Consolidation treatment improves outcomes in newly diagnosed multiple myeloma
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Consolidation treatment before maintenance therapy improved outcomes among transplant-eligible patients with newly diagnosed multiple myeloma, according to study results presented at the virtual ASH Annual Meeting and Exposition.
Patients assigned VRD consolidation — which consists of bortezomib (Velcade, Millennium/Takeda), lenalidomide (Revlimid, Bristol Myers Squibb) and dexamethasone — followed by continuous lenalidomide maintenance achieved longer PFS and higher-quality responses than those assigned maintenance alone, results of the randomized phase 3 EMN02/HOVON95 trial showed.
“The benefit was independent of prior intensification,” Pieter Sonneveld, MD, PhD, professor of hematology and head of the department of hematology at Erasmus MC Cancer Institute and professor of hematology at Erasmus University in the Netherlands, said during a presentation. “Toxicity was acceptable, with 97% of patients completing consolidation without any problems.”
No randomized trial had prospectively assessed the role of consolidation treatment for transplant-eligible patients with newly diagnosed multiple myeloma.
The European Myeloma Network’s EMN02/HOVON95 trial enrolled patients aged 65 years or younger with symptomatic multiple myeloma treated at 172 centers.
In the initial randomization, 497 patients underwent intensification therapy with four cycles of VMP, which consists of bortezomib, melphalan and prednisone. The other 695 patients received high-dose melphalan plus single or double autologous stem cell transplantation.
Sonneveld and colleagues performed a second randomization in which they assigned 878 patients to VRD consolidation followed by lenalidomide maintenance (n = 451) or no consolidation followed by lenalidomide maintenance (n = 427).
Consolidation included two 28-day cycles of VRD, which consisted of IV or subcutaneous bortezomib dosed at 1.3 mg/m2 on days 1, 4, 8 and 11; lenalidomide dosed at 25 mg orally on days 1 through 21; and dexamethasone dosed at 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12.
Maintenance consisted of lenalidomide dosed at 10 mg daily until disease progression or unacceptable toxicity.
The consolidation and no-consolidation groups were balanced with regard to age (median, 58 years vs. 57 years), sex (male, 57% vs. 58%), International Staging System stage (stage I, 42% vs. 42%; stage II, 40% vs. 37%) and percentage of patients with high-risk cytogenetics (22% vs. 22%).
At the time of second randomization, a comparable percentage of patients in the consolidation and no-consolidation groups had achieved stringent complete response (4% vs. 5%), complete response (18% vs. 13%) or very good partial response (45% vs. 49%).
PFS from first randomization and second randomization served as primary endpoints. Response and survival served as secondary endpoints.
At ASH, Sonneveld presented the final analysis of outcomes from second randomization, based on median follow-up of 84 months.
A higher percentage of patients assigned consolidation achieved stringent complete response or complete response (59% vs. 46%; P < .001).
Results showed longer median PFS (59 months vs. 43 months; HR = 0.81; 95% CI, 0.68-0.96) and a higher 5-year PFS rate (50% vs. 42%) after second randomization among patients assigned consolidation.
Researchers observed the PFS benefit across most predefined subgroups — including those with International Staging System stage I to stage III disease and standard-risk cytogenetics — and regardless of treatment group assignment during first randomization.
Cox regression analysis identified two adverse prognostic factors: International Staging System stage III disease (HR = 2.05; 95% CI, 1.43-2.92) and amplification of chromosome 1q (HR = 1.68; 95% CI, 1.38-2.06).
Median duration of maintenance treatment was 33 months (range, 0-97+), and nearly one-third (32%) of patients remained on treatment 5 years after lenalidomide initiation.
Researchers reported no significant OS difference after second randomization but follow-up will continue.
The majority (97.5%) of patients assigned VRD consolidation completed it without dose reduction. Toxicity appeared manageable and acceptable, according to investigators.
Twenty-three percent of patients experienced grade 3 adverse events and 5% experienced grade 4 events. The most common grade 3 or grade 4 adverse events were neutropenia (grade 3, 11%; grade 4, 2%) and thrombocytopenia (grade 3, 10%; grade 4, 2%). All cases were transient, Sonneveld said.
A comparable percentage of patients (5% to 6%) in the consolidation and no-consolidation groups developed second primary malignancies — excluding superficial skin cancer — at 6 years.
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Sonneveld P, et al. Abstract 550. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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