Song, Kevin

7546 Background: MRD assessment informs relapse risk in MM but is typically bone marrow-based and invasive. We therefore compared two minimally invasive MRD assays: BM-informed cfDNA whole-genome sequencing (cfWGS) and plasma proteomic MRD (EasyM). Methods: 71 longitudinal plasma samples (22 diagnosis, 49 follow-up) from 22 newly diagnosed MM patients across 8 Canadian sites (TFRIM4) had paired cfWGS and EasyM (Rapid Novor Inc). cfWGS MRD used patient-specific mutation lists from diagnostic BM WGS (Abelman et al., medRxiv 2025). EasyM used mass spectrometry to quantify residual M-protein from baseline. The primary endpoint was progression-free survival (PFS). Results: Among 22 MM patients (8 male, 14 female; median age at diagnosis 62 years), 8 progressed at a median follow-up of 52.6 months (range: 10-79 months). At 1-year maintenance (n = 18 available), cfWGS MRD+ (6/18) predicted inferior PFS (HR 20.12, 95% CI 2.23-181.60, p = 0.007). EasyM any-detect positivity was frequent (16/18, reflecting delayed clearance) and not prognostic (p = 0.99), with poor agreement vs cfWGS (44.4%, κ = 0.118). An exploratory EasyM clearance threshold of 0.93% (hypothesis-generating) classified 5/18 patients as MRD+ and stratified PFS (HR 8.78, 95% CI 1.55-49.82, p = 0.004), improving agreement with cfWGS (17/18, 94.4%, κ = 0.870). Progression clustered in cfWGS+/EasyM-high patients (EasyM >0.93%; 4/5; median 11.9 months post-collection [1.9–22.8]) and occurred once in cfWGS−/EasyM-low patients (1/12, 27.6 months). The only discordant case (cfWGS+/EasyM−) progressed 8.7 months after collection. Higher quantitative MRD burden was associated with inferior PFS (cfWGS: HR 2.92 per 1 SD, 95% CI 1.29-6.59, p = 0.01; EasyM: HR 5.48 per 1 SD, 95% CI 0.79-37.90, p = 0.085). At ~100 days post-autologous stem cell transplantation (ASCT; n = 16 available), EasyM was uniformly MRD+ (16/16) while cfWGS was MRD+ in 7/16 patients. Applying an EasyM clearance threshold (2.13%; 9 cleared vs 7 residual) improved agreement with cfWGS (14/16; 87.5%; κ = 0.746). Of two discordant cases, one cfWGS+/EasyM-cleared patient relapsed 38.6 months post-collection and one cfWGS−/EasyM-residual patient remained progression-free at last follow-up. At post-ASCT, both assays showed consistent but underpowered associations with PFS (cfWGS HR 6.32, 95% CI 0.70–56.76, p = 0.100; EasyM-clearance HR 2.36, 95% CI 0.39–14.18, p = 0.335). Across all post-treatment samples (n = 49), continuous cfWGS burden correlated with EasyM residual M-protein (rho = 0.535, p < 0.001). Conclusions: BM-informed cfWGS MRD strongly stratified PFS, whereas EasyM required a clearance definition due to near-universal early positivity. Concordant plasma burdens support complementary MRD information. Future work will validate these findings in larger cohorts and quantify the incremental value of combined cfWGS and proteomic MRD for early relapse prediction.

Abstract Introduction: Early relapse limits durable remissions in multiple myeloma (MM). Cell-free DNA (cfDNA) fragment patterns capture tumor burden and nucleosome positioning. We tested whether a fragmentomics signature trained at MRD time points stratifies progression-free survival (PFS) when applied to pretreatment plasma. Methods: We performed 30-40× whole-genome sequencing of plasma cfDNA from 43 newly diagnosed MM patients, with 65 additional MRD timepoint samples from 41 of those patients (post-ASCT n=30; 1-year maintenance n=30; other maintenance n=5) across eight Canadian sites (TFRIM4 and IMMAGINE studies) and one U.S. site (Mayo SPORE). MRD testing used multiparameter flow cytometry for all follow-up samples (n=65) and clonoSEQ in a subset (n=31). Logistic and elastic-net models were trained at MRD timepoints on fragmentomics features (short-fragment burden; a combined model integrating fragment-length distributions with inferred nucleosome positioning at MM-specific chromatin accessibility regions [Ordoñez et al., Genome Res. 2020]). A decision threshold was fixed by the Youden index during training and applied unchanged to diagnosis samples. PFS was analyzed by Kaplan-Meier, log-rank, and Cox models. Results: After a median follow-up of 49.1 months, 16 of 43 patients (37%) progressed. Using the prespecified locked threshold, patients classified as MRD+ by the proportion-of-short-fragments model had significantly shorter PFS than MRD- patients (HR = 5.12; 95% CI 1.16-22.57; log-rank p = 0.016), with median PFS of 49.2 months for MRD+ cases versus not reached for the MRD- group. Fixed-horizon PFS favored MRD- samples at 24/36/48 months (100/94/87% vs 85/81/53% for MRD+). A combined model integrating weighted fragment lengths with inferred nucleosome positioning also separated outcomes (log-rank p=0.054); the Cox HR was not estimable because no MRD- patients relapsed. At 24, 36, and 48 months, baseline MRD positivity by the short-fragment model identified 100%, 83%, and 86% of patients who relapsed within those intervals (specificity 44%, 43%, and 52%), while the combined model detected all early relapses across the same horizons (specificity 15-21%), indicating consistently high sensitivity but modest specificity for predicting early progression. Conclusions: A cfDNA fragmentomics signature trained at MRD time points stratified PFS when applied to diagnostic plasma, identifying patients at risk of early relapse. Short-fragment burden was most discriminative, and a combined model with nucleosome positioning recapitulated it with higher sensitivity, albeit lower specificity. These data support cfDNA fragmentomics as a practical liquid-biopsy risk biomarker in MM and suggest higher signals may proxy aggressive disease with greater tumor shedding and chromatin disorganization. Future work will validate findings in larger cohorts and integrate cytogenetic and immune features. Citation Format: Dor David Abelman, Jenna Eagles, Aimee Wong, Saumil Shah, Jeffrey Bruce, Stephanie Pedersen, David S. Scott, Cecilia Bonolo de Campos, Signy Chow, Darrell White, Irwindeed Sandhu, Kevin Song, Esteban Braggio, Shaji Kunnathu Kumar, Alli Murugesan, Tony Reiman, A. Keith Stewart, Suzanne Trudel, Trevor J. Pugh. Baseline cfDNA fragmentomics identifies multiple myeloma patients at risk of early progression [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 2597.

Abstract Introduction: Monitoring minimal residual disease (MRD) is critical in multiple myeloma (MM) to predict outcomes and guide therapy. Traditional bone marrow (BM) aspirates for MRD detection are invasive and limited by sample quality. We therefore explored cell-free DNA (cfDNA) fragmentation as a less invasive alternative for MRD detection. Methods: We performed 30-40X whole-genome sequencing (WGS) on peripheral blood cfDNA from 45 MM patients, collecting baseline (n = 45) and follow-up samples (n = 98) from eight Canadian sites (M4 and IMMAGINE studies) and one U.S. site (SPORE study), plus 25 healthy controls. Samples were collected post-induction therapy (n = 13), 100 days post-autologous stem cell transplantation (ACST, n = 36), and during maintenance therapy (n = 49). Multiparameter flow cytometry (MFC) MRD testing was conducted on 77 samples. We evaluated insert size metrics and MM-specific chromatin accessibility (from Ordoñez et al., 2020) using Griffin (described in Doebley et al., 2022). Results: Baseline samples had a higher proportion of short fragments (20-150 bp) than follow-up samples (p = 0.0037) and healthy controls (p = 0.019). A fragment score (FS) based on weighted fragment distribution (per Vessies et al., 2022) was highest at baseline (mean = -0.384), followed by MRD-positive (mean = -0.495) and MRD-negative (mean = -0.550) samples. MRD-negative FS was lower than baseline samples (p &lt; 0.001) but higher than healthy controls (mean = -0.639; p = 0.016). Baseline samples had lower coverage at MM-specific chromatin regions than MRD timepoints (p &lt; 0.05; baseline mean = 0.982; MRD-positive = 0.989; MRD-negative = 0.994; healthy = 0.993), suggesting higher transcriptional activity pre-treatment. MRD-negative samples had higher coverage than MRD-positive cases (p &lt; 0.01). Using logistic regression, we assessed the predictive performance of FS and coverage at MM-specific sites. FS alone achieved an AUC of 0.632 (sensitivity [SN] 39.4%, specificity [SP] 92.1%, accuracy [AC] 67.6%). Coverage yielded an AUC of 0.681 (SN 75.8%, SP 60.5%, AC 67.6%). Combining FS and coverage at MM sites improved performance (AUC = 0.734; SN 48.5%, SP 92.1%, AC 71.8%). We next evaluated whether adjusting the BM tumor cell percentage cutoff by MFC could improve performance. At 0.017% (1 in 5, 789 cells) for MRD positivity, the combined model’s accuracy reached 83% with an AUC of 0.757 (SN 17%, SP 97%). Conclusions: cfDNA fragmentomic analysis achieved high specificity (92-97%) in detecting MRD, providing a less invasive alternative to facilitate serial monitoring. While sensitivity remains an area for improvement, the high specificity of cfDNA makes it valuable for confirming MRD negativity and reducing invasive procedures. Future efforts aim to enhance sensitivity by integrating additional fragmentomic features. Citation Format: Dor D. Abelman, Jenna Eagles, Aimee Wong, Saumil Shah, Stephanie Pedersen, Stephenie Prokopec, David S. Scott, Sarah Bridges, Darrell White, Irwindeep Sandhu, Kevin Song, Esteban Braggio, Alli Murugesan, Anthony Reiman, Suzanne Trudel, Trevor J. Pugh. Tumor-independent monitoring of minimal residual disease in multiple myeloma using cfDNA fragmentomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3250.

AbstractThe phase 3 FIRST trial demonstrated significant improvement in progression‐free survival (PFS) and overall survival (OS) with an immune‐stimulatory agent, lenalidomide, in combination with low‐dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed‐duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49‐0.97]; p = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT (p = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment‐emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent‐to‐treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant‐ineligible patients with NDMM.

8583 Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n = 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM + LoDEX vs. HiDEX in each of the 5 relevant domains. The cross-sectional analysis indicated statistically or marginally significant (P < .10) differences favoring POM + LoDEX in Global Health Status (C2, 4), Physical Function (C2, 3, 4), Emotional Function (C2, 3, 4), and Fatigue (C2) scores. Longitudinal comparisons between arms confirmed the significance of score changes for Global Health Status (C2; P = .01), Physical Functioning (C3 and 4; P = .018 and .028, respectively), Emotional Functioning (C3; P = .018), and Fatigue (C5; P = .008) for POM + LoDEX vs. HiDEX. HiDEX pts exhibited clinically meaningful worsening in Global Health Status and Physical Functioning scores vs. POM + LoDEX by C2 (P = .04) and C3 (P = .02), respectively. POM + LoDEX extended median time to meaningful worsening vs. HiDEX for Global Health Status (114 vs. 85 days, P = .05), Physical Functioning (174 vs. 106 days; P = .09), Fatigue (113 vs. 60 days; P = .02), Emotional Functioning (190 vs. 124 days; P = .04), and Pain (147 vs. 113 days; P = .2). Conclusions: In heavily pretreated pts who failed LEN and BORT, POM + LoDEX resulted in better clinical outcomes as well as improvement in clinically relevant QOL measurements over the course of treatment. Clinical trial information: NCT01311687.

8528 Background: RRMM patients (pts) who fail lenalidomide (LEN) and bortezomib (BORT) have poor prognosis. High-risk cytogenetics predict shorter survival. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT and high-risk cytogenetics. MM-003 is an open-label, multicenter, phase III trial comparing POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT treatment (Tx) and have progressed on their last therapy. Methods: Pts must have been refractory to the last prior Tx (progressive disease [PD] during or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-day cycles). Tx continued until PD or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and AEs. This analysis examined pts meeting modified high-risk cytogenetic criteria—del(17p13) and/or t(4p16/14q32). Results: 302 pts received POM + LoDEX, and 153 pts received HiDEX. 225 and 107 pts, respectively, were evaluable for cytogenetics. Baseline characteristics were similar. Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX, regardless of cytogenetic risk (Table). The most common grade 3/4 AEs were neutropenia, anemia, and infection (Table). Discontinuation due to AE was low: 4% vs. 6% (high risk) and 10% vs. 4% (standard risk). Conclusions: Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX in pts with cytogenetically-defined high-risk disease, consistent with results from the intent-to-treat population. Tolerability was acceptable. POM + LoDEX should be considered a new Tx option in pts failing LEN and BORT. Clinical trial information: NCT01311687. [Table: see text]

8527 Background: Pts who have exhausted lenalidomide (LEN) and bortezomib (BORT) treatment (Tx) have a poor prognosis. A significant proportion of pts have RI with increasing incidence during disease course. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT, including those with RI. MM-003 is an open-label, multicenter, phase 3 trial comparing POM + LoDEX vs HiDEX in RRMM pts who failed LEN and BORT and progressed on their last Tx. Methods: Pts must have failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination) and must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days). Pts with creatinine clearance (CrCl) < 45 mL/min were excluded. Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) qw; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-D cycles). Tx continued until PD or unacceptable adverse event (AE). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and AEs. This analysis examined pts with or without moderate RI (CrCl < 60 vs ≥ 60mL/min). Results: 302 pts received POM + LoDEX; 153 pts received HiDEX, 31% and 39% had moderate RI, respectively. Pts with moderate RI were more likely to be older (64% vs 36% aged > 65 y) vs no RI. Median follow-up was 4 mo. Median PFS and OS were significantly longer with POM + LoDEX vs HiDEX regardless of RI (Table). Similar AE rates for POM + LoDEX as well as HiDEX Tx were seen in pts with and without moderate RI (Table). Discontinuation due to AE was 5% vs 7% (no moderate RI) and 11% vs 5% (moderate RI). Conclusions: POM + LoDEX significantly extended PFS and OS vs HiDEX in pts with or without moderate RI. Tolerability of POM + LoDEX was acceptable across subgroups, with few discontinuations due to AE. Clinical trial information: NCT01311687. [Table: see text]

8510 Background: RRMM patients (pts) who have exhausted treatment (Tx) with bortezomib (BORT) and lenalidomide (LEN) or thalidomide have a poor prognosis with short overall survival (OS). HiDEX is a well-established standard Tx in RRMM. POM has demonstrated clinical efficacy in pts refractory to LEN and BORT. MM-003 compared POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT and who progressed on their last Tx. Methods: Pts must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20. Tx continued until PD or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS, overall response rate (ORR; ≥ partial response), and safety. Analyses were based on intent to treat. Results: 455 pts were randomized to POM + LoDEX (n = 302) or HiDEX (n = 153). The median number of prior Tx was 5 (range 1-17). 72% were refractory to LEN and BORT. Median follow-up was 4 months. POM + LoDEX significantly extended median PFS (3.6 vs. 1.8 months, HR = 0.45, P < .001) and OS (not reached vs. 7.8 months, HR = 0.53, P < .001) vs. HiDEX. The OS benefit was observed despite 29% of HiDEX pts receiving POM after PD. The trial met the primary endpoint of PFS, crossed the upper boundary for OS superiority, and the Data Monitoring Committee recommended crossover from HiDEX to POM ± DEX. With updated data, the ORR was 21% for POM + LoDEX vs. 3% for HiDEX (P < .001) and 24% vs 3% for pts randomized ≥ 6 months post-enrollment (P < .001). The most frequent grade 3/4 adverse events (AEs) for POM + LoDEX vs. HiDEX were neutropenia (42% vs. 15%), anemia (27% vs. 29%), and infection (24% vs. 23%). Discontinuation due to AEs was infrequent (7% vs. 6%). Updated data will be presented. Conclusions: POM + LoDEX significantly extended PFS and OS vs. HiDEX in pts who failed LEN and BORT. POM + LoDEX should become a standard of care in RRMM pts who have exhausted Tx with LEN and BORT. Clinical trial information: NCT01311687.

SummaryNon‐endemic Burkitt lymphoma (BL) is a rare germinal centre B‐cell‐derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic‐based and population‐based lymphoma registries from six countries were used to identify 264 real‐world patients. The median age was 47 years and the majority had advanced‐stage disease and elevated LDH. Treatment protocols were R‐CODOX‐M/IVAC (47%), R‐hyper‐CVAD (16%), DA‐EPOCH‐R (11%), R‐BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two‐year overall survival and event‐free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two‐year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post‐remission event‐free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real‐world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow‐up strategies with increased focus on survivorship and less focus on routine disease surveillance.