Ailawadhi, Sikander

Abstract Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.

Abstract When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time-to-event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the “true” trial-like and “mis-measured” real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. Quantitative bias analyses allow researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, cumulative incidence curve correction and survival regression calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with newly diagnosed multiple myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapies are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Idecabtagene vicleucel (ide-cel) is a B-cell maturation antigen-targeted CAR T-cell therapy approved for patients with RRMM with ≥2 prior lines of therapy. Developing a better understanding of the relationship between patient age and CAR T-cell therapy outcomes may help guide treatment and clinical practice. This analysis of data from the KarMMa-3 trial (NCT03651128) describes efficacy and safety outcomes in older and younger patients who received either ide-cel or standard therapy regimens. Methods: KarMMa-3 is an open-label, phase 3 trial that includes adults with RRMM who have received 2-4 prior treatment regimens with disease refractory to the last therapy. Enrolled patients were randomized (2:1) to receive either a one-time infusion of ide-cel or 1 of 5 standard regimens. This subgroup analysis evaluated the efficacy and safety of ide-cel compared with standard regimens in KarMMa-3 patients by age group (≥70 vs <70 yrs). Outcome measures assessed include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), patient-reported quality of life (QoL), and incidence of selected adverse events. Results: A total of 386 patients were evaluated; 19.3% (49/254) of those receiving ide-cel and 20.5% (27/132) of those receiving standard regimens were aged ≥70 yrs. Compared with older patients, younger patients receiving ide-cel exhibited more high-risk baseline characteristics, including high-risk cytogenic abnormalities (44.4% vs 32.7%) and triple-class refractory disease (66.8% vs 55.1%). The median time to progression during the most recent prior anti-myeloma treatment was longer for patients aged ≥70 yrs who received ide-cel vs standard regimens (8.6 mo vs 6.7 mo) but was similar for patients aged <70 yrs (6.5 mo vs 6.9 mo). ORR for patients aged <70 yrs was 68.8% (95% CI: 62.4, 75.1) with ide-cel and 41.0% (95% CI: 31.5, 50.4) with standard regimens (P<0.0001). Patients aged ≥70 yrs treated with ide-cel achieved an ORR of 81.6% (95% CI: 70.8, 92.5) vs 48.1% (95% CI: 29.3, 67.0) with standard regimens (P<0.01). Median PFS for patients aged <70 yrs was longer with ide-cel treatment vs standard regimens (12.5 mo [95% CI: 11.2, 15.4] vs 4.2 mo [95% CI: 3.5, 5.7]; P<0.0001). Similar trends were seen in patients aged ≥70 yrs, where median PFS was 18.9 mo (95% CI: 12.1, 24.5) with ide-cel treatment and 5.7 mo (95% CI: 2.2, 12.2) with standard regimens (P<0.01). Median OS was not reached in older patients in either treatment arm; in younger patients, median OS was 39.5 mo (95% CI: 27.8, NR) with ide-cel and 27.9 mo (95% CI: 20.6, NR) with standard regimens. Incidence of adverse events reported with ide-cel treatment was generally similar between age groups for cytokine release syndrome, neurotoxicity, and infections. Analyses of patient-reported QoL data and other relevant safety endpointsare ongoing and will be included in the presentation. Conclusions: In the KarMMa-3 trial, patients aged ≥70 years derived substantial benefit from ide-cel treatment, demonstrated by longer PFS and a notable ORR compared with standard regimens. While efficacy and safety outcomes of ide-cel treatment in older patients were consistent with younger patients, it is important to note that patients in the trial aged ≥70 yrs were more likely to have favorable baseline characteristics and less aggressive and heavily pretreated disease. This may reflect a selection bias towards enrolling older patients considered to be easier to treat. In contrast, real-world data from late-line settings suggest that older patients are undergoing treatment based on less restrictive selection criteria—eg, including those with higher-risk baseline features—reflecting a more representative and broader population. These observations reinforce the potential for durable benefit with a single ide-cel infusion in a real-world context without additional adverse safety signals, supporting its use across age groups.

Abstract Introduction: DRd is the standard of care for frontline (FL) treatment (tx) of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). This is supported by its superior efficacy and tolerable safety profile vs lenalidomide and dexamethasone (Rd) and vs bortezomib plus Rd (VRd) per the phase 3 MAIA clinical trial and real-world data. However, based on recent phase 3 CEPHEUS and IMROZ trial data, the tx paradigm is shifting toward the use of quadruplets for suitable TIE patients with NDMM. CEPHEUS demonstrated the superior efficacy of DVRd vs VRd in TIE and transplant-deferred patients with NDMM. DVRd-treated patients achieved significantly higher rates of minimal residual disease negativity and significantly improved progression-free survival vs VRd-treated patients. DVRd is listed as a National Comprehensive Cancer Network (NCCN) Category 1 preferred regimen in this setting and is therefore used in US real-world clinical practice. The objective of this study was to evaluate real-world usage patterns of FL DVRd and FL DRd in nontransplanted patients with NDMM and to assess the characteristics of patients treated with these regimens. Methods:Data from the Flatiron Health Research database were used for this retrospective observational study. Patients were included in this analysis if they received FL tx with DVRd or DRd for NDMM between Jan 1, 2019, and Dec 31, 2024. The index date was defined as the initiation date of FL DVRd or FL DRd. As the Flatiron database does not capture transplant eligibility status, the analysis excluded all patients who underwent hematopoietic stem cell transplantation at any time during the study period. Patients were also excluded if they were <18 years of age, enrolled in a clinical trial, had presence of other cancers, received chimeric antigen receptor T-cell therapy, or were diagnosed with amyloid light-chain amyloidosis before the index date. High cytogenetic risk was defined as the presence of abnormalities including del(17p), t(4;14), or t(14;16). Descriptive statistics were used to report demographic and clinical characteristics. Kaplan-Meier methods were used to estimate duration of therapy. Results: Among the nontransplanted NDMM cohort, 704 FL DVRd-treated patients and 396 FL DRd-treated patients were identified. At index, FL DVRd patients were generally younger than FL DRd patients (median age, 68 vs 78 years, respectively), more likely to be male (55.3% vs 49.5%), and less likely to have Medicare coverage (8.4% vs 17.2%). The 2 cohorts had similar proportions of Black/African American patients (18.9% and 18.7%). Among patients with available data, high cytogenetic risk was more frequently observed in FL DVRd (29.2%) vs FL DRd (17.5%) patients; a lower proportion of FL DVRd patients had International Staging System (ISS) stage III disease (27.1%) than ISS stage I disease (39.9%), whereas a higher proportion of FL DRd patients had ISS stage III disease (32.9%) than ISS stage I disease (25.5%). FL DVRd patients were more likely to be nonfrail (Intergroupe Francophone du Myélome simplified frailty score <2) vs FL DRd patients (64.6% vs 28.2%). Use of both DVRd and DRd increased during the study period; however, the increase was greater for DVRd, particularly in the later years. Notably, FL DVRd was started in 10 patients in 2019, increasing to 146 in 2022 and 222 in 2024. By comparison, FL DRd was initiated in 17 patients in 2019, increasing to 85 in 2022 and 97 in 2024. Median follow-up was 15.6 mo in the DVRd cohort and 20.3 mo in the DRd cohort. Median duration of DVRd therapy was 18.5 mo (95% CI, 14.8–22.7) and was 23.5 mo (95% CI, 19.0–31.7) for DRd therapy. Bortezomib as part of the DVRd regimen was given once weekly or less frequently in the majority (65.6%) of patients. Conclusions: These real-world data show the increasing FL use of the daratumumab-based quadruplet regimen DVRd among nontransplanted patients with NDMM. FL DVRd patients were generally younger and less frail but more likely to have high cytogenetic risk than those treated with DRd. These data also show that daratumumab-based regimens, either as a triplet (DRd) or a quadruplet (DVRd), are increasingly adopted over time in real-world clinical practice. These data further suggest that DRd and DVRd may be considered foundational for the tx of nontransplanted patients with NDMM regardless of patient characteristics, including age, frailty, cytogenetic risk, and ISS stage.

Abstract Background: MM is the second most common hematologic malignancy, which despite significant therapeutic advancements, remains incurable. The complexity of MM and its intricate management creates substantial informational demands for patients navigating their care. Methods: A cross-sectional survey study (Mayo Clinic IRB # 25-004671) was conducted to assess MM patients’ awareness about disease basics. A voluntary English language survey (47 questions) encompassing multiple domains of patient MM awareness was administered (REDCap) via the patient EMR portal (Mayo Clinic) and MM support groups nationally. Responses were analyzed using descriptive and inferential statistics (R; Bluesky Statistics, V 10.3.4). Multiple model logistic regression was used for multivariate analysis using age (≤70 or >70 yrs), gender, education (high school or less vs bachelor's and above), income (≤$74999 vs ≥$75000) and insurance status (private vs public). Results: The survey was completed by 2353 patients (pts) with 2177 MM (83.4% active, 16.6% smoldering) and 176 MGUS. Among MM pts median age was 63 yrs with 52.5% males, 91.5% white and 95.7% non-Hispanic. 17.5% had a prior diagnosis of MGUS and 20.2% of smoldering MM prior to MM, and 79.5% were not aware of MM prior to their own diagnosis. Majority (77%) depended most on their doctors to gain MM information but 24.3% reported not having sufficient discussion about MM at diagnosis. 31.2% were not sure what type of MM they had, 22.9% could not correctly report the cell of MM origin (plasma cell), 40.6% did not receive MM stage information at diagnosis, 45.4% were either unsure or reported wrong risk factors for MM and 22% were unsure or mistaken about MM symptoms. Majority (62.9%) did not understand genetic risk categories of MM, 32.3% did not report adequate understanding of MM tests and 31.9% did not understand the difference between response and remission. 57.5% reported not understanding about MRD status and 57.1% never had MRD testing. Majority (86.8%) felt they got adequate opportunity to participate in treatment decisions but only 54.2% felt confident in managing MM with their current knowledge and 28.2% had not discussed their prognosis although 77.7% wanted to know about it. Majority (64.4%) felt they had knowledge gaps about MM and its management. Multivariate analysis showed that females were less likely (OR 0.67) while those with public insurance were more likely (OR 1.35) to report receiving adequate information at diagnosis. Older pts (OR 0.55), males (OR 0.43), with lower education (OR 0.5), lower income (OR 0.5) and public insurance (OR 0.72) were less likely to identify the cell of MM origin correctly. These same groups were significantly less likely to be aware of types of MM as well. Older pts (OR 0.73), with lower education (OR 0.6), lower income (OR 0.77) and public insurance (OR 0.76) were less likely to be aware of MM genetic risk categories. Females (OR 0.81), with lower education (OR 0.68) and lower income (OR 0.63) were less likely to understand MM lab tests. Females and those with lower income were significantly less likely to report receiving adequate information about treatment options. Females reported that they did not get adequate opportunities to participate in treatment decisions (OR 0.65). Older pts, and those with lower income, lower education or public insurance were less likely to understand minimal residual disease (MRD) and all these groups were less likely to have had MRD testing. Those with lower income (OR 0.75) and lesser education (OR 0.72) felt less confident in managing MM with current knowledge. Older pts, females and those with lesser education, lower income and public insurance were also significantly less likely to have discussed about MM prognosis. Conclusion: This study demonstrates substantial basic knowledge deficits integral to managing and prognosticating MM among patients. Patients from unfavorable sociodemographic-economic groups were more likely to have awareness gaps and report lack of information which is integral to having adequate understanding of MM being provided to them. These findings highlight the critical need for structured, comprehensive educational interventions that address fundamental disease concepts to empower pts, overcome healthcare disparities, and engage pts in shared decision-making.

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine >2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p<0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p<0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

Abstract Background The advent of T-cell redirecting bispecific antibodies (BsAb) therapies has led to deeper and durable responses in patients with RRMM. We sought to identify adverse prognostic factors for patients treated with BsAbs. We also explored whether the extent of the non-involved free light chain (niFLC) suppression could serve as a potential marker of T-cell engager activity, given the binding of BsAbs to both clonal and non-clonal plasma cells and the short half-life of serum FLCs. Methods We conducted a retrospective analysis of RRMM patients treated with BsAbs between 2022 and 2025 at Mayo Clinic. Baseline lymphocyte counts and ferritin levels were collected and analyzed both as continuous and dichotomized variables. niFLC was considered undetectable if it was below the quantification limit, while the magnitude of niFLC suppression was defined as the absolute difference between niFLC levels and the lower normal range threshold at the time of best response. In addition to standard statistical methods, interaction models were used to explore the potential effect modification of niFLC dynamics. Results A total of 158 patients were included (teclistamab, 73%; talquetamab, 15%; elranatamab, 12%). The median follow-up is 12 months (range 0 to 28 months). Median age is 71(range 65 to 77); 52% (n=85) were triple-class refractory (refractory to an IMiD, a PI, and CD38-antibody) and 37% (n=60) were penta-refractory. CAR-T therapy was previously administered in 28% (n = 46) patients, and 70% had undergone an autologous stem cell transplant. One or more high risk cytogenetic features including del(17p), gain(1q), amp(1q), del(1p), t(4;14), and t(14;16) were present in 57% (n = 90) of patients. Extramedullary disease was noted at the time of BsAb therapy in 44% of patients. Utilizing IMWG response criteria, 68% (n=107) achieved ≥partial response, and 64% (n=101) had ≥ very good partial response (VGPR) as best response following BsAb treatment. The median time to best response was 1.6 months (range 0.7 to 4.4). On multivariable analyses, baseline immunoparesis (HR 1.96; 95% CI, 1.08–3.58; p = 0.0274) and elevated ferritin levels (≥ 337 ng/mL) (HR 1.96; 95% CI, 1.24–3.09; p = 0.0041) were independent predictors of inferior progression-free survival (PFS). Lower baseline absolute lymphocyte count, analyzed as a continuous variable, was significantly associated with shorter PFS in the univariable analysis (HR 0.66; 95% CI, 0.44–0.98; p = 0.04), but not in the multivariable model (HR 0.75; 95% CI, 0.5–1.13; p = 0.166). Detectable niFLC at the time of best response was also significantly associated with inferior PFS (HR 1.80; 95% CI, 1.14–2.84; p = 0.0114). However, the magnitude of niFLC suppression did not show a statistically significant impact on PFS. The median PFS was 5 months in patients with high ferritin levels (≥ 337 ng/mL) and 21 months in those with lower ferritin (p = < 0.005). Similarly, PFS was 8 months in those with immunoparesis and not reached in those without baseline immunoparesis (p = 0.008). At the time of best response, detectable niFLC was associated with a trend toward shorter PFS (5 vs. 13 months), although the difference was not significant (p = 0.06). Logistic regression analysis supported these findings, with higher ferritin levels (OR 2.28; 95% CI: 1.09–4.96; p = 0.032) and the presence of baseline immunoparesis (OR 2.60; 95% CI: 1.18–6; p = 0.02) being significantly associated with higher likelihood of progression or death. Patients with deep reduction in niFLC achieved a VGPR or better. In contrast, those with detectable or higher-than-normal niFLC levels did worse in terms of response. Notably, niFLC became undetectable in 72% of patients with ≥VGPR (73/101), compared to 52% of those who did not achieve this level of response (30/57). Conclusion Among RRMM patients treated with BsAbs, baseline immunoparesis and elevated ferritin levels emerged as independent predictors of worse PFS. While failure to induce a deep reduction in niFLC at the time of best response suggests a tumor extrinsic mechanism of resistance, and it is also linked to inferior outcomes.