Zanwar, Saurabh

ABSTRACT Light chain multiple myeloma (LCMM) is a subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains and accounts for 15%–20% of newly diagnosed MM. A comprehensive comparison of LCMM with MM producing intact immunoglobulin (non‐LCMM) remains limited. In this retrospective study, we described distinct clinical and cytogenetic features and assessed long‐term outcomes in 852 LCMM patients diagnosed between 01/01/2004 and 12/31/2022, compared with non‐LCMM controls matched for age, sex, and year of diagnosis. On univariable analysis, LCMM patients were more likely to present with elevated creatinine (> 2 mg/dL), beta‐2‐microglobulin ≥ 5.5 mg/L, elevated LDH, hypercalcemia, t(11;14), del(13q), and t(6;14). Conversely, IMS‐IMWG high‐risk disease, hyperdiploidy, t(4;14), and serum albumin < 3.5 g/dL were less common. On multivariable analysis, elevated creatinine (OR: 5.1, 95% CI: 1.2–27, p = 0.04), t(11;14) (OR: 2.6, 95% CI: 1.3–5.2, p = 0.006), and del(13q) (OR: 4.1, 95% CI: 2.1–8.2, p < 0.001) were independently associated with LCMM, while IMS‐IMWG high‐risk disease (OR: 0.3, 95% CI: 0.1–0.8, p = 0.02) and hyperdiploidy (OR: 0.3, 95% CI: 0.1–0.7, p = 0.002) were less frequent. Despite these differences, progression‐free survival with frontline treatment (HR: 0.97, 95% CI: 0.84–1.11, p = 0.63) and overall survival (HR: 0.99, 95% CI: 0.87–1.13, p = 0.94) were similar between LCMM and non‐LCMM patients. This study highlights the distinct clinical and cytogenetic features of LCMM, marked by higher rates of renal failure, t(11;14), and del(13q), lower prevalence of IMS‐IMWG high‐risk disease, and comparable survival outcomes.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Abstract This retrospective analysis examined 15 years of autologous stem cell transplantation (ASCT) for light chain (AL) amyloidosis at the Mayo Clinic (2010-2024). We aimed to assess ASCT utilization trends, factors influencing practice changes, and current indications amid newer therapies. Four hundred and forty-one ASCTs were divided into cohort 1 (2010-2019) and cohort 2 (2020-2024), revealing a significant ASCT reduction in cohort 2 (385 vs 56, average 71% annual decrease). Cohort 2 patients were older, more likely to have relapsed/refractory disease, and had higher baseline bone marrow plasma cell burden compared to cohort 1. Pre-ASCT induction was more frequent in cohort 2 (89.3% vs 56.4%), with daratumumab (Dara)–cyclophosphamide-bortezomib-dexamethasone (CyBorD) replacing CyBorD as the predominant induction regimen. Lymphoma-based regimens were also more common in cohort 2 (15.1% vs 5.3%, P = .02). Day-100 satisfactory hematological response improved in cohort 2 (91.1% vs 72.7%, P = .001), although hematological complete response rates did not significantly differ (50.9% vs 38.8%, P = .09). In summary, there is a decrease in the utilization of ASCT in AL amyloidosis. This procedure is primarily reserved for patients with suboptimal responses, relapsed/refractory disease, lymphoplasmacytic clones (predominantly immunoglobulin M amyloidosis), or high bone marrow plasma cell burden (myeloma phenotype). This study underscores a significant shift in ASCT practice, driven by novel therapies, emphasizing more personalized management in AL amyloidosis.

7052 Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2-10% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). The CNS-International Prognostic Index (CNS-IPI) is a validated tool used to assess the risk of CNS relapse. However, with advancements in molecular profiling and treatments, the predictors of SCNSL, including the predictive ability of CNS-IPI combined with other molecular markers and treatment regimens, have become uncertain. This study evaluates new prognostic markers for CNS relapse in DLBCL, focusing on cell-of-origin (COO), gene rearrangements, and treatment types. Methods: DLBCL pts enrolled from 2002-2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Pts with primary CNS lymphoma or CNS involvement at diagnosis, and pts treated with high-dose methotrexate containing regimens were excluded. COO classification (GCB vs non-GCB) was determined using Hans algorithm and/or NanoString data. Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of SCNSL. Survival analysis was performed from time of DLBCL diagnosis using Cox proportional hazards model. Results: Among 1278 newly diagnosed DLBCL pts included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) pts. Pts with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than pts without SCNSL (63.9%, p=0.02). The 3 yr SCNSL incidence was 0.016 (0.008-0.0033) in low CNS-IPI vs 0.043 (0.031-0.0060) in high CNS-IPI. Those with SCNSL were significantly more likely at baseline to have non-GCB COO (56.3% vs. 36.5%, p=0.02), and advanced stage (76.1% vs. 59.9%, p=0.03) compared to those without SCNSL. The incidence of SCNSL was not influenced by MYC, BCL2, or BCL6 rearrangements, nor by treatment with R-CHOP, R-EPOCH, or other immunochemotherapy regimens. MVA showed that intermediate CNS-IPI (HR 2.32, 95% CI 1.09-4.92, p=0.029), high CNS-IPI (HR 3.59, 95% CI 1.49-8.62, p=0.004), and non-GCB COO (HR 2.19, 95% CI 1.08-4.42, p=0.0029) were independently associated with increased SCNSL risk. After a median follow-up of 12 years (IQR 9–15), overall survival (OS) was 52.1% for the cohort, with OS significantly worse for SCNSL pts (17.4% vs. 53.4%, p<0.001). Conclusions: This large cohort with extensive follow-up highlights the role of COO as an additional prognostic factor for SCNSL while reinforcing CNS-IPI’s prognostic value. Non-GCB COO pts had a higher risk of SCNSL even when adjusted by CNS-IPI risk. Despite advancements in management, SCNSL pts continue to have poor outcomes. Strategies to reduce the incidence of CNS relapse in high-risk pts require further investigation. MER CNS relapse hazard ratios (95% CI). Characteristics Hazard Ratio 95% CI P-Value CNS-IPI Group 0-1 Low Ref Ref Ref 2-3 Intermediate 2.32 1.09 - 4.92 0.029 4+ High 3.59 1.49 - 8.62 0.004 Cell of Origin* GCB Ref Ref Ref non-GCB 2.19 1.08 - 4.42 0.029 Double Hit* non-DHL Ref Ref Ref DHL 1.08 0.14 - 8.3 0.941 Not Done/Missing 1.38 0.76 - 2.51 0.297 Double Expressor* Negative Ref Ref Ref Positive 2.36 0.71 - 7.85 0.162 Not Done/Missing 1.91 0.89 - 4.08 0.097 IC Group* R-CHOP R-EPOCH Ref 1.63 Ref 0.71 - 3.74 Ref 0.249 Other IC 1.18 0.57 - 2.46 0.660 Any EN Involvement* No Ref Ref Ref Yes 0.98 0.51 - 1.88 0.946 Albumin Group* >=Normal Ref Ref Ref <Normal 1.70 0.75 - 3.85 0.201 Head & Neck Involvement* No Ref Ref Ref Yes 0.35 0.048 - 2.63 0.310 *Adjusted by CNS-IPI risk group.

Abstract Extramedullary disease (EMD) is associated with an inferior prognosis and lower response rates to conventional multiple myeloma (MM)–directed therapies compared to MM without EMD. A deeper understanding of the molecular landscape and underlying drivers of EMD is essential to identify potential targets for novel therapeutic strategies. To address this, we performed whole-exome sequencing on EMD tumor tissue from 18 unique patients and bone marrow aspirates (BMAs) from 20 patients at the time of EMD development. Notably, paired EMD and BMA samples were collected from 6 patients at the point of EMD diagnosis, allowing for direct comparison of molecular profiles. Our analysis revealed a near-universal presence of mutations within the MAPK pathway in EMD samples (94%), compared to BMAs (60%; odds ratio, 10.7; P = .02; q &lt; 0.1). Additionally, mutations in established driver genes (NRAS, KRAS, and BRAF) were common and frequently clonal, suggesting their central role in EMD pathogenesis. We also identified alterations in genes associated with cell adhesion and migration (ROBO1, ROBO2, and FAT1) and the SWI/SNF complex and epigenetic regulators (ARID1A, KMT2C, KMT2D, and EP300), although these were predominantly subclonal. Furthermore, we frequently detected biallelic alterations in the tumor suppressor genes MAX (22%), a binding partner for MYC, and CDKN2C (17%). Genomic complexity was significantly higher in EMD samples than BMAs, as evidenced by increased tumor mutational burden and the enrichment of 1q gain/amplifications. These findings underscore the distinct molecular profile of EMD compared to BMA and highlight the genomically complex and heterogeneous nature of extramedullary disease in MM.

Extramedullary multiple myeloma (EMM), defined in this review as soft tissue plasmacytomas resulting from hematogenous spread, is characterized by the ability of MM cells to proliferate outside of the bone marrow microenvironment. It is aggressive, often associated with high-risk cytogenetics and early relapse, and independently portends significantly shorter progression-free and overall survival, even in the era of highly effective immunotherapies. The molecular and microenvironmental factors underlying extramedullary MM dissemination continue to be studied to inform the development of better treatments. In this review, we discuss our current understanding of the biology of EMM, focusing on its distinct molecular and microenvironmental characteristics vis-à-vis MM. We also review the current treatment strategies, acknowledging the paucity of large, randomized studies specific to this population.