Consensus updates on the management of symptomatic, untreated WM patients
| Plasmapheresis | Plasmapheresis should always and immediately be used for patients with symptomatic hyperviscosity. Furthermore, plasmapheresis can be used to prevent flare in patients with high IgM level (typically >4000 mg/dL) before rituximab administration. Plasmapheresis alone is not an effective treatment of the disease and must be followed by a rapidly acting cytoreductive treatment. |
| Rituximab as a single agent | Because of the lower chance of response in WM patients with high IgM levels, and the risk of an IgM flare, rituximab single-agent therapy should be avoided in patients with high IgM levels, but rather should be considered for WM patients with immunologic disorders secondary to WM, such as anti-myelin-associated glycoprotein neuropathy or in frail patients less likely to tolerate chemoimmunotherapy. |
| Dexamethasone- rituximab- cyclophosphamide (DRC) | DRC is an active and safe treatment choice for first-line treatment of WM with a manageable toxicity, and it can be considered in frail patients requiring combination therapy. |
| Bendamustine- rituximab (Benda-R) | Benda-R is effective in treatment-naïve WM patients. Treatment is well tolerated even in elderly patients with limited episodes of myelosuppression and infections when compared with purine analog-based regimens. In elderly patients and those with renal impairment, the dose of bendamustine needs to be lowered. Four cycles of Benda-R may be sufficient to achieve adequate response in most WM patients. |
| Bortezomib-based therapy | Primary therapy with bortezomib is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients in whom avoidance of alkylator or nucleoside analog therapy is desired. The panel also recommends that bortezomib should ideally be given once per week and possibly by a subcutaneous route; in case urgent reduction of the IgM level is needed, bortezomib can be started at twice-per-week doses for 1 or 2 cycles and then be changed to once-per-week dosing to reduce risk of neurotoxicity. |
| Carfilzomib-based therapy | Carfilzomib-based therapy represents an emerging neuropathy-sparing option for proteasome-inhibitor based therapy for WM. Cardiac toxicity has been reported in 3% to 4% of multiple myeloma patients and could be an issue especially in elderly WM patients with preexisting cardiac conditions. Other open issues include the optimal dose of carfilzomib and the optimal schedule of administration. |
| Ibrutinib | Ibrutinib is an option in symptomatic WM patients. Ibrutinib is approved as primary therapy in WM patients by the US Food and Drug Administration, Health Canada, and the European Medicines Agency as primary therapy in WM patients who are not candidates for chemoimmunotherapy. Ibrutinib should not be stopped unless toxicity or disease progression is suspected. Increases in serum IgM and reductions in hemoglobin can occur if ibrutinib is held and should not be regarded as treatment failure. The optimal use of ibrutinib (ie, in first-line treatment or previously treated disease) as a single agent or in combination continues to be a subject of investigation. |
| Plasmapheresis | Plasmapheresis should always and immediately be used for patients with symptomatic hyperviscosity. Furthermore, plasmapheresis can be used to prevent flare in patients with high IgM level (typically >4000 mg/dL) before rituximab administration. Plasmapheresis alone is not an effective treatment of the disease and must be followed by a rapidly acting cytoreductive treatment. |
| Rituximab as a single agent | Because of the lower chance of response in WM patients with high IgM levels, and the risk of an IgM flare, rituximab single-agent therapy should be avoided in patients with high IgM levels, but rather should be considered for WM patients with immunologic disorders secondary to WM, such as anti-myelin-associated glycoprotein neuropathy or in frail patients less likely to tolerate chemoimmunotherapy. |
| Dexamethasone- rituximab- cyclophosphamide (DRC) | DRC is an active and safe treatment choice for first-line treatment of WM with a manageable toxicity, and it can be considered in frail patients requiring combination therapy. |
| Bendamustine- rituximab (Benda-R) | Benda-R is effective in treatment-naïve WM patients. Treatment is well tolerated even in elderly patients with limited episodes of myelosuppression and infections when compared with purine analog-based regimens. In elderly patients and those with renal impairment, the dose of bendamustine needs to be lowered. Four cycles of Benda-R may be sufficient to achieve adequate response in most WM patients. |
| Bortezomib-based therapy | Primary therapy with bortezomib is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients in whom avoidance of alkylator or nucleoside analog therapy is desired. The panel also recommends that bortezomib should ideally be given once per week and possibly by a subcutaneous route; in case urgent reduction of the IgM level is needed, bortezomib can be started at twice-per-week doses for 1 or 2 cycles and then be changed to once-per-week dosing to reduce risk of neurotoxicity. |
| Carfilzomib-based therapy | Carfilzomib-based therapy represents an emerging neuropathy-sparing option for proteasome-inhibitor based therapy for WM. Cardiac toxicity has been reported in 3% to 4% of multiple myeloma patients and could be an issue especially in elderly WM patients with preexisting cardiac conditions. Other open issues include the optimal dose of carfilzomib and the optimal schedule of administration. |
| Ibrutinib | Ibrutinib is an option in symptomatic WM patients. Ibrutinib is approved as primary therapy in WM patients by the US Food and Drug Administration, Health Canada, and the European Medicines Agency as primary therapy in WM patients who are not candidates for chemoimmunotherapy. Ibrutinib should not be stopped unless toxicity or disease progression is suspected. Increases in serum IgM and reductions in hemoglobin can occur if ibrutinib is held and should not be regarded as treatment failure. The optimal use of ibrutinib (ie, in first-line treatment or previously treated disease) as a single agent or in combination continues to be a subject of investigation. |