Bendamustine and Bortezomib-Containing Regimens Produce Higher Response Rates and More Durable Responses Versus Cyclophosphamide-Based Therapy in Frontline Waldenstrom Macroglobulinemia

Background: Waldenstrom macroglobulinemia (WM) is an incurable IgM-secreting lymphoplasmacytic lymphoma. Primary therapy for symptomatic WM patients often consists of combination therapy with an alkylating agent or proteasome inhibitor with rituximab. However, randomized studies comparing these treatment regimens are lacking in WM patients.

Methods: We retrospectively searched our database for WM patients who received primary therapy with bendamustine-rituximab (Benda-R), bortezomib-dexamethasone-rituximab (BDR), or cyclophosphamide-dexamethasone-rituximab (CDR) between 2005 and 2016. Pertinent clinical data were collected. Response was assessed based on current criteria. Univariate and multivariate regression models were fitted to evaluate the association between clinical variables and response. Time to events was estimated using the Kaplan-Meier method. The Cox regression method was used to fit univariate and multivariate models for progression-free (PFS) and overall survival (OS). P<0.05 was considered statistically significant.

Results: 182 patients with WM were identified who received frontline therapy with Benda-R (n=57), BDR (n=88), and CDR (n=37). No differences in sex, hemoglobin level, platelet count, B2M, bone marrow involvement, IPSSWM, and MYD88 and CXCR4 mutational status were observed between treatment groups (p>0.05 for all comparisons). Patients treated with BDR were more likely <65 years, have serum IgM >4,000 mg/dl, and receive treatment for symptomatic hyperviscosity versus patients treated with Benda-R and CDR. Patients with extramedullary disease and peripheral neuropathy were more likely to be treated with Benda-R and CDR, respectively (p<0.01 for all comparisons). 116 patients (64%) received maintenance rituximab, and did not differ between treatment regimens (p=0.68). Rates of CR, VGPR, PR, minor response and no response to therapy were 12% (n=22), 27% (n=48), 47% (n=84), 6% (n=10), and 8% (n=14), respectively. The rate of major response (PR+) was 86%, and the rate of deep response (VGPR+) was 39%. No difference in response was observed between treatment regimens (p=0.45). In the multivariate logistic analysis, patients with serum IgM >4,000 mg/dl had lower odds of major response to therapy (OR 0.3, 95% CI 0.1-0.8; p=0.02), whereas patients who received maintenance rituximab had higher odds of both a major response (OR 13.9, 95% CI 4.4-44.1; p<0.001) and deep response (OR 2.1, 95% CI 1.1-4.0; p=0.02). For patients treated with Benda-R, BDR, and CDR, the median PFS was 5.5 years (95% CI 4.9-not reached [NR]), 5.8 years (95% CI 4.4-7.4), and 4.9 years (95% CI 2.8-7.0), respectively. In the multivariate regression analysis, an increased risk of progression was associated with B2M >3 mg/l (HR 2.33, 95% CI 1.37-3.96; p=0.002) and serum IgM level >4,000 mg/dl (HR 1.85, 95% CI 1.08-3.20; p=0.02). A decreased risk of progression was associated with both Benda-R (HR 0.2, 95% CI 0.1-0.5; p<0.001) and BDR (HR 0.6, 95% CI 0.3-1.0; p=0.05) when compared to CDR. Maintenance rituximab was also associated with a decreased risk of progression (HR 0.11, 95% CI 0.06-0.21; p<0.001), and the median PFS for patients who did and did not receive maintenance rituximab was 6.8 years (95% CI 5.9-NR) versus 2.8 years (95% CI 2.1-4.1), respectively. No difference in the risk of progression was observed between BDR and Benda-R (p=0.13). The estimated 5- and 10-year OS for all patients was 92% and 79%, respectively; median OS has not been reached. The estimated 5-year OS among patients treated with Benda-R, BDR, and CDR was 95%, 96%, and 81%, respectively; p=0.06). For patients treated with BDR and CDR, the estimated 10-year OS was 87% and 61%, respectively, and was not evaluable for patients treated with Benda-R. Treatment with BDR (HR 0.16, 95% CI 0.04-0.59; p=0.006) and maintenance rituximab (HR 0.17, 95% CI 0.05-0.61; p=0.006) were independently associated with a decreased risk of death.

Conclusions: Primary therapy with Benda-R, BDR, and CDR produces high response rates and durable PFS in patients with WM. The risk of progression is lower in patients treated with Benda-R and BDR when compared to CDR. Maintenance rituximab is associated with both major and deep responses to therapy as well as superior PFS and OS.