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Abstract Background Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of more than 5% circulating plasma cells on a peripheral blood smear. Despite advancements in therapy, including novel agents and autologous stem cell transplantation (ASCT), pPCL remains associated with markedly poorer survival outcomes compared to newly diagnosed MM. Although disease progression is common in pPCL, individual courses vary widely upon relapse and thereafter. We aim to describe the natural history of pPCL, focusing on clinical features and survival outcomes at the time of relapse or disease progression. Methods Patients with pPCL who were followed at our institution's cancer center between 2006-2024 were included for retrospective analysis. The electronic health record was reviewed to provide detailed information on patient demographics, disease characteristics, treatment regimens, and clinical outcomes. Time to next treatment (TTNT) and overall survival (OS) analysis were performed using the Kaplan-Meier method. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). Results We analyzed a cohort of 106 patients with relapsed pPCL after first-line therapy, all of whom received induction with novel agents. To date, 64 patients (60%) have died. Across the entire cohort, median OS is 39 months (mos) (95% CI: 25-68). 59 patients (56%) were diagnosed after 2015. Baseline FISH cytogenetics were available for 100 patients; 57 (57%) had one or more high-risk cytogenetic abnormality. Nearly all patients (96%) had ≥50% clonal plasma cells on initial bone marrow biopsy. While most patients (n = 61; 58%) were planned to undergo upfront ASCT, 20 (33%) experienced disease progression during induction therapy and required a more intensive salvage regimen (often infusional chemotherapy) prior to ASCT. The median TTNT after first-line therapy (TTNT#1) for the entire cohort was 10.4 mos (95% CI: 8–14). The median TTNT after second-line therapy (TTNT#2) for the entire cohort was 5.7 mos (95% CI: 4.3–7.1). Clinical details at first relapse, prompting initiation of second-line therapy, were available for 91 patients. Of these, 26 patients (29%) had symptomatic relapses—due to CRAB features or extramedullary disease—while 65 patients (71%) experienced asymptomatic biochemical progression. Symptomatic relapses were followed by significantly shorter TTNT#2 (3.9 vs. 7.0 mos; p = 0.039) and inferior OS from the start of second-line therapy (7.5 vs. 31.2 mos; p <0.0001) compared to asymptomatic relapses. The median TTNT#2 for patients who relapsed during induction and received salvage ASCT was 6.9 mos (n=20). In contrast, those treated after relapse with non-ASCT regimens (n = 86) fared worse; those receiving novel agent-based combinations, including doublets, triplets, or quadruplets (n=64) had respective median TTNT#2 of 3.3, 6.0, and 3.3 mos. Patients treated with infusional chemotherapy (n = 9) had the poorest outcomes, with a median TTNT#2 of just 1.4 mos. The median TTNT diminished with each subsequent line of therapy: TTNT#3 (n = 73) was 5.8 mos, TTNT#4 (n = 53) was 4.0 mos, and TTNT#5 (n = 35) was 2.6 mos. Patients with pPCL harboring the t(11;14) cytogenetic abnormality who were treated with venetoclax-based regimens (n = 8) during any line of therapy had a longer corresponding median TTNT of 15.0 mos. Additionally, 23 patients received anti-BCMA CAR-T cell therapy as a post-relapse line of therapy. At last follow-up, 15 of these patients (65%) had not relapsed, and after a median 20.7 mos of follow-up, the median TTNT following CAR-T cell therapy had not yet been reached. Patients who received CAR-T after 1-3 prior lines (n=15) had a median TTNT that was not reached; those who had received 4 or more prior lines (n=8) had a median TTNT of 20 mos. ConclusionsDespite the use of novel agent-based combination regimens and ASCT as first-line therapy, most patients with pPCL eventually experience disease progression. Consistent with MM, symptomatic relapse in pPCL is associated with poorer outcomes compared to asymptomatic biochemical progression. Additionally, the duration of response shortens with each successive line of therapy. Notable exceptions include venetoclax-based regimens in patients with t(11;14), and anti-BCMA CAR-T cell therapies: each appear to confer more durable responses than historical treatments in patients with relapsed pPCL.

Abstract Cardiac involvement in AL amyloidosis significantly impacts both short and long-term survival. Achieving cardiac complete response (CarCR) is linked to excellent survival, comparable to that of the general population. We undertook this study to characterize patients with AL amyloidosis who achieved CarCR. Methods: A single-center retrospective study of patients diagnosed with cardiac AL amyloidosis between 2004 and 2023 and achieved a documented CarCR for at least 12 months. Patients were included if they had evidence of cardiac involvement confirmed by cardiac imaging (transthoracic echocardiogram or cardiac magnetic resonance) and Congo red–positive tissue (non-cardiac or heart biopsy), and were evaluable for cardiac response based on baseline NT-proBNP > 650 pg/mL or BNP > 150 pg/mL. CarCR was defined as a reduction in NT-proBNP to less than 350 pg/mL (or BNP less than 80 pg/mL). Heart transplant patients were excluded. Results: Sixty-three patients were included, representing 4.6% of the cardiac evaluable population in the study period. This proportion increased in the second period compared to the first period (7.5% vs 3.2%, P<0.001). The median age at diagnosis of 57 years (ranging from 29 to 79); 63% were male. Lambda light chain disease was evident in 63% of patients. The median difference between the involved and uninvolved light chain (dFLC) at baseline was 429 mg/L (interquartile range [IQR] 143-708). While all patients had cardiac involvement, 63% also presented with extra-cardiac involvement [kidneys (52%), liver (16%), autonomic nerves (14%), luminal gastrointestinal tract (11%), and peripheral nerves (10%)]. The median baseline NT-proBNP for the entire cohort was 1977 pg/mL (IQR 1393-3026). The median troponin T (n=43) was 0.02 ng/mL (IQR <0.01-0.05) and the median high-sensitivity troponin T (n=19) was 49 ng/L (IQR 38-79 ng/L). Cardiac stage distribution, according to the European modification of the Mayo 2004 staging model, was as follows: 59% stage II, 39% stage IIIa, and 2% stage IIIb. At baseline, echocardiogram features included a median left ventricular (LV) ejection fraction of 63%, a median intraventricular septum thickness of 14 mm, and a median average LV longitudinal strain of -12%. The most common first-line therapies were autologous stem cell transplantation (ASCT; with or without induction, 54%), bortezomib-containing therapy (22%), and daratumumab-containing therapy (13%). Hematological complete response rates at 3-month, 6-month, and best response prior to CarCR were 32%, 49% and 76%, respectively. At CarCR, the median NT-proBNP was 265 pg/mL (IQR 220-307) with a median time from treatment onset to CarCR achievement of 20.6 months. At CarCR, 33% of patients were on loop diuretics. The CarCR rate at 6, 12, 24, 36, 48 and 60 months from treatment onset was 10%, 39%, 81%, 90%, 95% and 96%, respectively. Temporary increase of NT-proBNP above 350 pg/mL with return to CarCR was documented in 46% of patients. Echocardiogram parameters also improved significantly at the time of CarCR, with average left ventricular longitudinal strain showing the greatest median improvement in relation to baseline (from -12% to -17%, p<0.001). However, echocardiographic parameters did not fully normalize in all patients. Cardiac progression was seen in 14% of patients, at a median of 7.6 years from the initial time of CarCR. In addition, subsequent clone-directed therapy was given in 44% of patients at a median of 4.6 years from the initial treatment. With a median follow-up of 9.5 years, eight patients (13%) died, 4 due to causes unrelated to AL. We compared the survival of patients who achieved CarCR to the general U.S. population, matching for age, sex, and the year treatment. The observed survival of CarCR patients was similar to that of the general population (p=0.35). Conclusion: Patients with persistent CarCR >12 months in AL amyloidosis are uncommon and demonstrate excellent outcomes. The achievement of hematological CR was required in 3 out of 4 patients reaching a CarCR. Echocardiographic changes of amyloid infiltration may still persist in this highly favorable cohort, indicating that “complete” response refers primarily to functional and prognostic improvement, not necessarily a full restoration to pre-disease cardiac morphology and function. Achieving CarCR is associated with a low risk of cardiac progression, but the need for subsequent clone-directed therapy remains elevated.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

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 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.

Disease response and progression assessment in multiple myeloma (MM) is based on various measurements of monoclonal protein (serum and urine protein electrophoresis, serum free light chain (FLC, and or quantitative immunoglobulins). Currently, the IMWG consensus response criteria require two sequential assessments of any one marker made at any time before confirmation of disease progression and the institution of any new therapy. However, this can be cumbersome in clinical trials. Herein, we hypothesized that if two markers meet the progression criteria simultaneously, a repeat of either will not be necessary for confirmation. We retrospectively studied all sequential patients with myeloma enrolled in clinical trials at Mayo Clinic. We identified 583 episodes of confirmed progression in our study. Among the 583 progression episodes, nearly 70% (sensitivity of the simultaneous criteria) met the two simultaneous variable criteria at the first testing, indicating progression. Conversely, among 413 patients who met progression criteria by two simultaneous values, 98% (specificity of the simultaneous criteria) of patients subsequently had confirmed progression by sequential values. In summary, for patients with two disease burden markers meeting the simultaneous progression criteria, sequential assessment either one for confirmation may not be necessary to determine disease progression.

e19531 Background: Effective treatment and elimination of clonal plasma cells (PC) in multiple myeloma (MM) are typically associated with recovery of polyclonal (normal) plasma cells (PPC). Studies suggest that robust PPC recovery is associated with better outcomes. However, it is unclear if this remains valid in the context of monoclonal antibodies, such as Daratumumab, that selectively target plasma cells, and in turn, may adversely impact PPC recovery. Methods: We identified patients with MM who underwent MRD testing using Euroflow method at 6-12 months after treatment initiation. Eight patients had disease progression prior to MRD testing and were excluded from further analysis. PPC was quantitated by the proportion of total events acquired during flow examination. Patients were considered MRD-negative if they had <1 clonal PCs in 10 5 cells, as detected in the marrow. We first examined the impact of initial therapy (Daratumumab vs. non-Daratumumab based regimens) and MRD status on PPC recovery. Subsequently, we analyzed impact of PPC recovery on patient outcomes in terms of progression-free survival (PFS) and overall survival (OS). Results: We identified 572 patients who had MRD testing by flow at a median of 9 months (range 6-12) after treatment initiation. The median age was 63 years, 58% were male. Daratumumab was part of initial therapy in 17% of patients; the most common induction therapies were PI-IMiD triplets (73%), and dara-PI-IMiD quads (15%). In our cohort, 74% of patients were MRD-negative. In our practice, only samples with no monotypic PCs identified on initial low-sensitivity flow proceed to MRD testing, hence, the proportion of MRD-negative patients appears higher in our study than previously reported. Median PPC was 0.02% and was similar between MRD-negative and -positive patients. We found the median PPC was significantly low in patients who received Daratumumab compared to the non-Daratumumab treated cohort (0.011% vs. 0.023%; p<0.01). There was a trend towards lower PFS and OS among the lowest PPC quartile group compared to the upper 3 quartiles, although this was not significant (p=0.07 for PFS and OS, Wilcoxon). This trend was more evident among patients who did not receive Daratumumab. Conclusions: Our study demonstrates negative impact of anti-CD38 therapy with Daratumumab on recovery of PPCs after initial treatment, consistent with the persistent hypogammaglobulinemia seen in clinical practice among these patients. However, unlike the observation with the non-Daratumumab treated cohort, the low proportion of PPCs does not significantly impact patient outcomes among patients who received Daratumumab.