Bortezomib Regimen Yields Notable Efficacy in Waldenström Macroglobulinemia

Bortezomib (Velcade) plus dexamethasone, rituximab (Rituxan), and cyclophosphamide (B-DRC) demonstrated clinical benefit for patients with Waldenström Macroglobulinemia who had a higher tumor burden requiring a faster response, according to findings from the phase 3 European Consortium for Waldenström Macroglobulinemia (ECWM)-1 trial (NCT01788020).

"B-DRC has the advantage over [rituximab]-bendamustine [Treanda] to avoid long-lasting and deep T-cell depletion,” according to the authors of the phase 3 ECWM-1 trial.

The estimated 24-month progression-free survival (PFS) was 80.6% (95% CI, 69.5%-88.0%) with B-DRC vs 72.8% (95% CI, 61.3%-81.3%) with DRC alone (P = .32). Additionally, the 24-month PFS rate in each respective arm was 100.0% vs 100.0% for those with International Scoring System for Waldenström Macroglobulinemia (ISSWM) low-risk disease, 77.7% vs 68.3% for those with intermediate-risk disease, and 77.5% vs 69.8% for those with high-risk disease.

The median overall survival (OS) was not reached in the B-DRC and the DRC arms. Overall, lymphoma-related deaths occurred in 3 patients receiving DRC and 1 patient receiving B-DRC; there was also 1 death due to secondary neoplasia in each arm.

“B-DRC has the advantage over [rituximab]-bendamustine [Treanda] to avoid long-lasting and deep T-cell depletion,” the study authors stated. “This might be particularly important in the era of emerging novel therapies such as bispecific antibodies or CAR-T cells, which are compromised by T-cell exhaustion.”

In the ECWM-1 trial, all treatment-naïve patients with Waldenström Macroglobulinemia received 20 mg of dexamethasone orally once daily on day 1, 375 mg/m² of rituximab intravenously on day 1 and 1400 mg subcutaneously once daily on day 1 during cycles 2 to 6, and 100 mg/m² of oral cyclophosphamide twice a day on days 1 to 5. In the experimental arm, patients received bortezomib subcutaneously at a dose of 1.6 mg/m² once a day on days 1, 8, and 15.

The primary end point of the trial was investigator-assessed PFS. Secondary end points included overall response rate (ORR), best response, time to best response, time to first response, remission duration, and OS.

Patients 18 years and older with a clinicopathological diagnosis of Waldenström Macroglobulinemia were eligible for enrollment on the trial. Additional inclusion criteria included having a World Health Organization or ECOG performance status of 0 to 2 and a life expectancy longer than 3 months.

With a median follow-up of 27.5 months (interquartile range, 17.2-36.1) at time of data cutoff, 100 patients received DRC and 102 patients received B-DRC. In total, 99 and 96 patients, respectively, were treated. The median patient age was 68 years (range, 34-89) in both arms. In terms of ISSWM classifications, 11% of patients had low-risk disease, 39% had intermediate-risk disease, and 50% had high-risk disease in both treatment arms.

Overall, 87% of patients in the DRC arm and 92% in the B-DRC arm received 6 cycles of induction; 7% and 4% of those in each respective arm received 2 or fewer cycles of treatment. The mean dose intensity for bortezomib was 95% (range, 61%-100%) for everyone who received the agent and 40% of patients had bortezomib dose reductions, with a mean dose of 86% (range, 61%-97%) of the full dose.

At the end of treatment, B-DRC and DRC, respectively, yielded a major response rate of 80.6% vs 69.9% and a complete response (CR) or very good partial response (PR) rate of 17.2% vs 9.6%. Additionally, the median time to first response was 3.0 months (95% CI, 2.8-3.2) vs 5.5 months (95% CI, 2.9-5.8) in each respective arm. The major response rate was 57.0% with B-DRC vs 32.5% with DRC after 3 cycles of treatment (P <.01).

Grade 3 or higher adverse effects (AEs) occurred in 49.2% of all patients, including 49.5% of those receiving B-DRC and 49.0% of those receiving DRC. The most common grade 3 or higher AEs in the total patient population included neutropenia (25.6%), anemia (6.2%), and thrombocytopenia (5.1%).

Peripheral sensory neuropathy occurred in 18 patients receiving B-DRC and 3 patients receiving DRC. Of the 21 patients, 13 had their neuropathy resolved at the end of induction.

Reference

Buske C, Dimopoulos MA, Grunenberg A, et al. Bortezomib-dexamethasone, rituximab, and cyclophosphamide as first-line treatment for Waldenström’s macroglobulinemia: a prospectively randomized trial of the European Consortium for Waldenström’s Macroglobulinemia. J Clin Oncol. Published online February 10, 2023. doi:10.1200/JCO.22.01805