VRD Consolidation Proves Beneficial in Newly Diagnosed Myeloma

Consolidation treatment with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRD) followed by maintenance with lenalidomide improved progression-free survival (PFS) and the depth of response compared with maintenance alone in transplant-eligible patients with newly diagnosed multiple myeloma, researchers found.

At a median follow-up of 74.8 months, median PFS (adjusted for pretreatment) was 59.3 months for patients assigned to VRD consolidation versus 42.9 months for patients assigned to no consolidation (HR 0.81, 95% CI 0.68-0.96, P=0.016), reported Pieter Sonneveld, MD, of Erasmus MC Cancer Institute in Rotterdam, The Netherlands, and colleagues.

Consolidation reduced the risk of progression or death in most predefined subgroups, including revised International Staging System (ISS) stage I to III disease, standard-risk cytogenetics, and prior treatment. Significant adverse prognostic factors included revised ISS stage III disease (HR 2.00, 95% CI 1.41-2.86) and amplification of chromosome 1q (HR 1.67, 95% CI 1.37-2.04), they noted in the Journal of Clinical Oncology.

Additionally, a larger proportion of patients assigned to consolidation achieved a stringent complete response or complete response compared with those without consolidation (59% vs 46%; P<0.001). The authors observed a deepening of response after consolidation, which included a combined stringent complete response and complete response rate that increased from 22% to 34%, and a stringent complete response rate that increased from 6% to 12%.

“The results show that consolidation plus maintenance after either bortezomib, melphalan, and prednisone [VMP] or high-dose melphalan, autologous stem-cell transplantation [ASCT] deepens the response and significantly improves the PFS in comparison with maintenance alone,” Sonneveld and colleagues wrote.

High-dose melphalan followed by ASCT, as well as maintenance with lenalidomide, remain standard treatment for transplant-eligible patients with newly diagnosed multiple myeloma.

“Consolidation therapy is given to improve the response after ASCT and to prevent early relapse,” the authors noted. “However, there are few published randomized consolidation studies.”

In this study, patients received induction with 3 to 4 cycles of vincristine, cyclophosphamide, and dexamethasone, and mobilization of stem cells was performed, after which patients either underwent therapy with 4 cycles of VMP, or high-dose melphalan and single or double ASCT.

Within 2 months after ASCT or the last VMP cycle, 878 patients were then randomized to VRD consolidation (451 patients) or no consolidation (427 patients), followed by lenalidomide maintenance.

Consolidation consisted of 1.3 mg/m² of either intravenous or subcutaneous bortezomib administered once daily on days 1, 4, 8, and 11, combined with lenalidomide 25 mg orally once daily on days 1 to 21, and dexamethasone 20 mg orally once daily on days 1, 2, 4, 5, 8, 9, 11, and 12.

The primary endpoint of PFS was defined as time from the second randomization to disease progression or death. In addition to the longer median PFS in the group assigned to consolidation, Sonneveld and colleagues also observed that the 5-year PFS rate was 50% with consolidation versus 41% without consolidation.

Maintenance with 10-mg lenalidomide was initiated in 95% of patients with consolidation and 98% of patients with no consolidation. Median duration of maintenance was 35.7 months (IQR 13-78 months) and 31.8 months (IQR 14-88 months), respectively, and at 5 years 35% of patients with consolidation and 30% of those without were still receiving maintenance treatment.

At 4 years after the second randomization, the overall survival (OS) rate was comparable in both arms (81%-82%). However, at 6 years, the OS rate was 76% with consolidation and 69% without consolidation, “indicating that longer follow-up is required to evaluate OS,” the authors noted.

In a subgroup of 226 patients with stringent complete response, complete response, or very good partial response before start of maintenance, minimal residual disease (MRD) analysis by flow cytometry demonstrated a 74% MRD-negativity rate in VRD-treated patients.

Toxicity was “acceptable and manageable,” reported Sonneveld and colleagues, with 28% of patients in the consolidation group experiencing grade 3 or 4 adverse events, including neutropenia (13%), thrombocytopenia (12%), and infections (5%).