Gertz, Morie A

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

Summary Iron deficiency (ID) is often overlooked in patients with haematological malignancies due to other potential aetiologies. Daratumumab, an anti‐cluster of differentiation 38 (anti‐CD38) monoclonal antibody, is commonly used for treating multiple myeloma (MM) in the upfront and relapsed/refractory settings. Although anaemia is a common haematological toxicity associated with daratumumab, the contribution of ID in MM patients has not been systematically investigated. We conducted a retrospective case–control study to evaluate the prevalence of ID in newly diagnosed MM (NDMM) patients. Cases were patients receiving daratumumab, ixazomib, lenalidomide and dexamethasone (Dara‐IRD, n = 55). We compared this group with an age‐ and sex‐matched cohort of patients with NDMM who received bortezomib, lenalidomide and dexamethasone (VRD, n = 20) as induction therapy. At 1‐year, nearly 50% of Dara‐IRD‐treated patients met the criteria for ID (ferritin <30 mcg/L) compared with none of the VRD‐treated controls. All Dara‐IRD‐treated patients had a decrease in ferritin at 1‐year from baseline compared with only 45% of VRD‐treated patients. These findings identify a marked clinical signal of ID among NDMM patients receiving daratumumab‐based treatment. Although the study design does not establish causality or exclude regimen‐related confounding, it highlights the need for increased awareness of the importance of monitoring iron status in MM patients treated with daratumumab‐containing regimens.

Abstract Frailty influences treatment outcomes in older patients with multiple myeloma (MM), yet existing frailty tools capture limited geriatric domains and are incompletely studied in the context of contemporary therapies. We prospectively evaluated patient-reported comprehensive geriatric assessment (CGA) domains and their associations with treatment toxicity and patient-reported outcomes (PRO) in older adults with MM. Patients aged ≥60 years with newly diagnosed or relapsed/refractory MM initiating a new therapy completed electronic CGA and PRO questionnaires at baseline and 4 months. Outcomes included clinician- and patient-reported treatment toxicity, treatment adaptations, health care use, and health-related quality of life (HRQOL). A cumulative deficit frailty index (FI) was derived from CGA and HRQOL domains. Among 90 patients (mean age, 72 years), geriatric impairments were common, particularly physical function domains. High-grade nonhematologic toxicities were significantly associated with older age, comorbidities, patient-reported functional limitations, and anxiety. Toxicity rates on the PRO version of the Common Terminology Criteria for Adverse Events (CTCAE) were higher than on CTCAE, highlighting a discordance between physician- and patient-reported treatment toxicity. Frailty was present in 22% and associated with worse baseline HRQOL and increased high-grade nonhematologic toxicity but not treatment adaptations or health care use. Average CGA and HRQOL scores remained stable over 4 months, although individual trajectories varied. Patient-reported geriatric impairments are prevalent in older adults with MM and strongly associated with nonhematologic toxicities even in the contemporary treatment era. Physician-reported CTCAE may not fully reflect patients' symptom burden. Heterogeneity in individual geriatric trajectories during treatment emphasize the need for longitudinal assessment. This study was registered at www.clinicaltrials.gov as NCT05918185.

Abstract Measurable residual disease (MRD) is a powerful prognostic tool in multiple myeloma, but predictors of achieving MRD negativity after autologous stem cell transplantation (ASCT) are not well defined. We studied 814 patients who achieved at least a very good partial response after ASCT between January 2016 and January 2023 and underwent MRD assessment by next-generation flow cytometry. Overall, 387 (48%) achieved MRD negativity after ASCT. The presence of t(11;14) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.2; P&lt; .01) and pretransplant response less than complete remission (OR, 2.1; 95% CI, 1.2-3.7; P&lt; .01) independently predicted MRD positivity. Patients who were MRD positive had inferior progression-free survival (PFS; hazard ratio [HR], 1.99; 95% CI, 1.53-2.58; P&lt; .001) and overall survival (HR, 1.62; 95% CI, 1.10-2.28; P = .009). Despite lower MRD-negative rate, 5-year PFS was similar among t(11;14) MRD positive (58%) and patients who were MRD negative (63%; P = .12). In patients who were MRD negative, the 5-year PFS was 73% in those without ≥2 HRCA compared with 55% in those with ≥2 HRCA (HR 1.9, 95% CI 1.2–3.3; P = .01). In the MRD-positive cohort, 5-year PFS was 53% in patients without ≥2 HRCA vs 17% in those with ≥2 HRCA (HR, 2.4; 95% CI, 1.6-3.6; P&lt; .01). In addition, higher residual clonal plasma cell burden within MRD-positive disease was associated with inferior PFS (HR, 2.4; 95% CI, 1.2-6.9; P = .002). This study highlights that the presence of t(11;14) independently predicts MRD positivity after ASCT, although it does not significantly affect prognosis in this subgroup.

ABSTRACT Ciltacabtagene autoleucel (cilta‐cel) has demonstrated excellent efficacy and long‐term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early treatment failures. We investigated clinical factors associated with early progression or death (within 12 months) in patients with RRMM receiving standard‐of‐care cilta‐cel across the three Mayo clinic centers. Patients with a follow‐up of at least 12 months or progression or death within 12 months from infusion were included. Of the patients with early treatment failure ( n = 52), 69% had progressive disease and 31% had a non‐relapse mortality (NRM) event. In patients without early treatment failure ( n = 164), 13% of events were NRM. Among pretreatment factors, prior BCMA‐directed therapy, presence of extramedullary disease and a CAR‐HEMATOTOX score of ≥ 2 were independent predictors of early progression or death. The utilization of cilta‐cel in earlier lines of treatment (1–3 vs. 4 or more) demonstrated comparable PFS (12‐month PFS 73% vs. 77%, p = 0.94). Measurable residual disease positivity in the bone marrow at 3 months (11/197 patients) identified a small but high‐risk group with an increased risk of early treatment failure (OR 5.68; p = 0.012). Patients with less than a complete response on a FDG PET/CT at 3 months also had an increased risk of early treatment failure (OR 11.8; p < 0.0001). Our findings may help identify patients at high‐risk for early adverse outcomes despite receiving highly effective therapy, and support consideration of novel therapeutic strategies within a clinical trial setting.

Abstract Extramedullary disease (EMD) is increasingly recognized in relapsed/refractory multiple myeloma (MM), with central nervous system involvement (CNS-MM) representing a rare but highly aggressive manifestation associated with dismal outcomes. Data on its incidence and optimal management, particularly in the era of cellular and bispecific therapies, remain limited. We conducted a retrospective analysis of patients with MM with pathology-confirmed EMD treated at our institution between January 2000 and December 2023. CNS-MM was defined by parenchymal or leptomeningeal involvement. Clinical features, cytogenetics, treatments, and outcomes were analyzed, with predictors of CNS involvement evaluated among patients with EMD. Among 304 patients with EMD, 20 (6.5%) had CNS-MM. CNS involvement occurred a median of 19.2 months after MM diagnosis, though 15% presented at diagnosis. CNS-MM was strongly associated with high-risk cytogenetics (odds ratio [OR], 3.7) and additional visceral EMD (OR, 4.6). Median overall survival (OS) from CNS-MM diagnosis was 4.2 months. Outcomes were significantly improved in patients receiving chimeric antigen receptor T-cell therapy or bispecific antibodies, with a median OS of 19.2 months vs 1.2 months in those who did not receive immune effector therapies. Intrathecal (IT) chemotherapy demonstrated limited and transient benefit. In conclusion, CNS-MM is an aggressive complication enriched in high-risk, multifocal EMD with extremely poor prognosis. Cellular and bispecific therapies show promising activity and may meaningfully improve survival, whereas IT therapy appears to have limited efficacy. Prospective studies are needed to define optimal treatment strategies for CNS-MM.

Abstract Therapeutic options for Waldenström macroglobulinemia (WM) have expanded but improvements in overall-survival (OS) are difficult to interpret due to competing non–WM mortality. We conducted a large single-center retrospective study of 1,020 patients with WM to evaluate survival trends. Patients were stratified by era of active WM diagnosis using a two-era model (1996–2005 and post-2005) and a four-era model (pre-2001, 2001–2007, 2008–2013, and post-2013). OS did not differ significantly across eras in the overall cohort (p = 0.64 and p = 0.86 for the two- and four-era models). However, among patients aged < 65 years at the time of active WM diagnosis in the 2-era model, OS improved in the post-2006 era (median 18.8 vs 14.1 years, p = 0.018). Cause-specific-survival (CSS) improved across all eras, increasing from 15.6 years in 1996–2005 to 18.9 years post-2006 (p < 0.0001), and from 13.7 years pre-2001 to not reached in later periods in the four-era model (p < 0.0001). Competing-risk-analysis (CRA) demonstrated a reduction in WM-related mortality over time (p < 0.001). However, excess mortality persisted, with a standardized mortality ratio (SMR) of 2.79 (p < 0.001) among patients < 65 years compared with a matched U.S. population. Our findings highlight improvements in WM-specific survival, while gains in OS are observed in younger patients.

ABSTRACT High dose melphalan (HDM) with autologous stem cell transplant is an established treatment for systemic light chain amyloidosis, but its incremental benefit in the era of effective standard intensity therapy is unknown. We retrospectively analyzed 475 transplant‐eligible patients who completed standard intensity treatment with or without HDM within 12 months at six centers in Europe and the United States between 2010 and 2024 to evaluate outcomes by baseline risk factors, hematologic response, and receipt of HDM. Death was an equally competing risk after the 12‐month landmark chosen to address early non‐proportional hazards and to ensure completion of first‐line therapy. BMPC > 20% was associated with inferior outcomes (HR 1.7), and gain/amp 1q with shorter TTP (HR 2.15), whereas other high‐risk FISH abnormalities were not. In multivariable models, VGPR/CR after standard intensity therapy was associated with longer TTP (HR 0.49/0.29), while gain/amp 1q remained independently associated with shorter TTP (HR 2.18). Receipt of daratumumab and HDM were associated with longer TTP (HR 0.44/0.61). HDM benefited patients who had not achieved CR after standard intensity therapy (mTTP 21.0 vs. 5.7 months without HDM), whereas patients already in CR did not benefit. Higher BMPC at diagnosis was associated with earlier progression in patients not receiving HDM (HR 1.9 for 5%–20% and 4.09 for > 20%), a risk attenuated in the HDM cohort. Gain/amp 1q remained associated with shorter TTP regardless of HDM exposure. These findings support a selective role for HDM, primarily benefiting patients with residual disease after standard intensity therapy or higher BMPC burden at diagnosis.

ABSTRACT Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with inferior outcomes compared with multiple myeloma (MM). However, studies describing outcomes after first progression and subsequent lines of therapy remain limited. We retrospectively analyzed 104 patients with pPCL who progressed after first‐line therapy treated at one comprehensive cancer center between 2006 and 2024. Clinical characteristics, treatments, time to next treatment (TTNT), and overall survival (OS) were assessed using Kaplan–Meier methods. All pPCL patients received novel agent–based induction. At the time of analysis, 63% had died; median OS was 39 months. High‐risk cytogenetics were present in 71%. The median TTNT after first‐line therapy was 10 months. Symptomatic progression occurred in 29% of patients and was associated with significantly inferior subsequent OS (13 vs. 34 months) compared with those experiencing asymptomatic biochemical progression. The TTNT progressively shortened with subsequent lines of therapy (3rd line: 6 months; 4th line: 4 months; 5th line: 3 months). Notable exceptions included pPCL patients with t (11;14) treated with anti‐BCL‐2‐based regimens, who achieved a median TTNT of 13 months. Additionally, 24 patients received anti‐BCMA CAR T‐cell therapy. With a median follow‐up of 21 months, their median TTNT was 32 months. pPCL is characterized by frequent disease progression and diminishing response duration with successive therapeutic lines. Symptomatic progression portends particularly poor outcomes. Anti‐BCL‐2‐based therapy in t (11;14) disease and anti‐BCMA CAR T‐cell therapy appear to provide more durable disease control and represent important advances for the management of progressed pPCL.

Summary Renal response (RenR) in light‐chain (AL) amyloidosis is associated with a lower risk of end‐stage kidney disease and improved survival. However, substantial variation exists in the time to and depth of RenR. We investigated variables associated with RenR in a retrospective study of newly diagnosed AL amyloidosis patients ( n = 350) assessable for RenR between 2010 and 2022. RenRs were recorded at 6, 12 and 24 months and best response. Deep RenR was defined as a ≥renal very good partial response (RenVGPR, >60% reduction in 24‐h proteinuria or ≤200 mg). Logistic regression and competing risk methods were used to examine variables associated with RenR. The median age was 64 years, and median follow‐up was 5.5 years. On multivariable logistic regression, obtaining ≥HemVGPR within 6 months, kappa isotype, high baseline difference between involved and uninvolved free light chains (dFLC ≥40 mg/dL), renal stage and autologous haematopoietic stem cell transplant (AHSCT) were significantly associated with deep RenR. Cumulative incidence rates for deep RenR, treating death or renal progression as a competing event, demonstrated that early HemR, first‐line AHSCT, lower renal stage and dFLC ≥40 mg/dL significantly increased the likelihood of deep RenR. Specific clonal plasma cell features, namely light‐chain isotype and baseline dFLC levels, independently influence the timing and depth of RenRs in AL amyloidosis following treatment, in addition to renal stage and HemR.