Triple-class–exposed (TCE) relapsed/refractory multiple myeloma (RRMM) is associated with cumulative immunosuppression and heightened infection risk. In this longitudinal, retrospective, observational study, US claims data from the Komodo Healthcare Map (KHM; n = 2702; median follow-up, 9.5 months) and the All-Payer Claims Data (APCD; n = 1755; median follow-up, 14.9 months) were used to assess infection burden in patients with TCE RRMM receiving non-bispecific antibody therapies after ≥4 prior lines of therapy (LOTs). The study period was from 1/1/2016 through 10/31/2024. Median (range) index LOT number was 5 (5–5; KHM) and 5 (5–6; APCD); median (interquartile range) age was 67.0 (60–75; KHM) and 71.0 (64–77; APCD) years. Across datasets, the weighted average rate for any infection was 63.5% (95% confidence interval [CI], 61.2–65.8), with the most common infection type being bacterial (58.2%), then viral (27.4%) and fungal (8.2%). Severe infections occurred in 46.1% of patients (95% CI, 44.1–48.1). Cumulative infection rates increased from 49.5 (26 weeks) to 66.4% (52 weeks); cumulative severe infection rates increased from 31.5 to 44.9%, respectively. These findings demonstrate substantial real-world infection burden in heavily pretreated patients with TCE RRMM receiving non-bispecific antibody and non–CAR-T therapies, underscoring the need for infection prophylaxis and supportive care.
Lenalidomide (len) and rituximab (R2) is standard second-line therapy for follicular lymphoma (FL), and the backbone and comparator for several new therapies. This systematic review and meta-analysis of R2 or len-anti-CD20 monoclonal antibodies aims to clarify efficacy across trials, and to evaluate the benefit of triplet therapies including R2. Across 24 treatment arms involving 2245 patients, 63% received R2 or len-anti-CD20 and 37% received it with an additional agent. For R2/len-anti-CD20, the overall response rate (ORR) was 75.9% (95% CI 72.1–79.3, p = 0.0092; I2 = 53.5%), and complete response rates (CR), 39.6% (95% CI 32.4–47.3, p < 0.0001, I2 = 73.2%). ORRs were similar whether studies included or excluded rituximab-refractory, but CR appeared lower (28.6% vs. 42.9%). The number of prior lines of therapy did not affect response. Adding a third agent to R2 or len-anti-CD20 resulted in similar ORRs but significantly higher CR and 1- and 2-year progression-free survival appeared longer than that seen with R2. However, triplet regimens were associated with increased grade ≥3 toxicity. These findings reinforce the role of R2 in R/R FL in the modern treatment era. R2 at first relapse is effective across rituximab sensitivity profiles. Triplet combinations built on the R2 backbone improve efficacy but require careful patient selection and monitoring due to higher toxicity risks.
T-cell redirection therapies, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T therapy, have transformed the treatment of relapsed or refractory hematologic malignancies. However, comparative data on infectious complications between these treatments remain limited. We performed a propensity score-matched analysis of adults with hematologic malignancies treated with BsAbs or CAR T using the TriNetX global research network. To mitigate confounding, we utilized 1:1 propensity score matching (caliper 0.1) to balance cohorts on demographics, malignancy type, comorbidities, and prior treatments. The primary outcome was 1-year infection hazard in BsAbs vs. CAR T. We included 2 192 matched patients (1 096/group; mean age 65.8 (11.4) years for BsAbs, 65.4 (10.2) years for CAR T). Multiple myeloma was the most common malignancy (~62%). At 1 year, infection hazard was not statistically different between cohorts (BsAbs: 57% vs. CAR T: 55.9%; HR: 1.07; 95% CI: [0.96–1.20]). Early phase infection hazard (days 1–30) was lower with BsAbs but not statistically significant (HR: 0.87; 95% CI: [0.74–1.02]). However, BsAbs therapy was associated with higher infection hazard during intermediate (days 31–180; HR: 1.27; 95% CI: [1.10–1.46]) and late phases (days 181–365; HR: 1.20; 95% CI: [1.01–1.41]). In the late phase, BsAbs carried higher hazard for fungal (HR: 2.14; 95% CI: [1.26–3.64]) and viral pathogens (HR: 1.32; 95% CI: [1.02–1.73]). Respiratory tract infections were the most frequent complication and were higher with BsAbs across all time windows (1-year: 35.4% vs. 30.4%; HR: 1.32; 95% CI: [1.14–1.53]). In conclusion, among patients captured within TriNetX, the overall observed 1-year infection rate did not differ significantly between BsAbs and CAR T therapy. However, BsAbs therapy was associated with higher coded rates of late-onset infections after extensive adjustment, although residual confounding from disease severity and treatment duration remains possible. Further studies must better define this infection burden and optimize prevention strategies.
Multiple myeloma (MM) is an incurable plasma cell neoplasm characterized by diverse and complex genetic abnormalities, including translocations of immunoglobulin (Ig) genes and a hyperdiploid karyotype. Much of our current understanding of MM genetics, epigenetics, pathogenesis and response/resistance to myeloma directed therapies originated from studies on human MM-derived cell lines (HMCL). In this study, we conducted an integrated multi-omics analysis in five hyperdiploid cell lines established from serial samples from a single relapsed/refractory hyperdiploid MM patient, enabling detailed characterization of the genetic landscape and molecular alterations through disease progression.
Aberrant metabolism, a hallmark of cancer, reveals vulnerabilities across human tumors. Here, we demonstrate that transcriptomic alterations of metabolism-related genes (metabolic transcriptome) in multiple myeloma (MM), classify patients into six metabolic-transcriptional groups characterized by specific metabolic pathways and cytogenetic alterations, independent of currently described myeloma risk groups. Interestingly, hyperdiploid patients clustered into 2 groups (MM5 and MM6) with significantly distinct Progression-Free and Overall Survival. The MM5 group, with worse prognosis, showed a significant enrichment in myeloid and dormant cell signatures. Regulon analysis identified myeloid transcription factors (TFs) as regulators of metabolic, myeloid, and dormant genes in MM5. In addition to myeloid genes acting as potential biomarkers and therapeutic targets, the metabolic gene ACSL1 plays a crucial role in MM5, decreasing cell proliferation by affecting metabolism and mitochondrial function, sensitizing MM to BCL-2 family inhibitors. These findings highlight ACSL1 as a promising therapeutic target for MM5 and provide new insights into MM metabolic heterogeneity that may guide future precision medicine strategies.
High post-infusion absolute lymphocyte count (ALC) following ciltacabtagene autoleucel (cilta-cel) therapy is associated with an increased risk of immune effector cell–associated delayed neurotoxicity (IEC-DNT), including parkinsonism (IEC-PKS) and cranial nerve palsies (IEC-NP). Between December 2024 and August 2025, we evaluated a prophylactic strategy using a short course of dexamethasone (DEX) in 57 patients with high-ALC, defined as a post-infusion ALC of ≥3 × 10⁹/L on serial monitoring after CAR-T infusion. DEX was administered at 10 mg twice daily for a minimum of three days. Outcomes were compared with a historical control cohort of 104 patients with high-ALC treated between February 2022 and November 2024. While DEX appeared to attenuate the severity of facial nerve palsy, it did not significantly improve event-free survival for IEC-DNT, IEC-PKS, or IEC-NP, nor did it reduce the severity of IEC-PKS. Analysis of ALC kinetics demonstrated no statistically or biologically meaningful reduction in lymphocyte expansion, suggesting that the dose and duration of dexamethasone may be insufficient, or that additional immune and host factors contribute to the risk of IEC-DNT. These findings highlight the limited role of corticosteroid prophylaxis and underscore the need for more mechanistically targeted strategies to mitigate this challenging complication of BCMA-directed CAR-T therapy.
Bosmolisib is a novel triple inhibitor of PI3K-δ/γ and DNA-PK for malignancy treatment. This was a first-in-human, phase 1, open-label, dose-escalation, and dose-expansion trial with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Patients received bosmolisib orally once daily in 28-day cycles across four dose levels (50–325 mg) until disease progression or unacceptable toxicity. The study utilized a 3 + 3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), followed by expansion at RP2D. Primary endpoints were safety and MTD/RP2D determination; secondary endpoints included efficacy, pharmacokinetics, and pharmacodynamics. A total of 26 patients were enrolled in dose-escalation (N = 12) and dose-expansion (N = 14). Median age was 65 years with a median of 3 prior therapies. Bosmolisib demonstrated acceptable tolerability; dose-limiting toxicities were observed at 325 mg (alanine transaminase [ALT] increased and erythema multiforme), establishing MTD/RP2D at 200 mg. Most adverse events (AEs) were Grade 1–2, with the most common Grade ≥3 AEs (ALT 23.1%, aspartate transaminase 15.4%). Of 23 evaluable patients, the overall response rate (ORR) was 26.1%, and in PTCL patients, ORR was 31.6% with one patient achieving a durable complete response. Pharmacodynamics profiling showed statistically significant decrease in regulatory T-cells. These findings support evaluation of bosmolisib in a phase 2 trial (ClinicalTrials.gov number, NCT04018248).
Bispecific antibody (BsAb) treatment in multiple myeloma can be associated with adverse events including cytokine release syndrome (CRS), cytopenias, and infections. While granulocyte colony-stimulating factors (G-CSF) can be used to treat neutropenia, little is known about their safety during the BsAb initiation period and whether G-CSF can increase the risk of CRS. To assess the impact of G-CSF on risk of CRS, we included all patients with multiple myeloma who received at least one dose (step-up doses [SUD] and first treatment dose [FTD]), of commercial teclistamab, elranatamab, or talquetamab between November 2022 and April 2024 at Memorial Sloan Kettering Cancer Center (N = 186). Exposure to G-CSF was defined as administration of at least one dose of filgrastim from 48 h before up to 7 days after BsAb SUD or FTD, or one dose of peg-filgrastim between 7 days prior to up to 7 days after BsAb SUD or FTD. Of the 186 patients, 22 were classified as G-CSF exposed. CRS occurred in 16/22 (73%) patients with G-CSF exposure vs 76/164 (46%) of non-exposed. All CRS was grade 1 (56%) or grade 2 (44%) and the majority occurred prior to G-CSF was given (16/22 patients). The median absolute neutrophil count (ANC) at time of G-CSF exposure was 0.5 × 109/L (0.4–0.7). There was a trend towards increased risk of CRS after G-CSF exposure, although not significant (hazard ratio [HR] 1.7, 95% confidence interval [CI] 0.6–4.7, p = 0.3). These results suggest that G-CSF administration can be considered for neutropenia during BsAb initiation.
Outcomes in multiple myeloma (MM) have improved significantly but remain heterogeneous. We assessed the impact of non-biological social determinants of health on treatment and survival outcomes in Australia using data from the Australian and New Zealand Myeloma and Related Diseases Registry. A total of 4405 patients diagnosed with MM between June 2012 and October 2025 across 44 Australian sites were assigned an area-level socioeconomic status (SES) using individual postcodes. Baseline characteristics, treatment and survival outcomes were compared across high (n=1484), medium (n=1463), and low (n=1458) SES tertiles. Lower neighbourhood SES was associated with higher BMI, poorer functional status, more comorbidities (diabetes, cardiac and pulmonary disease), Asian ethnicity and greater remoteness. Independent of these baseline differences, patients from lower SES neighbourhoods were less likely to receive an autologous stem cell transplant (odds ratio = 1.1 medium vs low, p=0.41; 1.5 high vs low, p<0.01) and time to reach ASCT following induction was longer (p<0.001) despite this being standard-of-care therapy with proven survival benefit. Median overall survival was shorter for the low SES group at 78.5 months compared to 92.5 months (HR=0.85, p=0.01) and 86.7 months (HR=0.85, p=0.01) for the medium and high SES groups respectively. These findings demonstrate significant disparities in treatment and outcomes favouring higher SES, independent of biological factors, within a universal healthcare system. This suggests that non-biological factors continue to influence access to standard-of-care therapy and survival, warranting further research to identify and address barriers to equitable care.
Selinexor for the Treatment of Myelofibrosis. SVR35- spleen volume reduction ≥ 35%, TSS- total symptom score.
This phase 3 multicenter trial evaluated the efficacy and safety of adding dual epigenetic agents azacitidine and chidamide to CHOP (AC-CHOP) versus CHOP alone in previously untreated peripheral T-cell lymphoma (PTCL). A total of 128 patients were enrolled from 9 centers in China and assigned according to participating centers (AC-CHOP, N = 84; CHOP, N = 44). Azacitidine 200 mg on days 1–2, 100 mg on day 3 and chidamide 20 mg twice weekly were administered in the AC-CHOP arm. The AC-CHOP arm showed numerically higher ORR (60.7% vs. 54.6%) and CR rate (47.6% vs. 36.4%) than the CHOP arm, although the differences were not statistically significant. A trend toward improved PFS was observed in the AC-CHOP arm (median 10.2 months in the AC-CHOP arm vs. 8.4 months in the CHOP arm, P = 0.093), alongside a significantly improved OS (median 46.2 months vs. 24.1 months, P = 0.023). The safety profile was comparable between the two groups, with hematologic toxicity and infection being the most common adverse events. Genomic profiling showed that DNMT3A mutations were associated with lower response rates, while IDH2 and TP53 mutations were associated with inferior survival outcomes. In conclusion, the addition of chidamide and azacitidine to CHOP did not significantly improve ORR or PFS. Although OS was longer in the AC-CHOP arm, this finding should be interpreted cautiously given the imbalances in post-protocol treatments between the two arms. Integration of molecular profiling may improve risk stratification and inform future biomarker-driven therapeutic strategies in PTCL.
