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ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

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.

4500 Background: BM occur in ~30% of RCC pts and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in advanced prostate cancer. A pilot study of radium-223 with VEGF tyrosine kinase inhibitors (TKI) in RCC with BM showed safety and early efficacy (McKay, CCR, 2018). Cabozantinib is a TKI that showed efficacy in BM. RADICAL (NCT04071223) was designed to investigate cabozantinib ± radium-223 in RCC with BM. Methods: This open label multicenter study enrolled RCC pts with ≥1 symptomatic BM not previously irradiated and Karnofsky performance status ≥60%. Prior therapies were allowed; non-clear cell population was limited to 20%. Randomization was 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, baseline opioid use, and IMDC risk. In Arm A, cabozantinib was 40 mg daily cycle 1, 60 mg thereafter if tolerated; radium-223 was 1.49 microcurie/kg IV every 28 days for 6 doses. In Arm B, cabozantinib was 60 mg daily. The primary endpoint was SSE-free survival (SSE-FS). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study was designed with 85% power to detect improvement in 6-month SSE-FS from 65% to 78% (one-sided α=0.05), with planned interim futility analysis at 50% of expected events. Results: From 12/2019 to 9/2025, 90 pts were enrolled and evaluable for the interim analysis. Median age was 63 years; 74.4% male, 90.0% White, 83.3% clear cell histology. 11.1% were treatment naïve, 80.0% received OTT, 51.1% had baseline opioid use. IMDC risk was 16.7% favorable, 68.9% intermediate, 14.4% poor. Median cabozantinib dose was 31.4 mg (Arm A) and 40.0 mg (Arm B); median radium-223 cycles was 6. Median follow-up was 13.1 (range 0.1-49.4) months with 50 events, 17 SSEs (Arm A: 10; Arm B: 7) and 33 deaths (Arm A: 13; Arm B: 20). Outcomes are in Table. 71 pts were evaluable for response. ORR was 22.2% (Arm A), 22.9% (Arm B). Any grade treatment-related adverse events were 97.7% (Arm A), 93.2% (Arm B); grade ≥3 were 65.9% (Arm A), 56.8% (Arm B). The trial closed after interim analysis as SSE-FS did not meet the prespecified futility boundary (HR≤1). Conclusions: Radium-223 did not improve the primary endpoint of SSE-FS when added to cabozantinib but a numerical prolongation in OS was observed. Combination treatment was safe. Alternative radiotherapeutics warrant investigation in RCC. Clinical trial information: NCT04071223 . Interim efficacy analysis. Arm Median(95% CI) HR (95% CI) Stratified SSE-FS A 17.9 (15.0-NE) 1.24 (0.62-2.48) B 17.6 (10.9-NE) Unstratified SSE-FS A 17.9 (15.0-NE) 0.90 (0.51-1.59) B 17.6 (10.9-NE) OS A 32.2 (17.9-NE) 0.77 (0.42-1.41) B 21.3 (12.3-NE) Stratified PFS A 11.0 (5.8-17.4) 1.39 (0.72-2.66) B 11.2 (9.0-18.5)

4559 Background: Baseline QOL has been linked to survival in mRCC therapy clinical trials (Cella, 2024); however, there is a paucity of prospectively collected real-world QOL data across front-line management strategies. We used data from ODYSSEY to examine the relationship between baseline QOL and early death. Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology); have no prior systemic therapy (ST) or be within 3 months of starting ST; and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Early death was defined as death within 12 months post-enrollment. All pts with non-missing FKSI-19 or FKSI-DRS at enrollment were included. Cumulative event probabilities as a function of time were stratified by either < or ≥ median QoL value and plotted as a step function vs time since enrollment to create cumulative event curves. To determine association between QoL at enrollment and early death, separate Cox proportional hazards models (unadjusted and adjusted) for time-to-first-event as a function of baseline QoL were fit. The adjusted model controlled for the following baseline covariates: IMDC risk (favorable vs intermediate or poor), histology (clear cell vs non). Results: As of 1/5/26, 468 pts were enrolled; 425 had non-missing FKSI-19 or FKSI-DRS at enrollment (329 immediate ST, 96 deferred ST [DST]). ST included 129 IO-IO, 108 IO-TKI, 92 Other. DST included 57 Active Surveillance, 22 Local Therapy Planned, 17 Other/Missing. 209 and 190 pts have < median FKSI-19 (score = 59) and FKSI-DRS (score = 29), respectively; 216 and 235 pts have ≥ median FKSI-19 and FKSI-DRS, respectively. Those below the median have lower rates of nephrectomy, worse IMDC risk and KPS, shorter time since RCC diagnosis, and higher rates of bone metastasis (all p<0.05). Cumulative event probabilities for death at 12 months are 21% and 7% in those < and ≥ median baseline FKSI-19, respectively; and 21% and 7% in those < and ≥ median baseline FKSI-DRS, respectively. For FKSI-19, the unadjusted hazard ratio (HR) for early death is 0.55 (95% CI: 0.43 – 0.70; p<0.001) and adjusted HR is 0.65 (0.49 – 0.85; p = 0.002) per 1 SD higher score. For FKSI-DRS, the unadjusted HR for early death is 0.57 (95% CI: 0.46 – 0.71; p<0.001) and adjusted HR is 0.66 (0.51 – 0.86; p =0.002) per 1 SD higher score (higher score indicates better QOL). Conclusions: Across management strategies in our ODYSSEY cohort of systemic therapy naïve mRCC patients, better baseline QOL was associated with better survival. This is to our knowledge the largest reported real world mRCC cohort with prospectively collected PROs. Future analyses will focus on association of outcomes with longitudinal PROs. Clinical trial information: NCT04919122 .

TPS577 Background: Pembrolizumab (pembro) for one year following resection of localized high risk clear cell renal cell carcinoma (ccRCC) in a phase 3 trial resulted in improvement in relapse-free survival and overall survival (Choueiri, NEJM 2024). However, 20% of patients still experienced a relapse within 2 years with no biomarker yet identified to predict who will respond to or needs adjuvant therapy. Addition of a tyrosine kinase inhibitor (TKI) to immunotherapy (IO) is a standard of care in metastatic ccRCC, but to date no studies have addressed the addition of a TKI to IO in the adjuvant setting. Subsequently, phase 3 STRIKE! was developed to explore the benefit of 6 months of tivozanib (tivo) added to pembro vs pembro alone in the adjuvant setting for resected high risk ccRCC. Methods: Eligible patients have an ECOG performance status ≤2 and a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features after complete resection of the primary tumor, with pathology revealing pT2 grade 4 disease or any grade ≥ T3 or TxN1. Patients are also eligible if they developed metastasis within a year after resection and then underwent resection, definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) with no evidence of active disease (M1NED). Patients will be randomized 1:1 to intravenous pembro for 48 weeks with or without the addition of tivo 1.34 mg by mouth daily D1-21 q28D for 6 months stratified by stage (T2T3 vs T4/N1 vs M1NED) . With no limit on dose holds or interruptions of tivo, dose reductions of tivo to 0.89 mg D1-21 q28D or tivo 0.89 mg every other day are allowed. No dose reductions of pembro are permitted. Following baseline imaging to confirm no disease, imaging is performed every 12 weeks for first year, every 16 weeks for second year, every 24 weeks for third year and then annually until 5 years after registration or progression. The primary endpoint will be disease-free survival (DFS) as assessed by investigator, with secondary endpoints being overall survival, safety and tolerability. The study will enroll 1040 patients to detect a minimum detectable hazard ratio of 0.67 (24-month DFS 84% in experimental arm) with 90% power. Quality of life analysis will compare global quality of life and fatigue between the two arms. Imaging and specimens will be banked for future research. The study opened to accrual in April 2025 and at this time 106 patients have enrolled. Clinical trial information: NCT06661720 .

88 Background: The VISION (NCT03511664) and PSMAfore (NCT04689828) clinical trials have demonstrated the effectiveness of 177 Lu-PSMA-617 in patients with mCRPC who have previously received androgen receptor pathway inhibitors (ARPIs) with or without taxane-based chemotherapy. Sipuleucel-T is used for treatment of mCRPC in routine clinical practice, particularly among community urologists; however, to date, there are no data available to understand the effectiveness of 177 Lu-PSMA-617 in patients previously treated with sipuleucel-T. Methods: This was a retrospective, observational study of adult patients with a diagnosis of mCRPC who received 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, and had a history of treatment with sipuleucel-T. Data were obtained from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US that integrates electronic health records and claims data from community, academic, urology, and medical oncology settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and prostate-specific antigen (PSA) response rates were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was analyzed using Kaplan–Meier curves. Results: A total of 290 patients met the inclusion criteria, of whom 72% were White and 12% were Black. At index, 32% of patients were treated in urology and 68% in oncology settings. The median age was 74 years, the median baseline PSA was 35.3 ng/mL (interquartile range [IQR] 10.0–99.2 ng/mL), and 57% of patients had a Gleason score of ≥8. In addition to sipuleucel-T, prior to 177 Lu-PSMA-617, 97% of patients had received ≥1 ARPI and 79% had received ≥1 taxane. The median follow-up for this cohort was 9.4 months (IQR 5.3–17.5 months). Among 144 patients with available PSA values both before and during 177 Lu-PSMA-617 treatment (representing 50% of the cohort), PSA response rates were as follows: a ≥50% reduction in PSA from baseline (PSA50) was observed in 60%, PSA80 in 42%, and PSA90 in 33% of patients. Overall, the median PFS was 15.2 months (95% confidence interval [CI] 11.6–19.4 months). Conclusions: In this real-world analysis of patients who received 177 Lu-PSMA-617 after sipuleucel-T treatment, the median PFS was similar to that observed in clinical trials, suggesting that 177 Lu-PSMA-617 can be sequenced after sipuleucel-T treatment in appropriate patients.

81 Background: In the PSMAfore clinical trial, 177 Lu-PSMA-617 achieved a PSA50 (defined as a ≥50% reduction in prostate-specific antigen [PSA] from baseline) response rate in 58%, a median radiographic progression-free survival (PFS) of 12 months, and a median overall survival (OS) of 25 months among taxane-naïve patients with mCRPC who had received one prior androgen receptor pathway inhibitor (ARPI). The aim of the present study was to evaluate the real-world effectiveness of 177 Lu-PSMA-617 in taxane-naïve patients with mCRPC who had received one or more prior ARPIs. Methods: This retrospective, observational study included taxane-naïve adults with mCRPC initiating 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, after ≥1 prior ARPI. All data for the study were extracted from the PRECISION data platform, a harmonized dataset of patients with advanced prostate cancer in the US treated in a variety of clinical settings. The index date was the date of 177 Lu-PSMA-617 initiation. Patient characteristics and PSA response rates were evaluated descriptively. PFS, defined as the time from 177 Lu-PSMA-617 initiation to progression or death, was estimated using Kaplan–Meier methodology. Results: A total of 500 patients were included. The median age was 75 years, 75% of patients were White and 8% Black, and 18% were treated in urology centers while 82% were treated in oncology centers. The most common site of metastasis was bone (77%), followed by lymph node (21%), visceral (12%), and unknown (5%). Overall, 51% had received 1 previous ARPI while 49% had received ≥2. The median baseline PSA was 26.7 ng/mL (interquartile range [IQR] 10−105 ng/mL) and the median time from mCRPC diagnosis to 177 Lu-PSMA-617 initiation was 23.6 months. The median number of 177 Lu-PSMA-617 cycles received was 4 (IQR 2−6). Among 219 patients with available PSA measurements both before and during 177 Lu-PSMA-617 treatment (representing 44% of the cohort), PSA response rates were as follows: PSA50 in 137 (63%), PSA80 in 86 (39%), and PSA90 in 56 (26%) patients. Overall, the median PFS was 13.5 months (95% confidence interval 11.7–14.7 months). Conclusions: The effectiveness of 177 Lu-PSMA-617 as a standard-of-care treatment in real-world, taxane-naïve patients with mCRPC who had received prior treatment with ≥1 ARPI is consistent with results from the PSMAfore trial, confirming the applicability of those findings to the real-world population now eligible for 177 Lu-PSMA-617. Further research on sequencing 177 Lu-PSMA-617 after one or more prior ARPIs in taxane-naïve patients with mCRPC is needed to guide optimal treatment sequencing in clinical practice.

79 Background: In March 2025, the indication for 177 Lu-PSMA-617 was expanded to include prostate-specific membrane antigen (PSMA)-positive patients with mCRPC treated with ≥1 androgen receptor pathway inhibitor (ARPI) and considered appropriate to delay taxane-based chemotherapy. With 177 Lu-PSMA-617 moving earlier in the treatment journey, it is important to understand the clinical activity of other systemic therapies after 177 Lu-PSMA-617. The aim of this study was to evaluate the clinical outcomes among patients with mCRPC receiving a systemic therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis representative of patients with advanced prostate cancer in the US from diverse clinical settings. Patients with mCRPC treated with 177 Lu-PSMA-617 who received a systemic therapy ≥14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022, and June 27, 2025, were included. Systemic therapies included ARPIs (abiraterone, enzalutamide, darolutamide, apalutamide); chemotherapy (cabazitaxel, docetaxel, carboplatin, cisplatin, etoposide, mitoxantrone); immunotherapy (pembrolizumab, sipuleucel-T); poly (ADP-ribose) polymerase (PARP) inhibitors (niraparib, olaparib, talazoparib, rucaparib); and radium-223. Patient characteristics and prostate-specific antigen (PSA) response were evaluated descriptively. Progression-free survival (PFS) from subsequent therapy initiation was estimated using Kaplan–Meier methodology. Results: A total of 442 patients receiving any subsequent systemic therapy after 177 Lu-PSMA-617 were included. Overall, 95% of patients received ≥1 ARPI and 76% ≥1 taxane pre- 177 Lu-PSMA-617. The median age was 73 years. Most patients received a taxane (n = 188), an ARPI (n = 176), or a PARP inhibitor (n = 33) as their subsequent therapy. The median time to subsequent therapy initiation was 70 days (interquartile range 38−137 days) from the last 177 Lu-PSMA-617 administration. Among 299 patients receiving a systemic therapy after 177 Lu-PSMA-617 with PSA values available both pre-index and during subsequent treatment, 48% achieved a ≥50% reduction in PSA from baseline (PSA50), 31% a PSA80, and 18% a PSA90. The median PFS from the initiation of subsequent therapy was 8.6 months in the entire cohort; this was 10.7 months with a subsequent ARPI, 7.2 months with a subsequent taxane, and 7.1 months with a subsequent PARP inhibitor. Conclusions: In this real-world analysis, meaningful clinical responses were observed in a subset of patients who received subsequent systemic therapies after 177 Lu-PSMA-617.

78 Background: 177 Lu-PSMA-617 is currently under investigation in combination with an ARPI in those with metastatic hormone-sensitive prostate cancer (PSMAddition trial: NCT04720157). This observational study was performed to assess the effectiveness of 177 Lu-PSMA-617 in combination with an ARPI in patients with mCRPC in the real-world setting. Methods: This was a retrospective cohort study of adults with mCRPC in the PRECISION data platform, a comprehensive database of prostate cancer patients compiled from diverse clinical settings in the US. Patients who received 177 Lu-PSMA-617 during March 23, 2022–June 27, 2025 were identified, among whom two cohorts were selected for inclusion: those who had evidence of ARPI use (apalutamide, darolutamide, abiraterone, or enzalutamide) at any time during 177 Lu-PSMA-617 treatment (concomitant ARPI cohort), and those who had no other treatment for mCRPC during 177 Lu-PSMA-617 treatment (no concomitant therapy cohort). The index date was initiation of 177 Lu-PSMA-617. Patient characteristics and prostate-specific antigen (PSA) responses were evaluated descriptively. Progression-free survival (PFS), defined as the time from 177 Lu-PSMA-617 initiation to disease progression or death, was estimated using Kaplan–Meier analysis. Results: A total of 1,880 patients treated with 177 Lu-PSMA-617 were identified, 140 in the concomitant ARPI cohort and 1,740 in the no concomitant therapy cohort. The median age was 74 years. Demographic characteristics were balanced between the groups, except that median baseline PSA was lower in the concomitant ARPI cohort when compared with patients in the no concomitant therapy cohort (18 ng/mL vs. 32 ng/mL). Before 177 Lu-PSMA-617 initiation, 94.3% and 73.6% of patients in the concomitant ARPI and 80.9% and 56.7% in the no concomitant therapy cohort had received ≥1 prior ARPI and ≥1 prior taxane, respectively. PSA response rates were broadly comparable between cohorts. The median (95% confidence interval) PFS was 14.7 (11.7–21.3) months among patients in the concomitant ARPI cohort vs 12.5 (11.5–13.6) months in the no concomitant therapy cohort. Ongoing follow-up aims to evaluate the impact of combining ARPI with 177 Lu-PSMA-617 on long-term clinical outcomes, including overall survival. Conclusions: The results of this study demonstrate that 177 Lu-PSMA-617 delivers clinical benefits inpatients with mCRPC with or without ARPI; however, addition of an ARPI may potentially improve these benefits. Prospective randomized controlled studies are needed to confirm this.