BR Retains its Role in Frontline Waldenström Macroglobulinemia Despite the Utility of BTK Inhibitors

The treatment landscape of Waldenström macroglobulinemia is becoming increasingly complex with second-generation BTK inhibitors; however, the combination of bendamustine and rituximab remains the frontline standard of care for this patient population.

Morie A. Gertz, MD

The treatment landscape of Waldenström macroglobulinemia (WM) is becoming increasingly complex with second-generation BTK inhibitors; however, the combination of bendamustine and rituximab (Rituxan; BR) remains the frontline standard of care for this patient population, said Morie A. Gertz, MD, in a virtual presentation during the 25th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, an event hosted by Physician’s Education Resource®, LCC.

BR remains the frontline standard of care for patients with WM based on data from a phase 3 trial (NCT00991211) showing improved progression-free survival (PFS), less toxicity, and fewer relapses with BR vs R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] in patients with WM (n = 41), said Gertz, a consultant in the Division of Hematology, Department of Internal Medicine, and a professor of medicine at Mayo Clinic.1

To build upon this regimen, rituximab was evaluated as maintenance therapy in the phase 3 StiL NHL-2008 MAINTAIN trial. The study randomized 218 patients who responded to BR induction therapy to rituximab maintenance or observation. The 2-year course of rituximab maintenance led to a numerical improvement in PFS of 101 months compared with 83 months with observation in this patient population; however, the difference in PFS was not statistically significant (HR, 0.80; 95% CI, 0.51-1.25; P = .32).2 As such, rituximab maintenance is not indicated for patients with WM who respond to BR induction, said Gertz.

Other treatment options for patients with WM include bortezomib (Velcade) in combination with dexamethasone and rituximab. This regimen induced an overall response rate (ORR) of 96% in patients (n = 23) and a median time to response (TTR) of 1.4 months.3

Similarly, carfilzomib (Kyprolis) plus rituximab and dexamethasone led to an ORR of 87.1% in patients (n = 31) and a median TTR of 2.1 months.4 Moreover, responses were not affected by MYD or CXCR4 mutational status, and the combination did not cause higher than grade 1 peripheral neuropathy, explained Gertz.

“Carfilzomib is less neurotoxic than bortezomib,” Gertz said. “Neurotoxicity is a real issue in patients with IgM monoclonal proteins [because] they have high peripheral neuropathy rates with bortezomib.”

In addition to these therapies, BTK inhibitors have led to a paradigm shift in WM, said Gertz.

In 2015, ibrutinib (Imbruvica) was granted a breakthrough therapy designation by the FDA as monotherapy for the treatment of patients with WM.5 Updated results of the pivotal study that led to the approval reported an ORR of 90.5% and a major response rate of 79.4% at a median follow-up of 59 months.6 Improvement in immunoglobulin M serum (IgM), bone marrow disease involvement, and hemoglobin were also observed.

Grade 3 or greater adverse effects (AEs) included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Notably, a 12.7% rate of atrial arrhythmia was observed with ibrutinib.

“Atrial fibrillation in this elderly population raises issues of anticoagulation, rate control, and ablation. It is a serious complication in this group,” said Gertz.

In 2018, the FDA expanded the label for ibrutinib to include its use in combination with rituximab to treat patients with WM based on findings from the phase 3 iNNOVATE trial.7

In December 2020, the prescribing information for ibrutinib was updated to include efficacy and safety data from the final analysis of the iNNOVATE trial, which demonstrated significantly higher rates of PFS with ibrutinib/rituximab (n = 75) compared with placebo/rituximab (n = 75) in patients with treatment-naïve and relapsed/refractory disease.8

“At Mayo Clinic, we still use BR as our first-line [regimen], with the exception of central nervous system lymphoplasmacytic lymphoma, or so-called Bing-Neel Syndrome. In this situation, bendamustine does not cross the blood-brain barrier, but ibrutinib does,” said Gertz.

Additionally, the second-generation BTK inhibitor acalabrutinib (Calquence) was evaluated in a phase 2 trial in patients with treatment-naïve (n = 14) or relapsed/refractory (n = 92) WM.9 Findings from the study demonstrated an ORR of 93% in both cohorts of patients. Moreover, a lower rate of severe atrial fibrillation was observed with acalabrutinib (1%) compared with what had been reported with ibrutinib.

Another second-generation BTK inhibitor, zanubrutinib (Brukinsa) was compared with ibrutinib in the ASPEN trial, wherein the rate of complete response plus very good partial response was 28.4% with zanubrutinib compared with 19.2% with ibrutinib (P = .09).10 Notably, the 12-month PFS and 12-month overall survival rates in the overall and relapsed/refractory populations were numerically improved with zanubrutinib vs ibrutinib.

Additionally, regarding safety, zanubrutinib was associated with lower rates of atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, pneumonia, and AEs leading to treatment discontinuation or death compared with ibrutinib.

Although the efficacy improvements in the ASPEN trial were not considered statistically significant, the lower rates of toxicity suggest that zanubrutinib could have clinical utility for patients with WM, said Gertz.

Taken collectively, these data provide a potential treatment algorithm for patients with WM. At Mayo Clinic, current practice dictates that patients with IgM monoclonal gammopathy of undetermined significance with less than 10% lymphoplasmacytic infiltration, asymptomatic/smoldering WM, and patients with no cytopenias can be safely observed without therapeutic intervention. Single-agent rituximab should be given to those with IgM-related neuropathy, WM-associated hemolytic anemia, or symptomatic cryoglobulinemia. Finally, 4 to 6 cycles of BR without rituximab maintenance should be given to those patients with bulky disease, profound cytopenias, constitutional symptoms, and/or hyperviscosity symptoms, Gertz said.

Patients who had a response to previous therapy lasting 3 or more years could be considered for retreatment with their original therapy. Conversely, patients whose response was less than 3 years should be considered for zanubrutinib, acalabrutinib, or ibrutinib monotherapy if not previously used, bortezomib plus dexamethasone and rituximab if preexisting peripheral neuropathy is less than grade 2, rituximab plus dexamethasone and cyclophosphamide, or BR alone if not previously used.


  1. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
  2. Rummel MJ, Lerchenmüller C, Hensel M, et al. Two years rituximab maintenance vs. observation after first line treatment with bendamustine plus rituximab (B-R) in patients with Waldenström’s macroglobulinemia (MW): results of a prospective, randomized, multicenter phase 3 study (the StiL NHL7-2008 MAINTAIN trial). Blood. 2019;134(suppl 1):343. doi:10.1182/blood-2019-121909
  3. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009;27(23):3830-5. doi:10.1200/JCO.2008.20.4677
  4. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström’s macroglobulinemia. Blood. 2014;124(4):503-510. doi:10.1182/blood-2014-03-566273
  5. U.S. FDA approves IMBRUVICA® (ibrutinib) for the treatment of Waldenström’s macroglobulinemia: first FDA-approved therapy for this disease. Johnson & Johnson. News release. January 29, 2015. Accessed March 1, 2021.
  6. Treon SP, Meid K, Gustine J, et al. Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol. 2021;39(6):565-575. doi:10.1200/JCO.20.00555 7. IMBRUVICA® (ibrutinib) U.S. prescribing information updated to include long-term data for Waldenström’s macroglobulinemia (WM). News release. AbbVie. December 23, 2020. Accessed March 1, 2021.
  7. Buske C, Tedeschi A, Trotman J, et al. Five-year follow-up of ibrutinib plus rituximab vs placebo plus rituximab for Waldenstrom’s macroglobulinemia: final analysis from the randomized phase 3 iNNOVATETM study. Blood. 2020;136(suppl 1):24-26. doi:10.1182/blood-2020-134460
  8. Owen RG, McCarthy H, Rule S, et al. Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study. Lancet Haematol. 2020;7(2):e112-e121. doi:10.1016/S2352-3026(19)30210-8
  9. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007
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