Abstract
Over one-third of Americans are obese, yet guidance on chemotherapy dosing in this group is scarce. Melphalan remains the standard conditioning agent for autologous hematopoietic cell transplant (AHCT) in multiple myeloma. In 2012, the American Society for Clinical Oncology (ASCO) recommended using actual body weight (ABW) for chemotherapy in obese solid-tumor patients, but optimal strategies in hematologic malignancies are unclear. The American Society for Transplantation and Cellular Therapy (ASTCT) endorsed ABW-based melphalan dosing in 2014, acknowledging limited evidence. In practice, many clinicians dose by adjusted body weight (AdjBW) to mitigate toxicity. Prior studies have been confounded by comparisons across BMI categories, including obese and non-obese patients. We conducted a real-world analysis of AHCT outcomes in exclusively overweight and obese patients before and after our institution's protocol change from ABW to AdjBW dosing.
This retrospective study included 617 patients with BMI ≥25 kg/m² who received melphalan conditioning therapy for AHCT at our institution between January 2015 and March 2024. Patients were divided into two cohorts based on institutional dosing protocol: those treated before August 4, 2020 received ABW-based dosing, and those treated after received AdjBW-based dosing (using a 25% correction factor: AdjBW = [0.25 × (Actual − Ideal)] + Ideal). Time to neutrophil or platelet engraftment was defined as ANC >500 cells/µL for three consecutive days or platelet count >20,000 K/uL sustained for seven days without transfusion support. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared via log-rank testing. Fisher's exact test and Wilcoxon rank sum test were used to compare other outcomes between groups.
Of 617 included patients, 332 received ABW-based dosing and 285 received AdjBW-based dosing. Median BMI was similar between groups (30.7 vs 30.5 kg/m²). There were no significant differences in survival outcomes between groups. PFS at twelve months (89% for both) and at three years (67% vs 68%, p=0.74) was comparable. Overall median PFS was 89.8 months (95% CI: 67.0–NA). Similarly, OS at twelve months (95% vs 96%) and at three years (84% vs 87%, p=0.29) showed no significant difference. Overall median OS was not reached; 1-year OS was 96% (95% CI: 94–97%) and 3-year OS was 85% (95% CI: 82–88%).
Engraftment kinetics were also comparable. Median time to neutrophil recovery was 11 days in both groups (p=0.83), and platelet engraftment occurred at a median of 18 vs 19 days (p=0.07) for ABW and AdjBW cohorts, respectively. Length of hospital stay was similar between groups (median 12 days in both, p=0.13).
Notably, gastrointestinal (GI) toxicity, including nausea, vomiting, or diarrhea occurred significantly more frequently in the ABW group when compared to AdjBW (8.7% vs 3.9%, p=0.01). The incidence of infections after transplant was comparable between groups (44.9% vs 36.8%, p=0.1), including bacterial (21.0% vs 15.1%) and viral (22.9% vs 19.3%) infections. Clostridium difficile infections also occurred at similar rates (6.3% vs 4.6%, p=0.38) regardless of dosing.
In this large, retrospective analysis of overweight and obese patients undergoing AHCT for multiple myeloma, there was no survival advantage to melphalan dosing by actual body weight compared to adjusted weight. However, patients receiving ABW-based dosing experienced significantly higher rates of GI toxicity, which may reflect increased drug exposure and reduced tolerability. These findings suggest that adjusted dosing may offer a safer and equally effective strategy in this population. In the context of increasing obesity rates and the need to balance efficacy with tolerability, our results support reconsideration of universal ABW-based melphalan dosing in favor of more individualized approaches. Future prospective studies incorporating pharmacokinetics, toxicity profiles, and patient-reported outcomes are needed to guide optimized dosing strategies for patients with high BMI undergoing transplant.
