Hayman, Suzanne R.

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 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 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.

e19564 Background: Risk stratification in multiple myeloma (MM) relies on baseline staging systems and cytogenetic abnormalities, yet early relapse occurs in a subset of patients despite favorable risk features. Prior studies showed that clonal plasma cell S-phase assessed by flow cytometry using the plasma cell proliferation (PCPRO) assay at diagnosis and at autologous stem cell transplantation (ASCT) identifies biologically high-risk disease. The prognostic significance of clonal plasma cell S-phase following ASCT has not been well defined. Methods: We retrospectively analyzed MM patients who underwent ASCT within one year of diagnosis between January 1, 2013, and August 31, 2024. Patients without available post-ASCT clonal plasma cell S-phase assessment were excluded, yielding 150 evaluable patients. The proportion of clonal plasma cells in S-phase was determined by DNA content between G0/G1 and G2/M peaks and reported as a percentage. S-phase was assessed at the first post-ASCT marrow evaluation at day +60 (D45–75) and/or day +100 (D76–130), using the earlier assessment when both were available. Patients were classified as low (<2%) or high (≥2%) post-ASCT S-phase. Landmark progression-free survival (PFS) analyses were performed from the post-transplant assessment. Multivariable Cox models adjusted for cytogenetic risk, maintenance therapy, disease response at transplantation, International Staging System (ISS), and age. Results: Among 150 evaluable patients, 36 (24%) had high post-ASCT S-phase (≥2%) and 114 (76%) had low post-ASCT S-phase (<2%). Median age at ASCT was higher in the high S-phase group (64.5 vs 61.0 years; p=0.063), and advanced ISS stage (II/III) was more frequent (78% vs 57%; p=0.02). Cytogenetic risk, induction regimen, depth of response at transplantation, and maintenance therapy were similar between groups. Patients with high post-ASCT S-phase had significantly inferior PFS compared with those with low S-phase (median 17.0 vs 39.7 months; p=0.0003). On multivariable analysis, post-ASCT S-phase ≥2% remained independently associated with inferior PFS (HR 1.76, 95% CI 1.00–3.09; p=0.049). In an exploratory analysis among patients with paired S-phase assessments at the time of ASCT and post-ASCT, dynamic S-phase trajectories further stratified outcomes. Median PFS was longest in patients with persistently low S-phase (low→low; 39.7 months), intermediate in those converting from high to low S-phase (high→low; 27.2 months), and shortest in patients with newly emergent or persistently high post-ASCT S-phase (low→high: 15.0 months; high→high: 11.0 months) p=0.0019. Conclusions: Elevated proliferative activity of residual clonal plasma cells following ASCT identifies a biologically high-risk subset of MM patients with early relapse. Dynamic changes in post-ASCT S-phase further refine post-transplant risk stratification.

7518 Background: Monoclonal gammopathy of undetermined significance (MGUS) is common, yet only a minority progress to malignant plasma-cell disorders. Mayo risk stratification uses baseline factors and is commonly implemented/validated in a Cox proportional hazards (CoxPH) framework, which may miss prognostic longitudinal patterns. Methods: We assembled 15,158 MGUS patients with longitudinal laboratory data and progression outcomes (smoldering multiple myeloma, multiple myeloma, AL amyloidosis, or Waldenström macroglobulinemia). We compared a Mayo-factor Cox proportional hazards (CoxPH) baseline versus STRaTS, a transformer-based survival model, to predict progression risk at 3-, 5-, and 10-year horizons. STRaTS leveraged longitudinal trajectories of routine labs including hemoglobin, platelets, differential counts (neutrophils/lymphocytes/monocytes), immunoglobulins (IgG/IgA/IgM), free light chains (kappa/lambda), M-spike, and creatinine. To minimize bias, we used laboratory results collected from 1–3 years after diagnosis and started follow-up at year 3; patients progressing before year 3 or lacking follow-up beyond year 3 were excluded. A total of 7,305 patients met eligibility and were split into train/validation/test cohorts of 4,383/1,461/1,461. Discrimination was assessed by concordance index (C-index). Clinical operating performance was evaluated on a held-out test cohort by comparing sensitivity and specificity at the same proportion of patients selected for intensified surveillance (same workload). Results: Among MGUS patients with complete baseline Mayo factors(N=3,388), Kaplan–Meier–estimated 3-/5-/10-year cumulative progression risk was 0.1/0.4/3.4% (Low), 3.0/4.3/7.9% (Low-Intermediate), 4.4/6.4/14.1% (High-Intermediate), and 8.9/12.5/16.9% (High). On a held-out test cohort, STRaTS demonstrated superior discrimination versus the Mayo-factor CoxPH (C-index 0.75 vs 0.538; p<0.0001). Both models were trained and evaluated on identical train/test splits. At the same surveillance workload, STRaTS achieved higher sensitivity with comparable specificity; when 40.3% of patients were selected for closer surveillance, 3-year sensitivity was 81.0% for STRaTS versus 47.6% for CoxPH (Table). Conclusions: Among MGUS patients who remain progression-free at 3 years, transformer-based survival modeling of longitudinal laboratory trajectories provides more accurate individualized conditional progression risk estimates and improved workload-matched identification of progressors compared with the conventional Mayo/Cox approach. Sensitivity/specificity (%). Operating Point Flagged % STRaTS Sens / Spec (%) CoxPH Sens / Spec (%) Int+High, 3y 40.3 81.0 / 58.5 47.6 / 58.9 Int+High, 5y 40.3 81.2 / 60.4 46.9 / 58.8 Int+High, 10y 40.3 25.0 / 56.3 23.8 / 58.7 Two-Group High (≥2 factors), 5y 5.6 37.4 / 93.4 35.4 / 93.1

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P&lt; .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P&lt; .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.