respectively), but this was not statistically significant either (P = 0.068). The mean number of days to neutrophil and platelet engraftment in all patients was 12.6 and 17.6, respectively. The presence of CHIP mutations was not associated with prolonging these (P = 0.395 and P = 0.202, respectively). The mean number of bags of red cells and platelets required for transfusion during ASCT in all patients was 0.5 (0-8) and 1.0 (0-9), respectively. The presence of CHIP mutations did not increase these either (P = 0.109 and P = 0.230). The mean LOS in those with vs without CHIP mutations was 22.1 and 17.9 days, respectively, but the difference was not statistically significant (P = 0.197). Conclusion The presence of CHIP mutations in TE-MM patients was not associated with increased frailty, acute grade ≥3 transplant-related toxicity or any short-term transplant-related outcomes. However, this was a highly selected population that tends to be younger and fitter. Continued follow-up is required to evaluate whether these CHIP mutations affect longer-term treatment-related efficacy, toxicity or survival outcomes in TE-MM patients.

BACKGROUND:In a phase 1-2 trial, teclistamab, a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells, showed durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38 protein, has shown survival benefit in patients with multiple myeloma. METHODS:In this phase 3 trial, we randomly assigned patients with one to three previous lines of therapy to receive combination therapy with teclistamab-daratumumab or daratumumab combined with dexamethasone plus the investigator's choice of pomalidomide (DPd) or bortezomib (DVd) - the DPd or DVd group. The primary end point was progression-free survival, as assessed by an independent review committee. RESULTS:A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd). At a median of 34.5 months, progression-free survival was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month progression-free survival was 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a complete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Serious adverse events occurred in 70.7% of the patients in the teclistamab-daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively. CONCLUSIONS:In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab-daratumumab group had significantly longer progression-free survival than those in the DPd or DVd group. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT05083169.).

Introduction Regimens based on bortezomib and lenalidomide have been a mainstay of treatment for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM) patients (pts). Recently, the phase 3 MAIA trial established DRd as the new standard of care (SoC), with a median progression-free survival (PFS) of 61.9 months compared to 34.4 months with Rd and a significant benefit in overall survival (OS). In Canada, DRd was funded via the public healthcare system for first-line NDMM TI patients in 2022. The aim of this retrospective study was to evaluate the initial real-world outcomes of this regimen in the context of treatments used prior to the introduction of anti-CD38 antibodies in frontline therapy. Methods We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), a prospectively maintained disease-specific database with >10,000 pts enrolled in 21 centres across Canada. All NDMM TI pts >18 years treated with CyBorD, Rd, RVd, or DRd as first-line treatment between 01/01/2018 – 30/11/2024 were included. Pts were excluded if they were treated on a clinical trial, did not receive any treatment within 1 year of diagnosis, underwent stem cell transplant ≤1 year of diagnosis, or had amyloidosis, POEMS, or plasma cell leukemia. The primary objective of the study was to determine the following outcomes observed with these first-line regimens: early mortality rate (at 6 months and 1 year), overall response rate (ORR), best response, PFS, and OS. Secondary objectives included assessing the pattern of usage of these different regimens between 01/2018 -11/2024, and identification of variables affecting 1-year early mortality, ORR, and PFS by regimen. Descriptive analysis was used to report demographics, disease characteristics and treatment responses by regimen. Baseline characteristics were summarized by mean, standard deviation, median and ranges as appropriate. Time to event analyses were used to assess PFS and OS. Survival curves were constructed according to the Kaplan-Meier method and impact of covariates of interest were assessed using the log rank test. Results A total of 1,085 pts were eligible. Regimens included: CyBorD in 382 (35.2%), Rd in 292 (26.9%), RVd in 178 (16.4%) and DRd in 233 (21.5%). The median follow-up in months (95% CI) in these 4 cohorts was 41.0 (35.2, 44.7), 50.2 (45.4, 54.5), 29.7 (24.4, 34.4) and 9.3 (7.6, 11.3), respectively. The 6-month and 1-year mortality rates were 6.5% (95% CI 4.3-9.5) and 11.8% (95% CI 8.6-15.4) for CyBorD, 7.9% (95% CI 5.1-11.6) and 14.7% (95% CI 10.9-19.3) for Rd, 4.5% (95% CI 2.0-8.7) and 7.9% (95% CI 4.4-12.8) for RVd and 4.3% (95% CI 2.1-7.8) and 5.6% (95% CI 3.0-9.4) for DRd. The ORR/≥VGPR by regimen included: 95.9%/72.3% with RVd, 94.5%/71.9% with DRd, 89.2%/58.9% with CyBorD and 79.1%/45.3% with Rd. Median PFS was 41.4 months in RVd pts, 28.6 months in Rd pts and 20.2 months in CyBorD pts; an accurate median PFS was not yet available in DRd pts due to short follow-up. However, CyBorD pts had a statistically significant shorter median PFS, while there was no difference between the other regimens to date. Median OS was not yet reached for DRd, 62.2 months for RVd, 60 months for CyBorD, and 55.5 months for Rd (p=0.061). Of the 1,085 pts, 432 (39.8%) have received a 2nd line of therapy. The use of DRd in Canada significantly increased from 1.1% in 2020 to 30.3% in 2022, and was the most common regimen in 2023 (77.5%) and 2024 (78.4%). Conclusion In this real-world retrospective study, we demonstrate that, after public funding, DRd rapidly became the most frequently utilized first-line treatment in Canadian patients with TI NDMM. Early mortality rates at 6 months and 1 year were very low with DRd. Response rates with DRd and RVd were the highest and each produced an ORR of approximately 95% and ≥VGPR of 72%. CyBorD patients had a significantly shorter PFS. However, an accurate evaluation of DRd's PFS efficacy is premature due to its recent introduction into the Canadian treatment algorithm and short follow-up period (9.3 months vs 29+ months in other cohorts). More mature results of DRd, in addition to analyses of potential variables correlated with outcomes, will be assessed in the future. Nevertheless, our findings suggest that both RVd and DRd are highly effective options for treatment of TI NDMM.Financial support: CMRG received financial support from Janssen Inc. for the conduct of this study.

Introduction:Chromosome 1q copy gains (with-1q-gain) is a frequently observed genetic abnormality in multiple myeloma (MM) patients. Recent research has demonstrated that 1q gain is a prognostic factor, linked to poorer clinical outcomes. Methods:This study was conducted at the Princess Margaret Cancer Centre to examine the clinical outcomes of newly diagnosed MM patients' with-1q-gain or without-1q-gain abnormality. The study included 275 patients, with 161 (58.5%) with-1q-gain abnormality. The median follow-up time for the cohort was 94.3 months (95% CI 30.1-38.6). Results:The patients' with-1q-gain when compared to without-1q-gain were more likely to have other high-risk cytogenetic abnormalities (34.8% vs. 14.0%, p < 0.001) and more advanced disease according to the International Staging System (ISS III, p < 0.014). Furthermore, a relatively higher proportion of with-1q-gain patients received tandem autologous stem cell transplant (ASCT) as frontline therapy (36.2% vs. 8.7%, p ≤ 0.001).To assess the impact of 1q copy number, patients with 3 copies of 1q (1q-gain3) were compared to those with ≥4 copies (1q-Amp). No significant differences were observed between the two groups. Conclusion:In conclusion, our study provides insight into the clinical significance of 1q gain abnormality in MM patients at a single center, and highlights its association with adverse prognostic features and treatment outcomes.