A phase 2 trial found that bendamustine, rituximab, and bortezomib, used as second-line therapy, is an effective and well-tolerated salvage treatment for patients with relapsed or refractory (R/R) Waldenström macroglobulinemia (WM); these data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

According to Giulia Benevolo, MD, Division of Haematology, Città della Salute e della Scienza, Turin, Italy, and co-investigators, symptomatic patients with R/R WM treated with standard rituximab plus chemotherapy generally show a 18-month PFS of about 50 percent.

Thus, Dr Benevolo et al designed a multicenter phase 2 study to assess whether the combination of bendamustine, rituximab, and bortezomib could be considered a new treatment option for R/R WM.

The study tested the hypothesis that 18-month PFS is at least 65 percent, and enrolled 38 patients (median age 66.8) with R/R WM who received rituximab 375mg/m2 intravenously on day 1, followed by bendamustine 90mg/m2 intravenously on day 1 and 2, and subcutaneous bortezomib 1.3mg/m2 on day 1, 8, 15, and 22, every 28 days for 6 months (cycles).

The mutations MYD88^L265P and CXCR4^S338X were tested by ddPCR in bone marrow (BM), plasma, and peripheral blood (PB) samples, both at baseline and at the end of treatment.

Many patients had features of advanced disease, such as cytopenia (anemia 71%, thrombocytopenia 20%), systemic symptoms (40%), and symptomatic splenomegaly (24%). Out of 38 total patients, 16 (42%) had at least 1 comorbidity—mostly cardiovascular disease (21%) or metabolic disorders (16%). In all, 30 patients completed 6 cycles, 7 patients stopped therapy due to toxicity reasons, and 1 for progressive disease.

The overall response rate (ORR) at the end of therapy was 82 percent, including 4 complete response (CR), 1 very good partial response, and 12 partial responses, according to IWM response criteria.

The 18-, 24-, and 30-month PFS was 84 percent, 81 percent, and 79 percent, respectively. The 18-month OS was 92 percent. No deaths were observed between 18 and 30 months.

In terms of toxicities, 19 patients experienced a grade ≥3 hematologic toxicity, mainly thrombocytopenia, and 12 patients developed a grade ≥3 extra-hematologic toxicity, with only 1 cutaneous toxicity related to bendamustine. Bortezomib-related nervous system disorders were seen in 6 patients (5 of grade 1-2, 1 of grade 3) with no discontinuations.

“Mutational data were available for 21 patients: all patients scored MYD88^L265P in BM, 18/19 (95%) in plasma and only 18/21 (86%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. CXCR4^S338X was detected only in one patient at baseline,” continued Dr Benevolo and co-investigators.

The minimal residual disease (MRD) negative rates after treatment differed across investigation tissues, including 5 patients out of 17 in BM, 6 out of 14 in plasma, and 12 out of 16 in PB. Overall, positive harmony was observed between BM and plasma (Cohen’s kappa = 0.714), “suggesting the possibility of avoiding BM aspiration for mutational screening and MRD analysis,” said Dr Benevolo et al.

Results of the trial showed that bendamustine, rituximab, and bortezomib, used a second-line therapy, is an effective and well-tolerated salvage treatment for patients with R/R WM.

“The deep anti-tumor activity of the novel combination is highlighted by an absolute increase of PFS rate in comparison to historical controls (30-months PFS of 79%), as well as by high rates of clinical response, with an ORR of 82 percent. Moreover, MRD monitoring showed promising efficacy of BRB regimen in clearing the residual disease,” concluded Dr Benevolo et al.—Emily Bader 

Benevolo G, Ferrero S, Villivà N, et al. Treatment of Relapsed/Refractory Waldenström Macroglobulinemia Patients: Final Clinical and Molecular Results of the Phase II BRB Trial of the Fondazione Italiana Linfomi. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 48.