Crescentic renal amyloidosis is a rare complication of light-chain (AL) amyloidosis. We report the case of a 73-year-old man with AL amyloidosis involving the kidney and heart. At diagnosis, his creatinine was 0.94 mg/dL and proteinuria was 3.1 g/d. He achieved a hematologic very good partial response with ixazomib, cyclophosphamide, and dexamethasone. Creatinine briefly increased to 1.4 mg/dL after a coronavirus disease-2019 (COVID-19) infection but returned to baseline and remained stable for 11 months until receiving a COVID-19 vaccine. Following vaccination, creatinine progressively increased, and proteinuria increased to 8.5 g/d. Owing to worsening kidney function, therapy was switched first to daratumumab and subsequently to bortezomib. Although these agents further reduced lambda free light chains, creatinine continued to increase to 2.68 mg/dL, accompanied by a 25-pound weight loss. A kidney biopsy demonstrated diffuse amyloid deposition, cellular crescents, and fibrinoid necrosis in 2 glomeruli. Serologies for vasculitis were negative. Creatinine initially improved with dexamethasone, but treatment was discontinued owing to steroid myopathy. Cyclophosphamide was initiated, but creatinine increased further to 3.3 mg/dL. After switching to mycophenolate mofetil, creatinine steadily improved to 2.5 mg/dL. In this case, crescentic glomerulonephritis likely developed secondary to the COVID-19 vaccine, as evidenced by its lack of response to therapy targeting AL amyloidosis. This case emphasizes the importance of kidney biopsy in patients whose kidney function declines unexpectedly during successful treatment of systemic diseases such as AL amyloidosis.

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.

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.

The role of autologous stem cell transplantation (ASCT) is central in AL amyloidosis and continues to be defined in the era of newer therapies. To evaluate contemporary patient selection, practice patterns, and outcomes, we conducted a retrospective, multicenter study across nine tertiary referral centers, including 1047 patients with AL amyloidosis who underwent ASCT between 2010 and 2020. Most patients (67.9%) received full-dose melphalan conditioning, and 66.5% received pre-ASCT induction therapy, predominantly proteasome inhibitor-based regimens. Day-100 all-cause mortality was 3.0%, representing a substantial improvement compared with historical cohorts. Post-ASCT hematological responses were satisfactory in 75.4% of patients. Among patients with paired assessments, ASCT deepened responses in 56.3% who had not achieved a complete response with induction therapy. With a median follow-up of 5.1 years, the median overall survival was 6.3 years. Independent predictors of inferior survival included age ≥60 years, bone marrow plasma cells ≥20%, pre-ASCT dFLC ≥40 mg/L, elevated cardiac biomarkers, lambda-restricted disease, reduced eGFR and reduced-dose conditioning. In this contemporary cohort, ASCT for AL amyloidosis demonstrated low early mortality, high rates of deep hematologic response, and durable survival in carefully selected patients. These findings support its role as an effective consolidative strategy, while its optimal positioning alongside emerging therapies requires further study.

Quadruplets incorporating anti-CD38 monoclonal antibody have led to improved outcomes, potentially allowing limited-duration therapy and reduction in steroid doses. We designed this trial to examine the efficacy of the quadruplet regimen containing daratumumab, ixazomib, lenalidomide, and dexamethasone (Dara-IRd) given for fixed duration and to evaluate early discontinuation of steroids. Patients with untreated MM were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the ≥complete response (CR) rate. Treatment involved 28-day cycles of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and daratumumab 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and every 4-weeks thereafter during induction (12-cycles) followed by daratumumab and ixazomib maintenance (24-cycles). Seventy-eight patients were enrolled into two sequential cohorts: cohort A (n = 38) and B (N = 40), with dexamethasone given only for two cycles in Cohort B. At the time of the data cut-off, all patients had completed the treatment. The overall response rate was 96%, including a ≥CR rate of 32%, similar in both cohorts. Responses deepened over time; 32% achieved a marrow MRD negative status and 29% MRDneg-CR. After a median follow-up of 37.9 months, the median PFS or OS has not been reached. A grade ≥3 adverse event, at least possibly attributed to the study drugs, was seen in 55% of patients. The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy, diarrhea, and nausea. Stem cells were collected in 55 patients; the median sCD34+ cell yield (range) was 7.8 (2.8-15.9) × 106/kg. Dara-IRd is an active regimen in newly diagnosed MM, with high overall response rate as well as deep responses. Nearly a third of the patients attained MRDneg status, which improved over time. The PFS with finite-duration therapy is comparable to other studies in NDMM. Early discontinuation of dexamethasone did not impact efficacy.

Aims:We aimed to develop and validate echocardiography-based prediction models for light chain (AL) and transthyretin (ATTR) cardiac amyloidosis and to quantify the incremental value of integrating artificial intelligence-derived electrocardiography (ECG) probabilities. Methods and results:We conducted a retrospective, multisite study within a single health system including patients with AL or ATTR cardiac amyloidosis and matched control subjects. AL and ATTR cohorts were handled independently. For each subtype, patients were randomly split into training and test cohorts, with an additional temporally distinct test cohort. Logistic regression models were developed using structured echocardiographic variables with parsimonious core and extended feature sets, as well as models integrating these features with a previously validated AI ECG probability. Model performance was assessed using receiver operating characteristic and precision-recall (PR) analyses. In AL amyloidosis, echocardiography-based models demonstrated moderate discrimination in the primary test cohort (area under the PR curve, AUPRC 0.674) but were inferior to ECG alone (AUPRC 0.824, P < 0.001), with no significant improvement from model combination (AUPRC 0.841 vs. ECG, P = 0.267). In contrast, for ATTR amyloidosis, echocardiography alone (AUPRC 0.687) performed worse than ECG (AUPRC 0.745, P = 0.140), while the combined model showed substantial improvement (AUROC 0.845, P < 0.001). Absolute performance declined in temporally distinct cohorts, but AUPRC comparisons were preserved. Conclusion:Subtype-specific echocardiography-based models demonstrate robust discrimination for cardiac amyloidosis, with divergent contributions of echocardiographic features by subtype. These results support tailored modelling strategies and prospective concurrent deployment of AL and ATTR models.

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.

Background: Monoclonal gammopathy-associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late-onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Methods: Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG-kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. Results: A 69-year-old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG-kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non-rimmed vacuoles (0.3% of fibers) containing PAS-positive, diastase-labile material consistent with concurrent SLONM and glycogen storage myopathy-like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma-cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M-protein reduction. Further gains followed autologous stem cell transplantation. Conclusion: This case expands the MGAM spectrum, highlighting co-occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.

Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi-center retrospective cohort study to develop and validate a risk-prediction model for early mortality (all-cause death within 6 months) in patients treated with Dara-based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6-month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT-proBNP > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), Age > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on Cytogenetics (OR 3.0, p = 0.022), and ECOG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6-month mortality of 1.2% (low-risk), 11.7% (intermediate-risk), and 50.0% (high-risk). The PACE score demonstrated superior discrimination (C-index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C-index 0.73) with corresponding 6-month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara-based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra-high-risk patients requiring intensive monitoring and novel therapies.

Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signfiance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

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.

Liver involvement in light chain amyloidosis (AL) is seen in 10-20% of patients and is associated with poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria. AL patients diagnosed between 2010 and 2015 with liver involvement [serum alkaline phosphatase (AP) >1.5 upper reference limit (URL)] who achieved hematological response were included. Hepatic response was defined as >50% reduction (or normalization) of AP from baseline. Hepatic response was assessed at 6, 12, and 24-months after therapy initiation and at best response. Overall survival (OS) was assessed from time of therapy initiation. Hepatic response was evaluated in 116 patients. The median baseline serum AP was X2.6 URL. Hematological very good partial response (VGPR) or better was achieved in 69% of patients. AP decreased with time, with a median reduction of 22%, 34%, and 53% at 6-, 12-, and 24-months, respectively, and a median AP reduction of 56% at the time of best response. The median time to hepatic response was 13.3 months and was longer for patients undergoing autologous stem cell transplantation. Achievement of hepatic response, particularly as early as 12 months, and at best response, was associated with improved survival, independent of other prognostic factors. Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematological ≥VGPR, and cardiac and renal responses, when applicable. Hepatic response measured by the change in alkaline phosphatase is a prognostic factor in patients with AL amyloidosis.

In newly diagnosed multiple myeloma (NDMM), current risk stratification relies on cytogenetics and disease burden, but emerging immune parameters may refine prognosis. While a higher non-clonal plasma cell fraction (NCPF) predicts favorable outcomes in smoldering myeloma, its relevance in NDMM remains unexplored. We retrospectively analyzed 798 patients with NDMM where baseline bone marrow aspirates were tested to determine the NCPF, defined as the proportion of non-clonal plasma cells among total plasma cells. An NCPF ≥ 5

Abstract Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored. Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV, and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression. Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL. Citation Format: Yuan Yao, Kari G. Rabe, Eli Muchtar, Paul Hampel, Yucai Wang, Lindsey Roeker, Saad Kenderian, Amber Koehler, Catherine Wagner, Amy Behnken, Jose F. Leis, Mazie Tsang, Talal Hilal, Ricardo Daniel Parrondo, Susan M. Schwager, Min Shi, Curtis A. Hanson, Celine M. Vachon, Shaji Kunnathu Kumar, Esteban Braggio, Neil E. Kay, Susan Slager, Sameer A. Parikh. Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1191.

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.

AL amyloidosis often presents with nonspecific symptoms, leading to delayed diagnosis and increased early mortality, even in patients with known multiple myeloma or other monoclonal gammopathies. This study assessed the cardiac amyloid artificial intelligence electrocardiogram (CA-AI-ECG) tool’s utility in predicting treatment outcomes and detecting CA in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation (ASCT). Among 2934 multiple myeloma patients studied, 81% received early ASCT (< 12 months from diagnosis) and therefore had an early ECG performed (early ASCT/ECG cohort), with 5% having a positive pre-ASCT CA-AI-ECG score. In the early ASCT/ECG group, a positive CA-AI-ECG score did not correlate with decreased overall survival. However, in the delayed ASCT/ECG group, a positive CA-AI-ECG score was associated with significantly lower overall survival (HR: 1.73, 95% CI: 1.07–2.78), remaining an independent risk factor on multivariate analysis. The observed overall survival difference between cohorts may be attributable to the longer time interval from diagnosis to ECG in the delayed ASCT group, leading to prolonged light chain exposure. During follow-up, 25 patients developed AL amyloidosis, of which, 12 patients had systemic involvement. Those with a positive pre-ASCT CA-AI-ECG were five times as likely to progress to systemic amyloidosis compared to those with a negative score (LR 5.0 p=0.025). These findings suggest that the CA-AI-ECG tool may enhance subclinical CA detection, especially as an early screening tool.

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 .