Rituximab, Bendamustine, and Bortezomib Combination Improves Responses in Relapsed/Refractory Waldenström Macroglobulinemia

Second-line therapy comprising standard rituximab plus bendamustine and bortezomib was effective and well-tolerated as a salvage treatment option for patients with relapsed/refractory Waldenström macroglobulinemia (WM), according to research presented by Giulia Benevolo, MD, of the University of Torino in Italy. Compared with historical controls, the combination therapy was associated with increases in progression-free survival (PFS) rate and measurable residual disease (MRD) negativity. These results were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

In this single-arm phase II study, researchers hypothesized that the 18-month PFS rate with this regimen would be at least 65%. Patients received intravenous (IV) rituximab 375 mg/m2 on day 1, followed by IV bendamustine 90 mg/m2 on days 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22. Treatment lasted six months, with a total of six 28-day treatment cycles.

At baseline (for mutational screening) and at the end of treatment (for MRD analysis), patients’ bone marrow, plasma, and peripheral blood samples were tested for MYD88L265P and CXCR4S338X mutations using droplet digital polymerase chain reaction.

The median age of patients in the study was 66.8 years. Most patients had features of advanced disease, including cytopenia (anemia [71%], thrombocytopenia [20%]), systemic symptoms (40%), and symptomatic splenomegaly (24%). At least one comorbidity was present in 16 patients (42%), including cardiovascular disease (21%) or metabolic disorders (16%) such as diabetes mellitus.

A total of 30 patients completed treatment. At the end of the six cycles, the overall response rate (ORR) was 82%. According to IWM response criteria, there were four (11%) complete responses, 15 (39%) very good partial responses, and 12 (32%) partial responses. The PFS rates at 18, 24, and 30 months were 84%, 81%, and 79%, respectively. Overall survival (OS) was 92% at 18 months in the entire study population.

Seven patients discontinued therapy because of toxicity and one because of disease progression. Between 18 and 30 months of follow-up, no deaths were reported. Grade ≥3 hematologic toxicities were observed in half of patients (n=19). Although nervous system disorders related to bortezomib were reported in six patients, these events did not result in discontinuation of treatment, the investigators reported.

All 21 patients for whom mutational data was available scored MYD88L265P in bone marrow, 95% in plasma and 86% in peripheral blood, “prospectively confirming the risk of false negative results when only peripheral blood of rituximab pretreated patients is analyzed,” the authors wrote. CXCR4S338X was detected in one patient at baseline. After treatment, MRD negativity rates were 29% (n = 5/17) in bone marrow, 43% (n = 6/14) in plasma, and 75% (n = 12/1) in peripheral blood.

“Overall, a good concordance was observed between bone marrow and plasma, suggesting the possibility of avoiding bone marrow aspiration for mutational screening and MRD analysis,” the authors wrote.