Faculty Bibliography

BACKGROUND:Bispecific T-cell-engaging antibodies against BCMA and GPRC5D demonstrate high efficacy in relapsed/refractory multiple myeloma (RRMM) but are associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), traditionally prompting inpatient monitoring when commencing therapy. Contemporary step-up dosing and prophylactic strategies may enable safe outpatient administration. PATIENTS AND METHODS/METHODS:We conducted a single-center retrospective study evaluating outpatient step-up dosing (SUD) of teclistamab or talquetamab in adults with RRMM. Patients met institutional outpatient eligibility criteria and received standard pre-medications; prophylactic tocilizumab was administered at physician discretion. The primary endpoint was incidence and severity of CRS/ICANS. Secondary endpoints included SUD completion, healthcare utilization, and need for hospitalization. RESULTS:Thirty-eight patients underwent 43 outpatient SUD initiations (teclistamab n = 30; talquetamab n = 13). Median age was 72 years, and disease burden was high. SUD completion occurred in 93%. CRS occurred in 26% of initiations and was exclusively grade 1-2; no grade ≥ 3 CRS occurred. One possible grade III ICANS event (2%) occurred after completion of SUD. CRS incidence was similar with and without prophylactic tocilizumab (29% vs 32%). Most events occurred during the first two step-up doses. Hospitalization occurred in 5 (12%) SUD initiations for CRS/ICANS events and overall healthcare utilization was modest. CONCLUSION/CONCLUSIONS:Outpatient administration of teclistamab and talquetamab SUD in RRMM is feasible and safe with low rates of low-grade CRS. Toxicities occur early and are manageable with structured monitoring, supporting outpatient delivery in appropriately selected patients.

BACKGROUND:Bispecific T-cell-engaging antibodies against BCMA and GPRC5D demonstrate high efficacy in relapsed/refractory multiple myeloma (RRMM) but are associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), traditionally prompting inpatient monitoring when commencing therapy. Contemporary step-up dosing and prophylactic strategies may enable safe outpatient administration. PATIENTS AND METHODS/METHODS:We conducted a single-center retrospective study evaluating outpatient step-up dosing (SUD) of teclistamab or talquetamab in adults with RRMM. Patients met institutional outpatient eligibility criteria and received standard pre-medications; prophylactic tocilizumab was administered at physician discretion. The primary endpoint was incidence and severity of CRS/ICANS. Secondary endpoints included SUD completion, healthcare utilization, and need for hospitalization. RESULTS:Thirty-eight patients underwent 43 outpatient SUD initiations (teclistamab n = 30; talquetamab n = 13). Median age was 72 years, and disease burden was high. SUD completion occurred in 93%. CRS occurred in 26% of initiations and was exclusively grade 1-2; no grade ≥ 3 CRS occurred. One possible grade III ICANS event (2%) occurred after completion of SUD. CRS incidence was similar with and without prophylactic tocilizumab (29% vs 32%). Most events occurred during the first two step-up doses. Hospitalization occurred in 5 (12%) SUD initiations for CRS/ICANS events and overall healthcare utilization was modest. CONCLUSION/CONCLUSIONS:Outpatient administration of teclistamab and talquetamab SUD in RRMM is feasible and safe with low rates of low-grade CRS. Toxicities occur early and are manageable with structured monitoring, supporting outpatient delivery in appropriately selected patients.

The phase III CEPHEUS trial (ClinicalTrials.gov identifier: NCT03652064) of patients with transplant-ineligible (TIE) or transplant-deferred newly diagnosed multiple myeloma (NDMM; N = 395) demonstrated improved overall minimal residual disease (MRD) negativity rates among patients achieving ≥complete response and progression-free survival (PFS) with daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) versus VRd. We present efficacy and safety outcomes in the CEPHEUS TIE subgroup (N = 289; DVRd, n = 144; VRd, n = 145). Patients were either age 18-70 years with ≥1 comorbidity likely to negatively affect tolerability of high-dose chemotherapy with autologous stem cell transplantation or age ≥70 years. At a median follow-up of 58.7 months, the MRD negativity rate (10^-5) was 60.4% (DVRd) versus 39.3% (VRd; P = .0004). Rates of sustained MRD negativity (10^-5) for ≥12 months (47.2% v 28.3%; P = .0010) and ≥24 months (40.3% v 22.8%; P = .0015) were significantly higher with DVRd. Risk of disease progression or death was 49% lower for DVRd versus VRd (hazard ratio [HR], 0.51 [95% CI, 0.35 to 0.74]; P = .0003). Although immature, overall survival favored DVRd (HR, 0.66 [95% CI, 0.42 to 1.03]). Adverse events were consistent with known safety profiles. This analysis demonstrates that the deep responses achieved with DVRd translate into improved PFS in patients with TIE NDMM, reinforcing DVRd as a standard of care.

BACKGROUND:Social determinants of health (SDOH) influence cancer prevention and outcomes. Among SDOH, economic stability-including food insecurity, income, employment, and housing stability-has a major impact on health. However, data linking food security status with cancer screening completion remain limited. We examined whether lower food security status was associated with lower completion of colorectal, breast, cervical, and prostate cancer screening. METHODS:We performed a retrospective analysis of the 2018-2023 National Health Interview Survey. Analyses were limited to cancer-specific complete-case cohorts: colorectal (N = 59,849), breast (N = 30,867), cervical (N = 56,229), and prostate (N = 20,518). Food security was categorized as high, marginal, or low/very low. Screening completion was the dependent variable. Multivariable logistic regression estimated adjusted odds ratios (aORs) for screening by food security status, controlling for sociodemographic and clinical covariates. Sensitivity analyses used age-stratified eligibility definitions across survey years. RESULTS:Compared with high food security, marginal food security was associated with lower odds of screening across cancers (aOR range, 0.63-0.88), and low/very low food security showed similar or larger deficits (aOR range, 0.60-0.88). Associations were significant for all four cancers and were similar in sensitivity analyses. CONCLUSIONS:Lower food security status was associated with lower completion of cancer screening. Addressing food insecurity may improve screening equity and reduce cancer disparities. IMPACT/CONCLUSIONS:Lower food security status was associated with lower completion of guideline-recommended screening across four cancers, even after multivariable adjustment. Future work should test whether interventions addressing food insecurity can improve screening.

Artificial Intelligence (AI) is rapidly being incorporated within healthcare, including medical education. Hematology-oncology (HO) is a complex field and AI is of great value in education and practice. We explored HO fellow's confidence and concerns with use of AI, AI training that HO fellows currently receive, and interest in future AI training. Multi-institutional survey administered to fellows in six adult HO programs. The survey was distributed electronically over one month with weekly reminders. Results were collected in RedCap and analyzed using R. 36 of 153 potential participants responded (23.5% response rate). Almost all (35, 97%) reported using AI. Fellows who reported using AI for work used it primarily for patient care (28, 82%) and/or research (29, 85%). Most were "somewhat confident" in the accuracy of AI-generated clinical information (25, 74%) and found AI "somewhat reliable" for clinical decision support (25, 74%). Respondents cited concerns about the use of AI in clinical practice, most often reliability of clinical data (32, 94%). Only one respondent (2.8%) received formal education on AI during fellowship and over who received informal training only reported its quality as "fair" or "poor" with 29 of these remaining 35 (83%) respondents interested in formal training. 31 fellows (86%) reported thinking AI would be important in their future career plans and 17 (49%) felt AI training should be required for HO fellows. While almost all HO fellows use AI, formal education in AI is rare in HO fellowship. Most fellows expressed interested in such training and believe that AI will be important in their careers, but also expressed concerns about use of AI, especially reliability of AI-generated clinical data. We plan to create formal curricula specific to HO training.

In the phase 3 CEPHEUS study, daratumumab plus bortezomib/lenalidomide/dexamethasone (D‑VRd) increased overall MRD-negativity rates versus VRd in transplant-ineligible/transplant-deferred patients with NDMM. We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible, or deferred transplant as initial therapy, were randomized 1:1 to receive D-VRd or VRd. Overall MRD negativity (NGS) was defined as the proportion of patients achieving ≥CR and MRD-negative status assessed at 10-5 (primary endpoint) and 10-6 thresholds. A total of 395 patients were randomized (D-VRd, n=197; VRd, n=198). With 58.7-months median follow-up, overall MRD-negativity rates were significantly higher with D-VRd versus VRd (10-5, 60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; 10-6, 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P<0.0001 and P=0.0001, respectively). Sustained MRD negativity (≥12 months) was also significantly higher with D-VRd versus VRd (10-5: 49.2% vs 27.3%; 10-6: 34.0% vs 16.2%; each P<0.0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all pre-specified timepoints, and cumulatively, with D-VRd versus VRd (10-5 and 10-6). Among patients who achieved MRD negativity, PFS trended in favor of D-VRd versus VRd (10-5, HR, 0.61; 95% CI, 0.35-1.06; P=0.0755; 10-6, 0.66; 95% CI, 0.31-1.41; P=0.2811). Responses with D-VRd are deeper and more durable versus VRd, increasing overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS for patients treated with D-VRd versus VRd (intent-to-treat), with the potential to improve PFS even among patients who achieve MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. Registered at www.clinicaltrials.gov: NCT03652064.

We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.