Addition of Bortezomib Shows Efficacy/Safety in Waldenström's Macroglobulinemia

Article

A phase 3 trial of bortezomib, dexamethasone, rituximab, and cyclophosphamide shortened the median time to first response and increased the number of patients with Waldenström's macroglobulinemia.

The combination of bortezomib (Velcade), dexamethasone, rituximab, and cyclophosphamide (B-DRC) proved to be highly effective and well-tolerated in patients with Waldenström's macroglobulinemia (WM), according to a large randomized study (NCT01788020).

“The data demonstrate that adding bortezomib to DRC shortened median time to first response and increased the number of patients achieving a [complete response/very good partial response [CR/VGPR]]. This resulted in an improved [overall response rate] and a significant increase in the major response rate after three cycles of treatment for the bortezomib arm. The high activity of B-DRC was confirmed at best response with nearly every third patient achieving a CR/VGPR compared with 20.9% for DRC. This high activity of B-DRC did not translate into an improved [progression-free survival [PFS] or overall survival [OS] compared with the DRC regimen, with few events for both PFS and OS at the data cutoff,” wrote the study authors.

In this multicenter, prospective, randomized, open-label, 2-armed, phase 3 trial, treatment-naïve patients with WM were randomly assigned to receive DRC or B-DRC for a total of 6 cycles.

A total of 204 patients were enrolled across European countries in 53 different sites. Ultimately, 202 patients were randomly assigned in a 1:1 ratio to DRC vs B-DRC over a period of 4 years and 8 months. Patients were required to have WM with a diagnosis confirmed by national reference pathology with lymphoplasmacytic lymphoma and the presence of a monoclonal serum IgM.

For those given the DRC regimen, dexamethasone was given at 20 mg orally once daily on day 1, rituximab at 375 mg/m2 intravenously (IV) once a day on day 1 of cycle 1, 1,400 mg SC once a day on day 1 of cycles 2-6, and cyclophosphamide at 100 mg/m2twice orally on days 1-5. Those given bortezomib-DRC received the regimen at a dose of 1.6 mg/m2 once daily on days 1, 8, and 15 for 6 cycles. One hundred two patients were randomly assigned to receive the B-DRC combination while 100 were assigned into the DRC arm. Further, 99 and 96 patients were treated, respectively

Investigators assessed the primary end point of progression-free survival (PFS) and secondary end points of investigator-assessed response rates, including complete response (CR), very good partial response (VGPR), partial response (PR), and minor response, overall response rate (ORR) 4 weeks after the end of induction therapy, best response, time to best response, time to first response, time to treatment failure, remission duration, and overall survival.

Those enrolled continued to be followed on the trial every 3 months for disease progression, subsequent treatment, and survival for 2 years after completion or discontinuation of the induction treatment. Additionally, patients were watched every 6 months for an additional 3 years.

Among the patients enrolled, the median age was 68 (range, 34-89) years across both arms, and according to the ISSWM prognostic score, 11% of patients were at low-risk, 39% at intermediate-risk, and 50% at high-risk in both arms. The median baseline hemoglobin level was 10.0 for those given B-DRC and 9.8 g/dL for those given DRC, and the median baseline IgM levels were 31.7 and 31.9 g/L, respectively.

In the B-DRC arm 92% received 6 cycles of induction vs 87% in the DRC arm, and only 4% and 7% received 2 or fewer treatment cycles. For bortezomib, the mean dose density was 95% (range, 61%-100%) for all patients, and in 40% of these patients, bortezomib was reduced. The addition of bortezomib did not lead to major dose reductions in any patients given the DRC regimen vs those given DRC alone.

Findings showed that with a median follow-up of 27.5 months, the estimated 24-month PFS rate was 80.6% (95% CI, 69.5-88.0) for those given B-DRC and 72.8% (95% CI, 61.3-81.3) for those given DRC (P = .32). B-DRC and DRC induced major responses at the end of treatment in 80.6% (75 of 93) and 69.9% (58 of 83) of patients in the B-DRC vs DRC arms. CRs or VGPRs were observed in 17.2% vs 9.6% of patients, respectively.

For patients in the B-DRC arm, the median time to first response was shorter at 3.0 (95% CI, 2.8-3.2) compared with 5.5 (95% CI, 2.9 to 5.8) months for the DRC arm, leading to higher major response rates as well (57.0% vs 32.5%; P < .01) after 3 cycles of B-DRC vs DRC.

Looking at the best response, the CR/VGPR increased to 32.6% for B-DRC. Safety findings showed that both treatments were well-tolerated and grade 3 or higher adverse events (AEs) were seen in 49.2% of all patients, including 49.5% of those given the B-DRC regimen and 49.0% given DCR. Two patients treated with B-DRC had grade 3 peripheral sensory neuropathy vs none given DRC.

The median OS has not been reached in either treatment arm. There were 5 deaths in the B-DRC arm and 6 in the DRC arm linked to lymphoma in 4 patients (3 in the DRC arm and 1 in the B-DRC arm), and 2 patients developed secondary neoplasia (1 in each arm).

The most common grade 3 or greater AEs included neutropenia (25.6%), anemia (6.2%), and thrombocytopenia (5.1%). A total of 46 patients developed infections, serious AEs occurred in 40 patients, including 26 (27.1%) in the DRC arm and 14 (14.1%) in the B-DRC arm.

“Longer follow-up is needed to evaluate the impact of adding bortezomib to DRC on PFS. There were around 10% more patients with intermediate-/high-risk ISSWM progression-free at 2 years in the B-DRC arm compared with DRC alone, but longer follow-up will clarify whether B-DRC is able to improve PFS compared with DRC in the different risk groups,” concluded the study authors.

REFERENCES:
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 [published online ahead of print, 2023 Feb 10]. J Clin Oncol. 2023;JCO2201805. doi:10.1200/JCO.22.01805
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