Background: As a minimally invasive procedure, abdominal fat pad biopsy is commonly used as an initial diagnostic screening tool in cases of suspected systemic amyloidosis. However, the reported utility of abdominal fat pad biopsies is highly variable in the literature and sample collection methods are not standardized. A clinical suspicion of poor test performance at our 500-bed academic hospital prompted a retrospective review of abdominal fat pad biopsies performed over a period of twenty-seven months. Methods: The laboratory information system was queried for the terms “amyloid”, “fat pad”, and “biopsy” for the period between January 1, 2022 and April 15, 2024. For identified cases, patient charts were reviewed for the indication for biopsy, biopsy results, follow up studies, clinical outcomes, and follow up duration. Tissue volume for each case was calculated based on the maximum tissue volume that could be derived from measurements noted in the gross sample description. For example, the volume of tissue cores was calculated as though the cores were cubic rectangles (using length * diameter * diameter) rather than cylinders (π(diameter/2)2). For quality control, 10 random negative specimens were sent to a reference laboratory for Congo Red staining and pathologic interpretation. Results: Forty-eight biopsies were identified from 47 patients. The average age was 66 ± 11 years and the average follow up duration for confirmed negative biopsies was 24 ± 9 months. Excluding one excisional biopsy, all other biopsies were needle core biopsies that had a median tissue volume of 36 mm3 (average 295 ± 1444 mm3). In terms of indications for biopsy, 18 cases (38%) were for suspected cardiac amyloidosis and 17 (35%) for neuropathy. Patients had a known monoclonal gammopathy in 25 cases (53%). Of the 48 biopsies, 46 (96%) were negative for amyloid by Congo Red and only 2 (4%) were positive. There was 100% agreement for ten random negative cases sent to a reference laboratory for quality control of staining and interpretation. Follow up for the 45 patients with negative fat pad biopsies showed that 10 (22%) had amyloid confirmed in subsequent targeted organ biopsies, of which 6 were AL-type amyloid and 4 were ATTR. Confirmation of the 2 patients with positive fat pad biopsies showed that 1 was positive for AL-type amyloid by mass-spectrometry, while the other was a false positive. Accordingly, the sensitivity of abdominal fat pad biopsy for systemic amyloidosis in our hands was 9%. No relationship between biopsy size, reading pathologist, or the presence monoclonal gammopathy and biopsy results was found. However,patients being evaluated for cardiac amyloidosis were more likely to have false negative fat pad biopsies than those being evaluated for neuropathy. Conclusions: At our institution, abdominal fat pad biopsy showed limited utility in screening patients suspected of having systemic amyloidosis, with only a 9% sensitivity compared to 43% - 91% reported in the literature. Given the wide range of sampled tissue volumes with the vast majority of biopsies yielding tissue volumes less than 100 mm3, far below the recommended 200 mm3 - 700 mm3, we suspect performance can be improved with standardization of the biopsy procedure with minimal tissue submission requirements. We recommend that institutions periodically review the diagnostic performance of abdominal fat pad biopsies to determine if they are meeting expected diagnostic standards.

Background: Teclistamab, a BCMA×CD3 bispecific T-cell engager, offers an off-the-shelf immunotherapy option for relapsed/refractory multiple myeloma (RRMM). Despite pivotal trial efficacy, real-world outcomes in elderly, comorbid, and geographically isolated patients—underrepresented in MajesTEC-1—are poorly characterized. The Midwest is a high-priority region for study: 46% of residents live in rural areas (vs. 14% nationally), 78% of counties lack clinical trial infrastructure, and patients frequently travel >90 miles for care. This multicenter analysis evaluates real-world effectiveness, safety, and dosing adaptations of teclistamab in Midwest RRMM population, across four high-volume academic centers (Indiana University, the Ohio State University, Penn State University, and University of Wisconsin) serving large rural referral bases in the Midwest. Methods: This multicenter retrospective cohort study included 159 RRMM patients treated with teclistamab as a standard of care across four institutions from October 2022 to March 2025. All patients underwent inpatient step-up dosing and transitioned to outpatient maintenance. Demographics, treatment history (prior BCMA exposure, organ dysfunction), response (IMWG), progression (TTP), overall survival (OS), and toxicity were collected. Dose de-escalation patterns (weekly → biweekly/monthly) and off-therapy were analyzed. Kaplan-Meier curves, log-rank tests, and multivariable Cox models were used for outcome analysis. Results: Patient Characteristics: Median age was 73 years (range 38–88; 62% ≥75 years), with 45% having baseline organ dysfunction and 58% triple-class refractory disease. Prior BCMA-directed therapy was common (38%: 24% CAR-T/BiTE, 14% ADC). Efficacy: Overall response rate (ORR) was 63% (VGPR+: 42%; CR/unconfirmed CR: 21%). The median TTP for the entire cohort was 8.2 months (95% CI 6.1–10.3). A bimodal survival pattern emerged: Non-responders (37%, *n*=59) had rapid disease progression, with a median TTP of 2.1 months (95% CI 1.5–3.0) and accounted for 82% of deaths within 6 months. Responders (63%, *n*=100) demonstrated sustained disease control, with a median TTP of 15.8 months (95% CI 12.4–18.9). Patients responding by 3 months (early responders, 89% of ORR) had 12-month progression-free rate: 68%, while patients not responding by 3 months (late progressors, 11%) had median TTP of 4.3 months (95% CI 3.1–5.8) and 12-month OS was only 21%. TTP was significantly shorter in patients with prior CAR-T/BiTE exposure vs. BCMA-naïve (HR 2.1, *p*=0.003) but not prior ADC (*p*=0.27). Organ dysfunction did not impact TTP (HR 1.1, *p*=0.42). Safety: CRS occurred in 51% (≥G3: 4%), ICANS in 18% (≥G3: 2%), and grade ≥3 infections in 29% (5% fatal). Infection-related mortality was linked to fragmented care transitions (30% referred to community sites post-initiation) and delayed IVIG access (median 21 days from hypogammaglobulinemia). Dosing Heterogeneity & Outcomes: Dose reduction occurred at a median of 14 weeks (interquartile range: 12–18 weeks). Among the 108 patients (68% of the cohort) who underwent dose reduction, a majority (58%, *n*=63) reduced intensity upon achieving ≥VGPR, typically by Cycle 2–3 (median 10 weeks), with 92% maintaining progression-free survival at 12 months. Another 27% (*n*=29) reduced dosing due to adverse events (AEs), primarily infections, at a median of 16 weeks; this group had a 12-month PFS of 76%. The remaining 15% (*n*=16) had unclear cause for reduced frequency, with 81% remaining progression-free. Notably, 22% of AE-driven reductions occurred concurrently with deep responses (VGPR+), blurring the distinction between toxicity-driven and response-adapted decisions. Among responders who continued weekly dosing beyond 12 weeks (32%, *n*=32), 68% developed new or worsening infections, and 44% required unplanned reductions later in treatment. Conclusion: Teclistamab demonstrates robust efficacy and manageable safety in real-world RRMM, including patients traditionally excluded from trials due to age, comorbidities, and rural residence. Short overall TTP reflects aggressive early progression in high-risk subgroups; responders exhibit durable benefit with many remaining on extended or no therapy past 12 months. Response-adapted dosing (biweekly/monthly) optimizes adherence and safety without compromising efficacy—a critical strategy for rural patients. Prior CAR-T/BiTE (not ADC) significantly impairs outcomes, informing therapy sequencing.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10–5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high–risk disease (≥2 HRCAs).

Chimeric antigen receptor T cell (CAR-T) therapy has shown rapid, frequent, and deep responses in patients with relapsed/refractory multiple myeloma (RRMM). However, relapse frequently occurs following CAR-T therapy, and the cause of this resistance is not well defined. Among the potential mechanisms of resistance, T cell intrinsic factors may be an important source of failure. Here we used spectral flow cytometry to identify the changes in T cell phenotypes in bone marrow aspirates at different stages of multiple myeloma progression, including cases that relapsed after anti-BCMA CAR-T therapy. We identified completely different T cell phenotypes in RRMM and post CAR-T relapse cases compared to healthy donors and earlier stages of multiple myeloma, novel double-negative CD3+ T cells in RRMM and CAR-T relapsed cases, and differences in CD8 T cell phenotype at the baseline between peripheral blood and bone marrow from healthy donors. We found that the majority of T cells in RRMM patients and significant T cell subsets in post-CAR-T relapsed patients expressed multiple coinhibitory markers, including PD1, TIGIT, 2B4, and KLRG1.

Extra copies of chromosome 1q21 (+1q: gain = 3 copies, amp >= 4 copies) are associated with worse outcomes in multiple myeloma (MM). This systematic review assesses the current reporting trends of +1q, the efficacy of existing regimens on +1q, and its prognostic implications in MM randomized controlled trials (RCTs). Pubmed, Embase and Cochrane Registry of RCTs were searched from January 2012 to December 2022. Only MM RCTs were included. A total of 124 RCTs were included, of which 29 (23%) studies reported on +1q. Among them, 10% defined thresholds for +1q, 14% reported survival data separately for gain and amp, and 79% considered +1q a high-risk cytogenetic abnormality. Amongst RCTs that met the primary endpoint showing improvement in progression free survival (PFS), lenalidomide maintenance (Myeloma XI), selinexor (BOSTON), and isatuximab (IKEMA and ICARIA) were shown to improve PFS for patients with evidence of +1q. Some additional RCT’s such as Myeloma XI+ (carfilzomib), ELOQUENT-3 (elotuzumab), and HOVON-65/GMMG-HD4 (bortezomib) met their endpoint showing improvement in PFS and also showed improvement in PFS in the +1q cohort, although the confidence interval crossed 1. All six studies that reported HR for +1q patients vs. without (across both arms) showed worse OS and PFS for +1q. There is considerable heterogeneity in the reporting of +1q. All interventions that have shown to be successful in RCTs and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention. A more standardized approach to reporting this abnormality is needed.

Monoclonal proteins are common, with a prevalence in the United States around 5% and the incidence increases with age. Although most patients are asymptomatic, the vast majority of cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma (MM). In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. In this review, we summarize the current diagnosis treatment guidelines for MGUS and SMM and highlight recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Introduction: Extra copies of chromosome 1q21 (+1q: gain=3 copies, amp=4 or more copies) have been associated with worse outcomes for patients with multiple myeloma (MM). We performed a systematic review to evaluate current reporting of +1q, efficacy of existing regimens for +1q, and prognostic implications of +1q in MM randomized controlled trials (RCTs). Methods: We searched three databases for MM RCTs. Our inclusion criteria were all published MM RCTs from 2012-2022. Each MM RCT was analyzed for reported data on +1q. The following features specific to +1q were collected: +1q reported or not as a high-risk cytogenetic alteration, definition of gain1q with respect to percentage of cells with abnormality detected, documentation of distinction between Gain1q and Amp1q in analysis, prevalence of +1q in enrolled population, outcomes of patients [Overall Survival (OS) and Progression Free Survival (PFS)] in patients with +1q in the experimental versus control arm and in patients with and without +1q. Results: A total of 124 trials were included. Among these trials, 28 (23%) studies reported data on +1q, including 26 studies that reported data in the primary manuscript and two studies that reported in separate publication. These trials reported a total of 2692 patients with +1q which represented 25% of all the patients enrolled. Out of 28 trials, three trials (11%) specified the criteria for categorizing patients as +1q (example in IKEMA and IFM-99: the presence of at least three copies in at least 30% of analyzed plasma cells was required). Only four trials (14%) reported survival data on gain and amp separately and the remaining 24 (86%) studies reported for gain or did not specify gain vs amp. Amongst the trials that reported +1q, 22 (79%) considered this to be a high-risk cytogenetic abnormality. Amongst trials that met primary endpoint showing improvement in PFS and clearly reported on +1q, the following drugs also improved PFS for those with +1q (when comparing hazard ratio (HR) for intervention versus control arm in the +1q subgroup): lenalidomide (len) maintenance in Myeloma XI, selinexor in BOSTON, and isatuximab in IKEMA and ICARIA. Several trials met their endpoint and showed improvement in PFS in the +1q cohort in same direction as overall study results but had confidence intervals for +1q subgroup that crossed 1. These included addition of carfilzomib in Myeloma XI, addition of carfilzomib vs bortezomib to len and dex for +1q (but not in Amp1q) in ENDURANCE, addition of elotuzumab to pomalidomide and dex, and bortezomib-based treatment before and after autologous stem cell transplantation (auto-SCT) vs no bortezomib (Table 2). Seven studies reported HR for patients with +1q in the trial (across both arms) compared to those without. In six studies (all studies other than SWOG1211), worse outcomes were seen with respect to OS and PFS for those with +1q versus without (Table 2). Important interventions for which subgroup analysis of +1q was not presented in trial results, and hence conclusions about the efficacy of the drugs specifically for patients with +1q cannot be ascertained included pomalidomide and ixazomib. Although subgroup analysis of various daratumumab trials has shown improvement for high-risk MM, the effect on gain1q was not isolated. Two recent contemporary trials that isolated effect of auto-SCT (DETERMINATION and IFM-2009) did not report +1q. However, in FORTE Trial, adverse prognostic implications of +1q were not seen in the arm receiving carfilzomib, len, dex and auto-SCT, indicating a possible role of carfilzomib and auto-SCT in ameliorating the adverse prognostic implications of +1q. Although len maintenance improved PFS after auto-SCT as maintenance in Myeloma XI overall for those with +1q, it did not appear to improve PFS for patients with isolated +1q (with no other concurrent genetic abnormalities). Conclusion: This systematic review of MM RCTs finds considerable heterogeneity in the reporting of +1q abnormalities in the literature, and +1q to be inconsistently classified as a poor prognostic factor in subgroup analysis of randomized myeloma trials. Most interventions that have shown to be successful in randomized trials and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention in the +1q subgroup. A more standardized approach to reporting of this abnormality is needed.

Chromosome 1 abnormalities are associated with worse outcomes in multiple myeloma. In the accompanying retrospective analysis, the combination of both gain(1q21) and del(1p13.3) had a greater impact on outcomes compared to either abnormality on its own.

S166renal imparement (urea 11.2, creatinine 208), increased IgG, kappa light chains and Bence-Jonce proteinuria.A punch biopsy of the nodule showed infitration of entire dermis with monoclonal plasma cells.The cells were: CD38+, CD138+, CD117 focal+, CD56 +, LCA-, MPO staining of individual cells, CK-, CD34 + in blood vessels.Numerous atypical mitoses are present.A bone marrow biopsy showed up to 5% moncolonal plasma cells.He received Revlimid/Melphalan/Dexa, one cycle.Skin lesions resolved partially.Unfortunately he deceased month later, due to the progressionth of myeloma.Results: Cutaneous lesions of myloma tend to occur with relapses and in highly aggressive and progressive forms of multiple myeloma.In both cases the prognosis is poor with an average life expectancy of 12 months post diagnosis median survival is about 8 months, with less than 20% of patients found to be progression free at 5 years.Histopathological findings are characterised by monomorphic dermal and subcutaneous infiltrates of plasma cells.Immunohistochemically we see monoclonality of the plasma cells which have strong immunoexpression for CD138 (6).These lesions can occur anywhere in the skin but are most commonly seen in the chest and abdomen (44%) involvement of the skin of the extremities is less common.Conclusions: Treatment for cutaneous plasmacytoma in multiple myeloma involves chemotherapy, steroids and local radiotherapy.Surgical excision has a role in lesions resistant to radiotherapy or where lesions are very large and symptomatic.

Background: Quadruplet therapy increases the depth and duration of response in newly diagnosed multiple myeloma (NDMM) patients. In patients receiving same therapy in the context of clinical trials, the achievement of minimal residual disease (MRD) negativity is associated with improved outcomes, yet the use of MRD assessment to modulate therapy in NDMM remains elusive. Aims: We performed a multi-center, phase 2 trial of MRD response-Adapted Sequential ThERapy (MASTER) in patient with NDMM to test the feasibility and demonstrate outcomes of MRD response-modulated duration of therapy and therapy cessation. This is the final trial analysis with median follow up of 42.2 months. Methods: Recruitment included enrichment for patients with MM containing high-risk cytogenetic abnormalities (HRCA). Patients received induction therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd, 4 cycles), followed by autologous stem cell transplantation (ASCT) followed by up to two blocks of consolidation with Dara-KRd (4 cycles each). MRD by next generation sequencing was assessed at each phase of therapy. Duration of therapy was determined by achievement of MRD negativity (<10-5) in two consecutive phases. Patients reaching confirmed MRD negativity transitioned to observation with MRD surveillance (MRD-SURE), otherwise patients received maintenance lenalidomide. Results: MASTER accrued 123 patients. There were 53, 46 and 24 patients with 0, 1 and 2+ HRCA [t(4;14), t(14;16), del(17p), gain/amp 1q]. Of those, 20% had age ≥ 70, 20% R-ISS 3, and 118 (96%) had myeloma trackable by NGS-MRD. MRD negativity was reached in 78%, 86% and 79% (overall 81%) and sustained (>12 months) MRD negativity was reached in 64%, 73% and 46 % of patients with 0, 1 and 2+ HRCA respectively. MRD <10-6 was reached in 68%, 79% and 62% (71% overall) for patients with 0,1 and 2+ HRCA respectively. Overall 84 (71%) patients reached MRD-SURE with treatment cessation. Progression-free survival (PFS) at 3-years for the entire study population is 88.4 %, 78.9% and 50.0% and 3-year OS is 94%, 92% and 75% for patients with 0, 1 and 2+ HRCA respectively. The 3-year PFS was 82% for patients with sustained MRD negativity (N=75) compared to 55% for those without. For the 84 patients reaching MRD-SURE, median follow up from cessation of therapy is 32.7 months and the 2-year cumulative risk of progression is 9%, 9% and 47% for 0, 1 and 2+ HRCA. Twenty-three patients resumed therapy due to progression (N=16) or MRD resurgence without progression (N=7) with 100% OS 18 months after resuming therapy. Sixty-one patients (52% MRD evaluable patients; 73% MRD-SURE) remain free of therapy with sustained MRD negativity. Summary/Conclusion: The use of Dara-KRd induction, ASCT and MRD-modulated post-ASCT consolidation and treatment cessation approach with MRD surveillance provides excellent outcomes and a path for treatment cessation in most patients with standard or high-risk NDMM. Management of ultra-high-risk MM (2+ HRCA) remains an unmet medical need even in the context of quadruplet therapy and these patients maybe candidates for early deployment of strategies including T-cell redirection.Keywords: Monoclonal antibody, Myeloma, Minimal residual disease (MRD)

8014 Background: Despite the use of novel induction regimens, stem cell transplantation (SCT), and maintenance therapy, plasma cell leukemia (PCL) remains a challenging disease with a dismal prognosis. Currently, there is no agreed standard of care management for PCL. We conducted a multicenter retrospective analysis of the clinical presentation, treatment, and outcomes of 150 patients with PCL. Methods: Data of patients diagnosed with pPCL or sPCL between 01/2010 and 01/2021 were entered into a study-specific REDCap database from 7 different U.S. academic sites. PCL was defined as ≥ 5% circulating plasma cells. Clinical data included baseline patient characteristics, clinical presentation, treatment, therapeutic response, and survival outcomes. Overall survival (OS) curves were plotted using the Kaplan-Meier method. Cox proportional hazards regression tested associations between patient characteristics and OS, generating hazard ratios (HR) and 95% confidence intervals (CI), adjusted for PCL type (primary or secondary) and SCT. Results: The analytical cohort included 93 pPCL and 57 sPCL patients. Median age at diagnosis was 60 years. High-risk cytogenetics were found in 56.7% of the patients where it was documented. Of the 79 patients with a documented induction regimen, 58.2% received a proteasome inhibitor triplet, 22.8% received a VTD-Pace like conventional chemotherapy, and 3% received a daratumumab quadruplet regimen. SCT (autologous or allogeneic) was done in 56.1% of the patients. The median OS for all patients, those with pPCL, and those with sPCL was 20.3, 36.6, and 3.2 months, respectively. Secondary PCL was associated with worse survival outcomes compared with pPCL (HR, 2.46; 95% CI, 1.51-3.98; p<0.001) (Table). Median OS was better in patients treated with a proteasome inhibitor triplet regimen vs VTD PACE-like combination (28.2 versus 12.6 months). OS was prolonged among patients who underwent any type of SCT compared with those who did not undergo SCT (44.0 versus 5.7 months, p<0.001). Conclusions: This multicenter retrospective study is one of the largest PCL analyses performed to date and reveals the clinical practice patterns of treatment and survival of PCL patients across the U.S. in the novel treatment era. The survival analysis reinforces the poor prognosis in sPCL patients and the continued need for novel treatment approaches in this patient population. While limited by retrospective design, this analysis suggests prolonged survival with transplantation in both pPCL and sPCL. [Table: see text]