Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAF^V600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

Clinical trial eligibility criteria select a target population and reduce anticipated risks for participants but may unnecessarily limit participation both overall and differently across demographic groups. We previously abstracted eligibility criteria for 190 phase 2/3 acute myeloid leukemia (AML) trials and used US Food and Drug Administration and professional society guidance on modernizing criteria to develop alternative, safety-based eligibility criteria for each trial. In this analysis, these trial- and safety-based eligibility criteria sets were applied to a retrospective cohort of 2226 newly diagnosed patients across 8 hospitals to assess the impact on eligibility. Eligibility proportions increased from a median of 47.9% with trial-based criteria to 84.2% with safety-based criteria (median difference, 30.0%; P< .001); excluding age criteria, the increase was 11.5% (P< .001). Non-Hispanic (NH) Asian, NH Black, NH White, and Hispanic patients were eligible for median proportions of 41.1%, 44.0%, 47.9%, and 50.0%, respectively, with trial-based criteria, increasing by 27.9% to 31.6% when using safety-based criteria (within-group changes, all P< .001; between-group changes, all P> .05). Excluding age criteria, increases were between 10.0% and 11.9%. Moving from trial- to safety-based criteria decreased the proportion of trials with significant eligibility differences between NH White and NH Asian (−11.1%), NH Black (−4.2%), and Hispanic (−12.1%) patients. Criteria significantly associated with increased eligibility and decreased between-group differences in eligibility were coronary artery disease, congestive heart failure, aspartate transaminase level, upper age limits, and previous malignancy. These data suggest that modernization of eligibility for AML trials to focus on safety-based criteria can improve both overall enrollment and population representation.

Monoclonal gammopathy of renal significance (MGRS) is a clonal cell proliferative disorder, characterized by the production of monoclonal immunoglobulins in patients that do not meet hematological criteria for a specific malignancy. It can be present in B cell and plasma cell clonal proliferative diseases and accounts for 10% of monoclonal gammopathy of undetermined significance (MGUS) cases. We present a case of a patient presenting with acute kidney injury, hematuria, and nephrotic syndrome, who after renal biopsy was diagnosed with a proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMIDs), a subtype of MGRS, and treated with chemoimmunotherapy (daratumumab, cyclophosphamide, bortezomib, and dexamethasone), with complete renal function recovery.

Background: High-dose melphalan 140–200 mg/m² (HDM) with autologous stem cell transplant (ASCT) is standard first-line treatment in multiple myeloma (MM), yet standard BSA-based dosing results in wide variation in systemic exposure (AUC). We developed a pharmacokinetic (PK)-guided dosing strategy using a 100 mg/m² first dose, enabling real-time PK assessment and individualized adjustment for the second dose. We report final results of Phase A of our multi-center Phase 1 trial (NCT04483206, MyMel) evaluating feasibility and accuracy of this personalized approach. Methods: Patients received melphalan 100 mg/m² on Day −3, and seven PK samples were collected and shipped overnight for LC-MS/MS analysis. Real-time AUC estimation using noncompartmental analysis (NCA) guided Day −1 dosing to achieve pre-specified AUC targets (13.5 or 14.5 mg × h/L). For comparison, post hoc Bayesian estimation using a nonlinear mixed effects (NLME) model was performed. Sparse sampling designs were evaluated using NONMEM. Results: All 20 patients successfully received PK-guided dosing, with Day −1 doses determined within 48 h. PK-guided dosing reduced AUC variability (CV 4.20–5.62%), with 19 of 20 achieving AUCs within ±10% of the target, compared to what would have been achieved by BSA dosing (CV 9.74–15.34%). NLME improved accuracy, particularly in patients with missing samples, and maintained performance using only four PK time points. Conclusions: This study demonstrates that PK-guided dosing is accurate and feasible with HDM-ASCT. NLME enhances accuracy and enables simplified sampling. Phase B will identify maximum tolerated systemic exposure of seven additional AUC cohorts using the NLME model and a four-sample design.

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity with multiple therapeutic approaches, often modeled after therapies used for multiple myeloma, including anti-CD38 antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation (ASCT). However, because of its rarity, the optimal use of newer agents, ASCT, and maintenance therapy remains poorly defined. We retrospectively analyzed 50 patients with biopsy-proven MGRS treated across 3 institutions. The most common histopathologic diagnosis was proliferative glomerulonephritis with monoclonal immunoglobulin deposits (72%). Median estimated glomerular filtration rate was 32 mL/min (interquartile range, 17-51), and median 24-hour proteinuria was 3.28 g. A total of 37 patients received plasma cell (PC)–directed therapy, and 8 patients received B-cell–directed therapy. Common PC-directed induction regimens included daratumumab-based therapy (32.4%), CyBorD (cyclophosphamide, bortezomib, and dexamethasone; 29.7%), and bortezomib-dexamethasone (29.7%). Maintenance therapy was administered to 13 of 37 treated patients in the PC group (35.1%). With a median follow-up of 6.15 years, the median relapse-free survival (RFS) was 3.74 years in the PC group and 19 years in the B-cell group. Among PC-treated patients, RFS and overall survival (OS) did not significantly differ by induction regimen or use of ASCT. In contrast, maintenance therapy and induction duration >6 months were associated with significantly improved RFS, which remained significant on multivariate analysis. These findings suggest that maintenance therapy and prolonged treatment duration may improve disease control in MGRS and support further evaluation of extended treatment strategies to prevent renal damage and improve long-term outcomes.