Transplant-ineligible myeloma: Daratumumab added to VCD deepens haematological response, improves PFS

Addition of daratumumab to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen provides deeper haematological responses and improves progression-free survival (PFS) in patients with newly diagnosed myeloma who are not eligible for autologous stem cell transplantation (ASCT), according to the results of the AMaRC 03-16 phase II study.

Despite a lack of prospective studies, VCD is widely used as initial therapy in older populations, with most trials having been conducted in the transplant-eligible setting. [Leukemia 2015;29:1721-1729; Lancet Haematol 2020;7:e456-e468] At the same time, daratumumab, when added to standard-of-care regimens for relapsed and untreated myeloma, has consistently demonstrated significant improvements in response rates and induction of minimal residual disease (MRD)–negative responses associated with prolonged PFS and overall survival, with only minor increases in overall toxicity. [N Engl J Med 2016;375:1319-1331; N Engl J Med 2019;380:2104-2115; Lancet 2020;395:132-141]

AMaRC 03-16 was a prospective, multicentre, open-label, response-adapted randomized phase II trial of VCD induction compared with VCD and daratumumab (VCDD) induction followed by daratumumab maintenance until disease progression or toxicity. Patients (median age, 75 years), who were not considered candidates for high-dose chemotherapy with ASCT because of either age >65 years or the presence of comorbidities, were randomized to receive VCDD (n=64) or VCD (n=57). [Blood Adv 2024;8:3721-3730]

Median follow-up by reverse Kaplan–Meier method was 44.7 months. The best achieved overall response rate was 86 and 65 percent in the VCDD and VCD arms, respectively (p=0.007). The rate of very good partial response or better (≥VGPR) was significantly improved by daratumumab (52 vs 28 percent in VCD vs VCDD arm; p=0.009). “MRD assessment by flow cytometry was hampered by delays in transporting samples to the central laboratory caused by the COVID-19 pandemic, which disproportionately affected the VCDD arm. In the modified intent-to-treat analysis set, 16 vs 5 percent of patients in the VCDD vs VCD group were flow MRD–negative [p=0.06],” reported the researchers.

Median PFS was 25.8 and 16.8 months in the VCDD and VCD arms, respectively (hazard ratio [HR], 0.67; log-rank test p=0.066). The proportions of patients who were progression-free were 68 vs 48 percent at 18 months (p=0.0002), 52 vs 36 percent at 24 months (p=0.0001) and 41 vs 27 percent at 30 months (p<0.0001) in the VCDD vs VCD arm, respectively.

Daratumumab PFS benefit was consistent across several subgroups examined, with the exception of the older-age subgroup (age ≥75 years). In the younger-age subgroup (age <75 years), median PFS was 29.8 vs 16.3 in the VCDD vs VCD treatment arm (HR, 0.508; 95 percent confidence interval [CI], 0.265–0.975; p=0.042). In the older-age subgroup, median PFS was 19.0 vs 23.0 months in the VCDD vs VCD treatment arm (HR, 0.834; 95 percent CI, 0.474–1.470; p=0.533).

“This lesser relative efficacy could [be due] to increased infectious toxicity, especially respiratory tract infections, observed with the addition of daratumumab. Patients may not tolerate such infections, leading to dose delay or modification, early therapy cessation associated with loss of disease control, or premature death,” suggested the researchers.

The most common adverse events of any grade in the VCDD and VCD groups were pain (48 and 47 percent), nausea and vomiting (25 and 26 percent), diarrhoea (25 and 21 percent), peripheral neuropathy (28 and 18 percent), fatigue and lethargy (20 and 23 percent), lower limb oedema (22 vs 16 percent), and upper respiratory tract infections (27 and 11 percent). Pneumonia occurred in 11 and 5 percent of VCDD- and VCD-treated patients, respectively.