Bill Consolidation of VRD Proves Beneficial in Newly Diagnosed Myeloma
Bill Consolidation therapy with bortezomib (Velcade), lenalidomide (Revlimid) and dexamethasone (VRD) followed by lenalidomide maintenance therapy improved progression-free survival (PFS) and depth of response compared to maintenance treatment alone in transplant-eligible patients with newly diagnosed multiple myeloma, the researchers found.
At a median follow-up of 74.8 months, the median PFS (adjusted for pretreatment) was 59.3 months for patients assigned to VRD union versus 42.9 months for patients assigned to no union (HR 0.81 , 95% CI 0.68-0.96, P= 0.016), reported Pieter Sonneveld, MD, of the Erasmus MC Cancer Institute in Rotterdam, the Netherlands, and colleagues Bill Consolidation
Union reduced the risk of progression or death in most predefined subgroups, including revised International Staging System (ISS) stages I to III, standard risk cytogenetics, and prior therapy. Significant adverse prognostic factors included revised stage III ISS disease (HR 2.00, 95% CI 1.41-2.86) and chromosome 1q amplification (HR 1.67, 95% CI % 1.37-2.04), they noted in the Journal of Clinical Oncology.
In addition, a greater proportion of patients assigned to union achieved a complete response or a rigorous complete response compared to those without union (59% vs. 46%; P<0.001). The authors observed a deepening of the response after union, which included a combined strict complete response and a complete response rate that went from 22% to 34%, and a strict complete response rate that went from 6% to 12. %.
“The results show that consolidation plus maintenance after bortezomib, melphalan and prednisone [VMP] or high-dose melphalan, autologous stem cell transplant [ASCT] deepens the response and dramatically improves PFS over maintenance alone, ”wrote Sonneveld and colleagues.
High-dose melphalan followed by ASCT, along with maintenance therapy with lenalidomide, remains the standard treatment for transplant-eligible patients with newly diagnosed multiple myeloma.
“Consolidation therapy is given to improve response after ASCT and to prevent early relapses,” the authors noted. “However, there are few published randomized consolidation studies.”
In this study, patients received induction with 3-4 cycles of vincristine, cyclophosphamide, and dexamethasone, and stem cell mobilization was performed, after which patients underwent either treatment with 4 cycles of VMP or melphalan high dose and single or double ASCT.
Within 2 months of ASCT or the last VMP cycle, 878 patients were then randomized to receive VRD union (451 patients) or no union (427 patients), followed by lenalidomide maintenance therapy.
Consolidation consisted of 1.3 mg / m2 intravenous or subcutaneous bortezomib given once daily on days 1, 4, 8 and 11, together with 25 mg of oral lenalidomide once daily on days 1 to 21, and 20 mg of dexamethasone orally once daily times a day on days 1, 2, 4, 5, 8, 9, 11 and 12.
The primary endpoint of PFS was defined as the time from second randomization to disease progression or death. In addition to the longer median PFS in the group assigned to union, Sonneveld and colleagues also observed that the rate of 5-year PFS was 50% with union versus 41% without union.
Maintenance treatment with 10 mg lenalidomide was started in 95% of patients with union and 98% of patients without union. The 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 union and 30% of those without treatment continued to receive 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 union and 69% without union, “indicating that longer follow-up is needed to assess OS,” the authors noted.
In a subgroup of 226 patients with strict complete response, complete response, or very good partial response before the start of maintenance therapy, analysis of minimal residual disease (MRD) by flow cytometry demonstrated a 74% MRD negativity rate in patients treated with VRD.
The toxicity was “acceptable and manageable,” reported Sonneveld and colleagues, with 28% of patients in the consolidation group exhibiting grade 3 or 4 adverse events, including neutropenia (13%), thrombocytopenia (12%) and infections (5%).
This study was supported by the Dutch Cancer Society, the European Myeloma Network, and unrestricted grants from Celgene and Janssen.
Sonneveld has disclosed advisory or advisory roles with Celgene, Janssen, Amgen, Karyopharm Therapeutics and CARsgen Therapeutics, as well as research funding from Janssen, Amgen and Skyline Diagnostics.
Other co-authors have reported multiple relationships with the industry.