Real-world assessment of early toxicities, treatment modifications, and outcomes with daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) in multiple myeloma

Abstract

Abstract Background: Daratumumab combined with bortezomib, lenalidomide, and dexamethasone (D-VRd) is a widely used frontline regimen for multiple myeloma (MM) patients. While its efficacy has been demonstrated in clinical trials, real-world data regarding treatment-related toxicities, dose adjustments, and their impact on treatment outcomes remain limited. This study aimed to evaluate the incidence and timing of adverse events (AEs) associated with D-VRd in real-world clinical practice. Methods: This retrospective observational cohort study included adult MM patients who received a minimum of four cycles of D-VRd protocol at the National Center for Cancer Care and Research in Qatar between 2020 and 2024. Data were extracted from electronic medical records and included patient demographics, details of AEs, and management strategies for these events. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Descriptive statistics were used to report AEs' incidence and associated treatment modifications. Results: A total of 72 patients were evaluated, with a median age of 53 years (range: 29–69), reflecting the relatively young demographic profile of the country. Most patients were male (69.4%, n=50). The most common myeloma subtypes were IgG Kappa (29.2%, n=21) and IgG Lambda (29.2%, n=21), followed by FLC Kappa (16.7%, n=12). Patients received a median of 5 induction cycles (range, 4–7) before autologous stem cell transplantation (ASCT). Toxicities occurred early in the treatment (within the first 3 cycles at days 30 to 90), with a median time to first AE of 10.5 days. The most frequent AEs were neutropenia (All grade [61.1%]; most Grade 3 [45.5%], median onset 21 days), thrombocytopenia (All grade [45.8%]; most Grade 1 [75.8%], median onset 24 days), hepatotoxicity (All grade [34.7%], mainly Grades 1–2 [65.7%], median onset 13 days), and anemia (All grade [31.9%]; mostly Grades 1–2 [60.9%], median onset 21 days). Less common AEs included thromboembolism (6.9%; median onset 64 days), peripheral neuropathy (5.6%; median onset 61.5 days), dermatological toxicities (13.9%), infusion reactions (18.1%, mostly with intravenous daratumumab), and gastrointestinal AEs such as diarrhea (9.7%), constipation (6.9%), and nausea/vomiting (2.8%). Dose adjustments were required in 26.4% (n=19), and permanent discontinuation of the protocol occurred in 9.7% (n=7). The median time to first dose modification was 42 days. Among the 19 patients who required dose modifications, the most common reasons were neutropenia (n=6), transaminitis (n=2), renal impairment (n=1), thrombocytopenia (n=1), dermatitis (n=1), infections (n=2), baseline cardiomyopathy (n=1), and general treatment intolerance (n=5). Treatment rechallenge was successful in 42.1% of these cases. Lenalidomide was the most frequently modified agent (n=15), followed by bortezomib (n=2) and daratumumab (n=2). Treatment was discontinued in 9.7% (n=7) of patients, mainly due to disease progression (n=4). Other reasons included patient preference (n=2), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (n=1). Supportive care measures were employed with G-CSF often administered to manage neutropenia. Despite AEs-related modifications, the majority of patients were able to complete the intended treatment. At pre-ASCT evaluation, only three patients (4.2%) were refractory to first-line therapy, while most patients achieved complete response (70.8%; n=51), very good partial response (12.5%; n=9), and partial response (9.7%; n=7). The median follow-up duration was 21.2 months, during which 67 patients remained alive at the last follow-up. The median duration of response was 25.5 months. Fifty-seven patients (79.2%) proceeded to ASCT, with no reported cases of stem cell mobilization failure. The overall mortality rate was low at 6.9% (n=5), including one death attributed to Streptococcus meningitis and the other deaths (n=4) due to disease progression. Conclusion: Compared to clinical trials, this real-world study showed that the D-VRD protocol was associated with a comparable incidence of hematologic AEs, a higher incidence of hepatic toxicity, and a lower incidence of peripheral neuropathy. Despite toxicity-related challenges, most patients were able to complete therapy as intended. This supports the feasibility of D-VRd as a frontline regimen when guided by proactive toxicity monitoring and individualized supportive care strategies.