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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.

Rural populations are underrepresented in cognitive impairment research and have limited resources for education about brain and cognitive health, Alzheimer's disease and related dementias, or caregiving. As our Outreach, Recruitment, and Engagement team aimed to expand activities into more rural communities, we also wanted to better understand the characteristics of the communities surrounding our center and gain insight into the social exposome of the areas. The goal of the manuscript is to reflect on our experience and share measures that were useful in this effort, which can be further enriched and adjusted by other outreach teams.

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.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

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.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)

7514 Background: Iberdomide (Iber) is a CELMoD that binds with greater specificity & affinity to the cereblon protein of the E3 ligase complex than a traditional IMiD. Both transplant-eligible (TE) & ineligible (TIE) patients (pts) with newly diagnosed multiple myeloma (NDMM) are currently treated with quadruplet induction, consisting of an anti-CD38 monoclonal antibody, a proteasome inhibitor, an IMiD & dexamethasone (dex). We conducted a clinical trial (NCT05392946, IDEAL) to examine the efficacy of a novel finite-duration approach, using Iber, daratumumab, bortezomib & dex (Iber-DVd) quadruplet induction followed by Iber monotherapy maintenance. Methods: Both TE and TIE pts with NDMM were enrolled in this Phase 1 (3+3 design)/Phase 2 (single stage) trial. The primary goal was to assess the ≥complete response (CR) rate — utilizing the more sensitive serum MASS-FIX assay in lieu of serum immunofixation — during induction. Treatment involved twelve 28-day cycles of induction with Iber, given PO at the recommended phase 2 dose (RP2D), days 1-21, daratumumab 1800mg SQ, weekly for 2 cycles, every other week during Cycles 3-6, & every 4 weeks thereafter, bortezomib 1.3 mg/m 2 SQ, weekly & dex 40 mg, weekly, followed by Iber monotherapy (24 cycles). Growth factor was not allowed during the dose-limiting toxicity (DLT) assessment period (Cycle 1). Results: Among 47 pts enrolled, 9 pts were in Phase 1 portion which assessed the maximum tolerated dose (MTD), with Iber starting at 1 mg/day dose, days 1-21 [Dose Level (DL) 1]. DLT (all grade 4 neutropenia) was noted in 3 pts, 2 at DL 1 & 1 at DL -1. This analysis includes 44 pts who received Iber at the RP2D (0.75 mg/day, days 1-21), including 6 pts from the Dose Confirmation Cohort (Phase 1, DL -1), dosed at MTD, & 38 pts in the Dose Expansion Cohort. The median age at registration was 65 years (range 36-86 years), & 23 pts (52.3%) were deemed high-risk. At data cut-off, pts had received a median of 15 cycles (range 3-36) of therapy. Overall response rate was 100%; ≥CR rate, 36.4% (95% CI: 22.4, 52.2) during induction & 52.3% (95% CI: 36.7, 67.5), overall, including the maintenance phase. The marrow flow-based (10 -5 ) MRD negative rate was 29.5% during induction & 47.7% overall. At a median follow-up (FU) 18.3 mos, 2 pts have died (one during FU due to progressive disease & the other on-treatment due to COVID-19). 12- (& 18-) month progression-free survival & overall survival rates were 91% (88%) & 97% (94%), respectively. Most common toxicities at RP2D were lymphopenia, neutropenia (leading 27% of pts to require pegfilgrastim support), rash, peripheral neuropathy, diarrhea, & infections. Cases of high-grade fatigue were low (<5%). Updated data will be presented at the meeting. Conclusions: Iber-DVd is an active and safe regimen for both TE and TIE pts with NDMM, leading to high response rates which improved over time, with nearly one-half of the pts achieving MRD negative state. Clinical trial information: NCT05392946 .

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