The addition of daratumumab to bortezomib (Velcade), cyclophosphamide and dexamethasone (VCD) provides deeper haematological responses and improved progression free survival in newly diagnosed transplant-ineligible patients with myeloma.
An Australian phase 2 trial randomised 121 patients with newly diagnosed myeloma, not considered candidates for high-dose chemotherapy with ASCT due to either age >65 years or comorbidities, to either VCD or VCDD.
Patients received nine cycles of VCD or VCDD with daratumumab maintenance continued every 4 weeks until progression.
The study, published in Blood Advances [link here], found the median PFS was 16.8 months in the VCD arm and 25.8 months in the VCDD arm (HR 0.67, log-rank test p=0.066).
“While there is a trend to daratumumab improving PFS, the primary endpoint of the trial was not met which may be related to the sample size not being large enough to detect a significant difference between the arms,” the study authors said.
“It is also possible that imbalances in disease characteristics between the two treatment arms, such as greater advanced stage disease (14.1% vs 5.3%) and high-risk cytogenetics (18.8% vs 12.3%) in the VCDD arm, could have impacted the primary endpoint analysis.”
In a pre-planned analysis, the estimated PFS at specific fixed time-points post-randomisation demonstrated significantly improved PFS for the daratumumab-containing arm from 18 months onwards.
“The proportions of patients who were progression free at the following time points were: 18 months, 48% vs 68% (p=0.0002); 24 months, 36% vs 52% (p=0.0001); and 30 months, 27% vs 41% (p<0.0001) in the VCD and VCDD arms, respectively.”
The study also found the best overall response rate was 65% in the VCD arm and 86% in the VCDD arm (p=0.007).
“The rate of ≥ VGPR was significantly improved by daratumumab (28% in VCD arm vs 52% in VCDD arm, P=0.009). CR rates remained low in both arms (4% vs 6%, p=0.488).”
The investigators, from the Australian Myeloma Research Consortium (AMaRC) included Associate Professor Peter Mollee from Brisbane’s Princess Alexandra Hospital and Professor Andrew Spencer from Alfred Health in Melbourne.
Regarding safety, they found 78% of patients in the VCDD arm completed the planned nine cycles of induction.
The most common adverse events of any grade were: pain (47% in the VCD group and 48% in the VCDD group), nausea and vomiting (26% and 25%), diarrhoea (21% and 25%), peripheral neuropathy (18% and 28%), fatigue and lethargy (23% and 20%), and lower limb oedema (16% and 22%).
The investigators said infective adverse events appeared more common in the daratumumab arm such as upper respiratory tract infections (27% vs 11%) and pneumonia (11% vs 5%), consistent with other studies of daratumumab in myeloma.
“Daratumumab, lenalidomide and dexamethasone remains the current standard of care due to a superior efficacy and toxicity profile,” the study concluded.
“In jurisdictions where this combination is not reimbursed, however, this study supports VCDD, along with daratumumab-VMP as alternate regimens for the initial treatment of non-transplant eligible patients with myeloma.”