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Educational theme: Advances in treating Waldenström's macroglobulinemia

Over the next month, the Lymphoma Hub will be focusing on a new educational theme: Advances in treating Waldenström's macroglobulinemia. This article introduces the topic and summarizes some of the latest advances and key clinical trials in the field.

Waldenström's macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma that usually affects older patients (> 65 years). It is characterized by the accumulation of malignant immunoglobulin M (IgM)-secreting lymphoplasmacytic cells in the bone marrow and other organs.1 Although patients are often diagnosed at the asymptomatic, or ‘smoldering’ stage, they are typically not treated until the disease progresses, as curative therapy is not available and current standard treatment regimens are not proven to prolong the survival of patients at these early stages. Most patients will become symptomatic during the progression of the disease, due to anemia, hyperviscosity syndrome, neuropathy, extramedullary disease, or other processes, thereby requiring therapy.1 

Over 90% of patients with WM have the point mutation L265P in MYD88, while those without this mutation tend to have higher risk of aggressive transformation to diffuse large B-cell lymphoma, and a worse survival outcome.1 Approximately, 30–40% of patients with WM also have recurrent CXCR4 mutations, which are associated with higher IgM levels, higher risk of developing symptomatic hyperviscosity, but lower rates of extramedullary disease, such as lymphadenopathy and hepatosplenomegaly.1

Current treatment options and outcomes

The current treatment options for patients with symptomatic WM include anti-CD20 monoclonal antibodies, alkylating agents, proteasome inhibitors, and Bruton tyrosine kinase (BTK) inhibitors.

Anti-CD20 monoclonal antibodies

Rituximab, alone or in combination with other agents, is the most common treatment for WM. As a single agent, it was shown to have an overall response rate (ORR) of 40–50%, with a median progression-free survival (PFS) of 12–24 months. However, rituximab usage has been associated with paradoxical IgM flares and intolerance.1

Last year, at the 24th European Hematology Association (EHA) Annual Congress, the Lymphoma Hub talked to Simon Rule about the MabCute phase III study (NCT01461928). This compared the use of subcutaneous (SC) versus intravenous (IV) rituximab, and extended maintenance with SC rituximab versus observation, in patients with indolent non-Hodgkin lymphoma, including WM. He reported that there was no additional toxicity associated with SC rituximab compared to IV, even in the extended maintenance cohort. Watch the video below for more on the PFS results.

MABCUTE study: Extended maintenance with subcutaneous rituximab vs observation in iNHL

For patients with rituximab intolerance, ofatumumab can be used. It has demonstrated an ORR of 60% and a lower rate of IgM flare (10%), however, 25% of patients go on to develop ofatumumab intolerance. As an alternative, there is a currently recruiting phase II trial (NCT03679455) by the Polish Myeloma Consortium, which will evaluate the efficacy and safety of obinutuzumab monotherapy in patients with relapsed/refractory (R/R) WM.

Alkylating agent-based combinations

Alkylating agents like cyclophosphamide and bendamustine are commonly used in combination with other drugs for the treatment of WM. The two most used combinations are cyclophosphamide, dexamethasone, and rituximab (CDR) and bendamustine with rituximab (benda-R). Both treatment combinations have reported ORRs of 80-90% and median PFS between 36–60 months, with benda-R leading to a more prolonged PFS than CDR in comparative analyses.1

Proteasome inhibitors

The proteasome inhibitors, bortezomib and carfilzomib, have shown great efficacy for patients with newly diagnosed WM when combined with rituximab and dexamethasone. Such regimens provide a chemotherapy-free option for patients with WM, with an approximate ORR of 90%, median PFS between 48-60 months, and a well-tolerated toxicity profile.1 Bortezomib administration has been associated with a higher risk of peripheral neuropathy, but this can be minimized by dose reduction. More information on the long-term efficacy and safety of bortezomib in combination with dexamethasone and rituximab in naïve WM can be found here.

BTK inhibitors

Currently, ibrutinib, an oral BTK inhibitor, has expanded the treatment options for patients with WM both alone and in combination with rituximab. Ibrutinib monotherapy was approved in 2015 by the U.S. Food and Drug Administration (FDA) for the treatment of patients with symptomatic WM, based on the results of the PIVOTAL phase III trial (NCT01614821).1,2 The results of this trial showed that ibrutinib overall led to an ORR of 90% in pre-treated patients with WM, and the patient mutation profile affected the depth of response to therapy. More specifically, patients with the MYD88 L265P mutation achieved deep responses with ibrutinib monotherapy with an ORR of 80% and a 5-year PFS of 75%.1,2 However, patients with concomitant MYD88 and CXCR4 mutations achieved a lower ORR of 60% and a shorter median PFS of 4 years.1,2 The 5-year long-term outcomes and the effect of specific mutations to ibrutinib responses from the PIVOTAL trial were further discussed by Steven Treon during ICML 2019, in the video interview below.

Long-term outcomes of patients with Waldenstrom's macroglobulinemia treated with ibrutinib

Recently, the results of the phase III iNNOVATE trial (NCT02165397) have led the FDA to announce a review in ibrutinib’s prescribing information, for the addition of a supplemental new drug application for ibrutinib in combination with rituximab for the treatment of WM. For more information on this, read here. The iNNOVATE trial evaluated ibrutinib combined with rituximab versus rituximab alone in patients with R/R and naïve WM.3 The results of the trial demonstrated a significant improvement in PFS when ibrutinib was combined with rituximab over rituximab alone.3 The key findings from the trial have been summarized here and are discussed in the video interview below by Judith Trotman during EHA 2018.

Key findings from the INNOVATE study

Although these treatment options are efficacious, ibrutinib has been associated with bleeding complications and a higher risk of atrial fibrillation.1 Therefore, novel alternative agents with similar efficacy and lower or different toxicity profiles are always needed to accommodate for all patient subgroups. For this, multiple prospective trials are currently evaluating the efficacy of ibrutinib with various novel agents, including the anti-CXCR4 antibody ulocuplumab (NCT03225716) and ixazomib (NCT03506373). For more information, see the next section on upcoming agents for WM.

Upcoming novel agents/studies for WM

Novel treatment strategies under development for WM include the BTK inhibitors acalabrutinib, zanubrutinib, and vecabrutinib, the proteasome inhibitor ixazomib, the BCL2 inhibitor venetoclax, and the anti-CXCR4 antibody ulocuplumab.1

With regard to novel BTK inhibitors, acalabrutinib monotherapy in both previously treated and treatment-naïve patients with WM led to an average ORR of 93.5% at a median follow-up of 2 years post treatment. The results of this prospective phase II trial also revealed a 2-year PFS rate of 88% and 99% in pre-treated and naïve patients, respectively.1 Similar complications to ibrutinib were also reported with acalabrutinib, with increased risk of bleeding events and atrial fibrillation.1

Recently, results from the randomized, phase III trial ASPEN (NCT03053440) were reported, after directly comparing the efficacy of ibrutinib versus a new generation BTK inhibitor, zanubrutinib, in patients with WM.1 The primary endpoint of the trial was very good partial response  rate, which was not met. However, the investigators highlighted that despite not meeting the primary endpoint the importance of the study lies in the direct comparison of the safety profiles between ibrutinib and zanubrutinib. According to the preliminary results, zanubrutinib was better tolerated than ibrutinib with fewer adverse events, dose reductions, and treatment discontinuation events. Further analyses from ASPEN will provide more insights into the safety and efficacy of zanubrutinib in comparison to ibrutinib. These results were further discussed by Constantine Tam in the video interview below, during ASCO 2020.

ASPEN trial: Zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia

With regard to proteasome inhibition, ixazomib in combination with rituximab and dexamethasone has recently shown promising efficacy in patients with R/R WM in a phase I/II trial.4 The trial reported an ORR of 71%, a partial response of 51%, and a 2-year PFS of 60%. The treating combination led to minimal toxicities with no cases of hypersensitivity development and with mostly minor Grade 1 peripheral neuropathy cases.4 These promising results for the R/R WM setting were presented at EHA 2020 and are further discussed in the video interview with Judith Trotman below.

Ixazomib in combination with rituximab and dexamethasone in patients with relapsed WM

The BCL2 inhibitor venetoclax has also shown preliminary activity in a phase I trial in patients with pre-treated WM. Based on these preliminary findings, a prospective phase II trial was set up (NCT02677324) investigating venetoclax in patients with R/R WM. Initial findings of the study reported an ORR of 87%, with neutropenia and anemia being the most common Grade 3 adverse events.1

Other potential targets for WM with clinical interest that are currently under clinical investigation are phosphatidylinositol 3 kinase (PI3K) inhibitors, namely idelalisib and umbralisib.1 With multiple phase II trials undergoing accrual, it is certain that in the years to come we will have further insights into their therapeutic potential for WM.  Finally, it is of interest to mention that the radiotherapeutic phospholipid drug conjugate CLR 131 has recently received Fast Track Designation by the FDA for the treatment of patients with R/R WM or multiple myeloma.5 This decision was based on the results of the phase II CLOVER-1 trial, which reported an ORR of 100% and a complete response rate of 25% in the four patients with WM treated. For more information on CLR 131 and this announcement, please read here.


Considering the numerous agents discussed here, it is evident that the WM treatment field is rapidly expanding. Presently, patients with WM are mostly treated with alkylating agents, BTK or proteasome inhibitors, and anti-CD20 antibodies. However, as there is no single best treatment for all patients, the continuous clinical evaluation of novel therapeutic targets is essential for the identification of the best management algorithm for each patient, according to their history and their hematological and mutational profiles. Such advances will only benefit patients with WM and lead towards to better outcomes.

  1. Castillo JJ, Treon SP. What is new in the treatment of Waldenstrom macroglobulinemia? 2019;33:2555-2562. DOI:
  2. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):1430-40. DOI: 10.1056/NEJMoa1501548
  3. Dimopoulos MA, Tedeschi M, Trotman J, et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia. N Engl J Med. 2018;378:2399-2410. DOI: 10.1056/NEJMoa1802917
  4. Kersten MJ, Minnema M, Amaador K, et al. Ixazomib, Rituximab and Dexamethasone (IRD) in Patients With Relapsed or Progressive Waldenström’s Macroglobulinemia: Final Analysis of the HOVON124/ECWM-R2 Trial. Oral Abstract S226. EHA Annual Congress. 12 Jun, 2020. Virtual
  5. GlobeNewswire. Cellectar receives FDA fast track designation for CLR 131 in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. Published May 26, 2020. Accessed May 26, 2020.