Consolidation Therapy With VRD Plus Lenalidomide Maintenance Improves PFS in Newly Diagnosed Multiple Myeloma

Consolidation therapy with bortezomib, lenalidomide, and dexamethasone plus lenalidomide maintenance improved progression-free survival in patients with newly diagnosed multiple myeloma.

Progression-free survival (PFS) and depth of response improved from following consolidation bortezomib, lenalidomide (Revlimid), and dexamethasone (VRD) and lenalidomide maintenance in patients with newly diagnosed multiple myeloma, according to results from the phase 3 EMN02/HOVON95 trial (NCT01208766).

At the median follow-up of 74.8 months, the median PFS was 59.3 months for those receiving consolidation, and 42.9 months for those who did not (HR, 0.81; 95% CI, 0.68-0.96; P = .016). Patients had a median duration of treatment of 33 months, and 34% experienced a complete response (CR) after consolidation and 18% experienced it without consolidation (P <.001). A CR seen during maintenance with consolidation was 59% vs 46% without (P <.001).

A total of 1503 patients who were 65 years old or younger were enrolled between February 2011 and April 2014, 1500 of whom were eligible. A total of 1197 patients were randomized to receive either bortezomib, melphalan, and prednisone (VMP; n = 495), or high dose melphalan followed by autologous stem cell transplantation (HDM/ASCT; n = 702). In particular, patients who enrolled on the study received 3 to 4 cycles of induction treatment with vincristine, cyclophosphamide, and dexamethasone followed by VMP or HDM/ASCT. Within 2 months after ASCT or last VMP, patients were randomized a second time to receive consolidation VRD for 2 28-day cycles that included 1.3 mg/m2 of bortezomib, 25 mg of lenalidomide, and 20 mg of dexamethasone, or no consolidation therapy. Maintenance lenalidomide was administered at a dose of 10 mg daily.

A total of 878 patients were eligible for the second randomization, 24 were ineligible. Investigators reported that 427 patients were randomized to arm A and received no consolidation therapy and 451 were in the consolidation arm. The 5-year PFS rate was 50% (95% CI, 45%-54%) in the consolidation group compared with 41% (95% CI, 37%-46%) in the non-consolidation group. The comparison included patients from both randomization groups, and indicated that previous HDM/ASCT treatment was statistically significant (HR, 0.77; 95% CI, 0.64-0,92; P = .003).

A reduction in risk of progression or death was observed among most predefined subgroups, including patients with revised International Staging System (ISS) between stage I to III disease, standard-risk cytogenetics, and who were in prior treatment arms. Consolidation VRD was beneficial for those who did not have a del(17p) mutation (HR, 0.77; 95% CI, 0.64-0.94).

Adverse prognostic factors observed in a univariate Cox regression analysis and included factors at diagnosis among patients who were part of the second randomization such as revised ISS stage III disease (HR, 2.00; 95% CI, 1.41-2.86); B2M of more than 5.5, ISS stage III disease, t(4;14), revised ISS stage II vs I, and high-risk cytogenetics (HR, 1.49; 95% CI, 1.20-1.85); and the addition of chromosome 1q by fluorescent in situ hybridization (HR, 1.67; 95% CI, 1.37-2.04).

The duration of maintenance therapy was 35.7 months for those in the consolidation cohort and 31.8 months in the non-consolidation cohort (P = .24). At 5-years, 35% of patients on the consolidation am and 30% in the non-consolidation arm were still receiving treatment. A total of 288 patients in the consolidation cohort and 302 in the non-consolidation cohort discontinued maintenance therapy, mostly due to progressive disease.

At a median follow-up of 73.4 months, the median PFS from the beginning of maintenance in the consolidation arm was 57.5 months vs 42.3 in the non-consolidation arm (HR, 0.83; 95% CI, 0.70-0.99; P = .04). Four years following the second randomization, the overall survival (OS) from both arms was approximately 81% to 82%. At 6 years, the OS in the consolidation arm was 76% (95% CI, 71%-79%) and in the non-consolidation arm it was 69% (95% CI, 64%-73%).

The median PFS from the start of maintenance for patients who received no consolidation was 85.3 months among those who were minimal residual disease (MRD)–negative patients and 39.3 months in patients who were MRD-positive (HR, 0.49; 95% CI, 0.32-0.73; P <.001). Those in the consolidation arm had a median PFS of 70.1 months among patients who were MRD-negative and 50.6 months in those who were MRD-positive (HR, 0.65; 95% CI, 0.47-0.89; P = .008).

Twenty-eight percent of grade 3/4 toxicities were manageable, with the most common being neutropenia (13%), thrombocytopenia (12%), and infections (5%). Secondary primary malignancies such as superficial skin cancer occurred in 5% and 6% at 6 years in the consolidation and non-consolidation arms, respectively.

Reference

Sonneveld P, Dimopoulos MA, Beksac M, et al. Consolidation and maintenance in newly diagnosed multiple myeloma. J Clin Oncol. 2021;39(32):3613-3622. doi:10.1200/JCO.21.01045