Hans C. Lee

Multiple myeloma (MM) progresses from precursor states to active disease, and studying tumor microenvironment (TME) evolution across these stages is key to understanding immune dysregulation and therapeutic resistance. Here, we integrated paired single-cell RNA and T- and B-cell receptor sequencing data from bone marrow (BM) samples of 235 patients spanning the disease spectrum. This data set revealed dynamic changes in the abundance and functional states of diverse immune populations, including T, natural killer, B, and myeloid cells. Using nonnegative factorization of cell-subset composition, we identified 5 reproducible TME subtypes, or “ecotypes,” defined by coordinated cellular architectures. These ecotypes captured structured variation beyond disease stage and were associated with distinct cell-cell communication networks, cytokine signaling landscapes, transcription factor programs, and shared gene modules, reflecting a coordinated immune adaptation to microenvironmental constraints. By linking tumor features with immune changes and ecotype distributions, we identified context-dependent associations influenced by both disease biology and treatment effects on the TME. We found that an ecotype enriched for BM-resident populations and limited immune infiltration was associated with tumor expansion and inferior clinical outcomes, whereas ecotypes reflecting T-cell functional states showed distinct associations with immunotherapy response and survival. Our study provides a comprehensive single-cell immune atlas of MM and its precursors, offering insights into TME organization and progression, and may guide the development of stage-specific or ecotype-targeted immunotherapies.

Summary: Deletion (13q)/monosomy 13 (del[13q]/−13) is common in multiple myeloma (MM), but its independent prognostic value remains unclear, particularly in patients treated with modern therapy and upfront autologous haematopoietic stem cell transplantation (autoHSCT). This study aimed to assess its impact on progression‐free survival (PFS) and overall survival (OS), and to evaluate its prognostic impact in the context of established high‐risk cytogenetic abnormalities (HRCA). We conducted a retrospective, single‐centre study of MM patients undergoing autoHSCT between 2010 and 2021 with available fluorescence in situ hybridization results. Among 1680 patients, del(13q)/−13 was identified in 591 (35.2%). Compared with patients without HRCA or del(13q)/−13, isolated del(13q)/−13 was associated with shorter median PFS (37.3 vs. 64.6 months) and OS (105.4 vs. 131.0 months). Patients with concurrent HRCA and del(13q)/−13 had the poorest outcomes, with median PFS and OS of 33.9 and 81.6 months, respectively. Multivariable Cox regression confirmed that isolated/non‐HRCA‐associated del(13q)/−13, was independently associated with inferior PFS (hazard ratio [HR] 1.36, 95% confidence interval [CI]: 1.17–1.58, p = 0.0001) and OS (HR 1.49, 95% CI: 1.21–1.84, p = 0.0002). Del(13q)/−13 is independently associated with inferior PFS and OS in MM patients undergoing autoHSCT, with an additive adverse effect when co‐occurring with HRCA.

The B-cell maturation antigen (BCMA)–targeting bispecific T-cell engager pavurutamab (AMG 701) directs the cytotoxic T-cell response toward multiple myeloma (MM) cells. This phase 1/1b, open-label, dose-exploration and dose-expansion study evaluated the safety, tolerability, and efficacy of pavurutamab monotherapy in patients with triple-class relapsed/refractory MM (RRMM). Pavurutamab (5-18 000 μg) was administered IV weekly with step-up dosing in week 1. Overall, 172 patients received at least 1 dose of pavurutamab; 73 received the recommended phase 2 dose (RP2D; 18 000 μg), with 2 different step-up dosing regimens in phase 1b. Twelve patients had dose-limiting toxicities, which included cytokine release syndrome (CRS) and increased transaminases; none of which occurred at the RP2D. The most frequently reported treatment-emergent adverse events included CRS (74.4%), anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade ≥3 infections were noted in 60 patients (34.9%). The overall response rate (ORR) was 46.5% among all patients and 65.8% (very good partial response [VGPR] or better, 60.3%) among 73 patients treated at the RP2D. At median follow-up of 17.2 months, median duration of response (DOR) was 36.6 months (95% confidence interval [CI], 22.3 to not estimable). Median progression-free survival (PFS) for all patients was 5.5 months (95% CI, 2.8-10.1) and 16.8 months (95% CI, 5.0 to not estimable) with the RP2D. Pavurutamab exposure generally increased in a dose-proportional manner, with high soluble BCMA levels correlating with lower exposure level. The acceptable safety profile, pharmacokinetics, and preliminary efficacy of pavurutamab supports anti-BCMA T-cell engager therapy in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as NCT03287908.

Summary: Bortezomib, lenalidomide and dexamethasone (VRd) and carfilzomib, lenalidomide and dexamethasone (KRd) regimens have been widely used for induction in transplant‐eligible newly diagnosed multiple myeloma (NDMM), yet direct comparisons between these regimens have been limited and inconsistent. We retrospectively analysed 1129 NDMM patients who received KRd ( n = 364) or VRd ( n = 765) before upfront autologous haematopoietic stem cell transplantation at a single‐centre between 2006 and 2021. KRd‐treated patients more often had high‐risk cytogenetics and advanced Second revision of the International Staging System (R2‐ISS) stage. Pretransplant complete response (CR) and ≥very good partial response (VGPR) rates were higher with KRd (23% and 71%) than VRd (16% and 61%; p = 0.002), with superior best post‐transplant ≥CR (71% vs. 60%; p = 0.001) and higher pretransplant measurable residual disease (MRD) negativity (49% vs. 42%; p = 0.027). After a median follow‐up of 38.6 months, median progression‐free survival (PFS) was 62.2 versus 48.7 months (hazard ratio [95% confidence interval] 0.74 [0.59–0.93], p = 0.009) and median overall survival (OS) was not reached versus 122.7 months (0.86 [0.59–1.25], p = 0.43) for KRd and VRd respectively. In inverse probability–weighted multivariable analysis, KRd remained associated with improved PFS (0.76 [0.60–0.97], p = 0.025), with no OS difference. The PFS benefit was most pronounced in standard‐risk, younger and male patients, and those with fewer comorbidities. Overall, KRd induction led to deeper responses and improved PFS compared with VRd.

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

Antibody–drug conjugates (ADCs) represent an important therapeutic modality for the treatment of various hematologic malignancies. These include gemtuzumab ozogamicin and inotuzumab ozagamicin for acute leukemias; brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine for lymphoid malignancies; and belantamab mafadotin for multiple myeloma. Although ADCs do provide an effective off‐the‐shelf approach to selectively deliver cytotoxic agents by targeting specific cell surface antigens, many ADCs have also been associated with unique toxicities related to the antigen target, linker, or payload that have limited their development. In this review, the clinical development and current role of ADCs in the therapeutic landscape of hematologic malignancies are discussed.

In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.