Individualizing Therapy for Patients With Waldenstrom's Macroglobulinemia

Meletios Dimopoulos, MD

Improved understanding of Waldenström's macroglobulinemia (WM) and expanded treatment options have made individualized treatment based on clinical indications a feasible strategy, Meletios Dimopoulos, MD, said at the 2016 Society of Hematologic Oncology annual meeting.

Most patients can begin treatment with a short-duration (about 4 months) of rituximab (Rituxan), which has been shown to achieve a high response rate and a median progression-free survival (PFS) of 35 months (Blood. 2015. 126:1392-1394), Dimopoulos said at the meeting. Prior to initiating treatment, patients should be assessed for the need to undergo plasmapheresis.

Rituximab maintenance therapy has little or no supporting data and is not recommended.

“Patients with long remissions after initial rituximab-based therapy may be retreated with similar regimens,” said Dimopoulos, chair of Clinical Therapeutics at the University of Athens in Greece. “For patients with rituximab-refractory disease, ibrutinib [Imbruvica] is probably the best option. However, ibrutinib therapy is long-lasting and expensive.”

Limited data have been accumulated to provide therapeutic direction after ibrutinib failure, he added.

Classification criteria have been developed to distinguish symptomatic and asymptomatic WM from IgM-related disorders and monoclonal gammopathy of uncertain significance. Four key criteria identify a patient with symptomatic WM: presence of IgM monoclonal protein, bone marrow infiltration, symptoms attributable to IgM, and symptoms attributable to tumor infiltration. The first 2 criteria identify patients with asymptomatic WM and distinguish them from patients with IgM-related disorders, said Dimopoulos.

Recommendations for initiating treatment of WM have been in existence for more than a decade (Semin Oncol. 2003;30[2]:116-120). The key characteristics are hemoglobin ≤10 g/dL, platelet count <100,000 mm3; fatigue, fever, night sweats, and pruritus; symptomatic hyperviscosity, lymphadenopathy, splenomegaly, and infiltration of other organs; moderate or severe peripheral neuropathy; symptomatic cryoglobulinemia, cold agglutinin disease, or other autoimmune-related disorders; and presence of amyloidosis.

“Elevated IgM levels alone are not an indication for initiation of therapy,” said Dimopoulos.

Individualization of treatment requires careful assessment of disease and patient characteristics. Disease-specific findings include extent of disease (or bulkiness), presence or absence of IgM levels requiring immediate reduction, presence of cytopenias, and presence/absence of immunologic complications of IgM. Patient-specific considerations are age, comorbidities, preference for oral or parenteral therapy, and suitability for stem-cell transplant.

Over the past decade, multiple agents have demonstrated potential for amelioration of WM. Although rituximab remains the cornerstone for most patients, other agents may warrant consideration in rituximab-containing combination therapy.

Dimopoulos recently reviewed options for first-line therapy for WM (Blood. 2014;124[9]:1404-1411). The available evidence showed response rates ranging from 25%-30% for 4 cycles of rituximab monotherapy to 70%-90% for rituximab-containing combinations. The proportion of responses qualifying as very good partial response or better ranged from 0-5% to 30%-40% with the regimens.

Reviewing some of the novel combination therapies evaluated in WM, Dimopoulos noted that bortezomib (Velcade) combinations have been investigated for a decade or more. Published studies have involved small numbers of patients (10-64), but overall response rates (defined as a partial response or better) ranged from 41%-60% to as high as 90% (9/10 patients treated with bortezomib/rituximab).

Bortezomib/rituximab combination therapy has resulted in durable efficacy. In 1 study, 7-year follow-up data showed a median PFS of 42 months with the combination of bortezomib/rituximab/dexamethasone and an overall survival rate of 66%.

The newer proteasome inhibitor carfilzomib (Kyprolis) was evaluated in combination with rituximab and dexamethasone in 31 patients with WM, including 28 with previously untreated disease (Blood. 2014;124[4]:503-510). All but 1 of the patients had the MYD88^L265P mutation and 11 had the CXCR4^WHIM mutation.

The combination led to an overall response rate of 87.1% and major responses (greater than partial response) in two-thirds of the patients.

Interest in ibrutinib as frontline therapy for WM evolved from recognition that the MYD88^L265P mutation is a near-universal occurrence in WM. The mutation induces tumor growth by mechanisms involving BTK, the target of ibrutinib.

A preliminary trial of ibrutinib in WM yielded an overall response rate of 100% in 34 patients who had MYD88^L265P-mutant/CXCR4-wild type disease, including major responses in 88.2% of the patients (N Engl J Med. 2015;373:584-586).

Subsequently, Dimopoulos and colleagues conducted a phase III open-label trial of ibrutinib/rituximab combination therapy in 31 patients with rituximab-refractory disease and a treatment history of 4 prior regimens. The combination led to an overall response rate of 90%, including major responses (greater than partial) in 71% of cases. The cohort had a median 18-month PFS of 86% and 18-month overall survival of 97%.

Earlier this year, participants in the 8th International Workshop on WM published updated recommendations for initial treatment of WM (Blood. 2016;128:1321-1328). For patients with WM-related cytopenias or organomegaly, the panel recommended 3 choices: rituximab/cyclophosphamide/dexamethasone, bendamustine/rituximab, or ibrutinib monotherapy. Bortezomib/dexamethasone/rituximab was cited as an alternative.

For patients with symptomatic hyperviscosity, cryoglobulinemia, or cold agglutinin disease, the working group recommended frontline bortezomib followed by maintenance therapy with bortezomib and rituximab; bendamustine/rituximab; or ibrutinib monotherapy. The panel recommended 3 options for patients with paraprotein-related neuropathy: rituximab monotherapy, rituximab/cyclophosphamide/dexamethasone, and ibrutinib monotherapy.

Three options are reasonable for older patients with poor performance status: rituximab/cyclophosphamide/dexamethasone, oral fludarabine, and ibrutinib monotherapy. Older patients ineligible for systemic IV therapy might receive oral fludarabine or ibrutinib.

Finally, young patients eligible for stem-cell transplant should be considered eligible for rituximab/cyclophosphamide/dexamethasone, bortezomib/dexamethasone/rituximab, or ibrutinib.

In the setting of relapse, the working group offered recommendations for rituximab-sensitive and refractory patients. Considerations for rituximab-sensitive patients are retreatment with rituximab, rituximab-based combinations, and ibrutinib. For rituximab-refractory patients, the recommended options are ibrutinib and bortezomib-based therapy. Everolimus and stem-cell transplantation might be considered in select cases.