Current treatment options and investigational drugs for Waldenstrom’s Macroglobulinemia


Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Current treatment options and investigational drugs for Waldenstrom’s Macroglobulinemia. Expert Opinion on Investigational Drugs [Internet]. 2017;26(2):197 - 205.


Introduction: Waldenström’s Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM. Recently, the Bruton’s tyrosine kinase inhibitor ibrutinib has been licensed for use in WM with exciting results. Several investigational single agent and combination regimens are being evaluated for response, efficacy and tolerability in phase II clinical trials, including new generation monoclonal antibodies (ofatumumab), immunomodulatory agents (thalidomide and lenalidomide), proteasome inhibitors (bortezomib and carfilzomib), Bruton’s tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), and histone deacetylase inhibitors (panobinostat) both in the setting of newly diagnosed and relapsed/refractory disease. Expert opinion: WM therapeutic approach should be individualized for each patient in accordance to the intensity of the disease characteristics, age, comorbidities, efficacy, tolerability and safety profile of each drug. © 2017 Informa UK Limited, trading as Taylor & Francis Group.


Export Date: 18 February 2017References: Swerdlow, S.H., Campo, E., Harris, N.L., (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, , Lyon, France: IARC Press;Leblebjian, H., Agarwal, A., Ghobrial, I., Novel treatment options for Waldenström macroglobulinemia (2013) Clin Lymphoma Myeloma Leuk, 13, pp. S310-S316; Gertz, M.A., Waldenstrom macroglobulinemia: 2013 update on diagnosis, risk stratification, and management (2013) Am J Hematol, 88, pp. 703-711; Ghobrial, I.M., Witzig, T.E., Waldenstrom macroglobulinemia (2004) Curr Treat Options Oncol, 5 (3), pp. 239-247; Treon, S.P., How I treat Waldenstrom macroglobulinemia (2009) Blood, 114 (12), pp. 2375-2385; Dimopoulos, M.A., Ra, K., Anagnostopoulos, A., Diagnosis and management of Waldenstrom’s macroglobulinemia (2005) J Clin Oncol, 23 (7), pp. 1564-1577; Jemal, A., Murray, T., Ward, E., Cancer statistics (2005) CA Cancer J Clin, 55 (1), pp. 10-30; Buske, C., Leblond, V., How to manage Waldenstrom’s macroglobulinemia (2013) Leukemia, 27, pp. 762-772; Leblond, V., Kastritis, E., Advani, R., Treatment recommendations from the eighth international workshop on Waldenström’s macroglobulinemia (2016) Blood, 128 (10), pp. 1321-1328. , Sep, Epub 2016 Jul 18; Castillo, J.J., Olszewski, A.J., Cronin, A.M., Survival trends in Waldenstrom macroglobulinemia: an analysis of the surveillance, epidemiology and end results database (2014) Blood, 123, pp. 3999-4000; Garcia-Sanz, R., Montoto, S., Torrequebrada, A., Waldenstrom macroglobulinaemia: presenting features and outcome in a series with 217 cases (2001) Br J Haematol, 115, pp. 575-582; (2015) Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma, version 2, ,, Available from:, Oct; Vijay, A., Gertz, M.A., Waldenstrom macroglobulinemia (2007) Blood, 109 (12), pp. 5096-5103; Ghobrial, I.M., Fonseca, R., Ma, G., Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia (2006) Br J Haematol, 133 (2), pp. 158-164; Gobbi, P.G., Baldini, L., Broglia, C., Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance (2005) Clin Cancer Res, 11, pp. 1786-1790; Alexanian, R., Weber, D., Delasalle, K., Asymptomatic Waldenstrom’s macroglobulinemia (2003) Semin Oncol, 30, pp. 206-210; Ansell, S.M., Kyle, R.A., Reeder, C.B., Diagnosis and management of Waldenstrom macroglobulinemia: mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines (2010) Mayo Clin Proc, 85, pp. 824-833; Treon, S.P., Xu, L., Yang, G., MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia (2012) N Engl J Med, 367, pp. 826-833; Treon, S.P., Cao, Y., Xu, L., Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia (2014) Blood, 123, pp. 2791-2796; Kyle, R.A., Therneau, T.M., Rajkumar, S.V., Long-term follow-up of IgM monoclonal gammopathy of undetermined significance (2003) Blood, 102 (10), pp. 3759-3764; Treon, S.P., Hunter, Z.R., Aggarwal, A., Characterization of familial Waldenstrom’s macroglobulinemia (2006) Ann Oncol, 17, pp. 488-494; Kristinsson, S.Y., Bjorkholm, M., Goldin, L.R., Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patients: a population-based study in Sweden (2008) Blood, 112, pp. 3052-3056; US Prescribing Information (2014) Biogen Idec, Inc. and Genentech, Inc, , Aug; Dimopoulos, M.A., Zervas, C., Zomas, A., Extended rituximab therapy for previously untreated patients with Waldenström’s macroglobulinemia (2002) Clin Lymphoma, 3, pp. 163-166; Dimopoulos, M.A., Anagnostopoulos, A., Kyrtsonis, M.C., Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide (2007) J Clin Oncol, 25, pp. 3344-3349; Sp, T., Hanzis, C., Rj, M., Maintenance rituximab is associated with improved clinical outcome in rituximab naïve patients with Waldenstrom macroglobulinaemia who respond to a rituximab-containing regimen (2011) Br J Haematol, 154, pp. 357-362; Dimopoulos, M.A., Roussou, M., Kastritis, E., Primary treatment of Waldenstrom’s macroglobulinemia with dexamethasone, rituximab and cyclophosphamide (DRC): final analysis of a phase II study (2012) Blood ASH Annu Meet Abstr, 120 (21), p. 438. , Atlanta, Georgia; Rummel, M.J., Von Gruenhagen, U., Niederle, N., Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with Waldenstrom’s macroglobulinemia: first interim results of a randomized phase III study of the Study Group Indolent Lymphomas (StiL) [abstract] (2008) Presented at the 5th International Workshop on Waldenstrom’s macroglobulinemia, p. 139. , Oct, Stockholm, Sweden; Treon, S.P., Hanzis, C., Tripsas, C., Bendamustine therapy in patients with relapsed or refractory Waldenstrom’s macroglobulinemia (2011) Clin Lymphoma Myeloma Leuk, 11, pp. 133-135; Rummel, M.J., Al-Batran, S.E., Kim, S.Z., Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma (2005) J Clin Oncol, 23, pp. 3383-3389; Buske, C., Hoster, E., Dreyling, M., The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG) (2009) Leukemia, 23, pp. 153-161; Gupta, I.V., Jewell, R.C., Ofatumumab, the first human anti-CD20 monoclonal antibody for the treatment of B cell hematologic malignancies (2012) Ann N Y Acad Sci, 1263, pp. 43-56; Furman, R.R., Eradat, H., DiRenzo, C.G., A phase II trial of ofatumumab in subjects with Waldenstrom’s macroglobulinemia (2011) Blood (ASH Annu Meet Abstr), 118, p. 3701. , San Diego, California; US Prescribing Information (2009) Genzyme Corporation; Treon, S.P., Kelliher, A., Keele, B., Expression of serotherapy target antigens in Waldenstrom’s macroglobulinemia: therapeutic applications and considerations (2003) Semin Oncol, 30, pp. 248-252; Treon, S.P., Soumerai, J.D., Hunter, Z.R., Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab (2011) Blood, 118, pp. 276-281; Panwalkar, A., Verstovsek, S., Giles F Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies (2004) Cancer, 100, pp. 1578-1589; US Prescribing Information (2014) Millenium Pharmaceuticals, Inc, , Oct; Roccaro, A.M., Leleu, X., Sacco, A., Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia (2008) Blood, 111, pp. 4752-4763; Dimopoulos, M.A., Garcia-Sanz, R., Gavriatopoulou, M., Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN) (2013) Blood, 122, pp. 3276-3282; Treon, S.P., Ioakimidis, L., Soumerai, J.D., Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180 (2009) J Clin Oncol, 27, pp. 3830-3835. , Aug; Palumbo, A., Bringhen, S., Rossi, D., Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in newly diagnosed multiple myeloma patients (2012) ASH Annu Meet Abstr, 120, p. 200. , Atlanta, Georgia; Mateos, M.V., Oriol, A., Martinez-Lopez, J., Bortezomib/melphalan/prednisone (VMP) versus Bortezomib/Thalidomide/Prednisone (VTP) as induction therapy followed by maintenance treatment with Bortezomib/Thalidomide (VT) versus Bortezomib/Prednisone (VP): A randomized trial in elderly untreated patients with multiple myeloma older than 65 years (2010) Lancet Oncol, 11, pp. 934-941; Moreau, P., Pylypenko, H., Grosicki, S., Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study (2011) Lancet Oncol, 12, pp. 431-440; Ghobrial, I.M., Hong, F., Padmanabhan, S., Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia (2010) J Clin Oncol, 28, pp. 1422-1428; Dimopoulos, M.A., Gertz, M.A., Kastritis, E., Update on treatment recommendations from the fourth international workshop on Waldenstrom’s macroglobulinemia (2009) J Clin Oncol, 27, pp. 120-126; US Prescribing Information (2012) Onyx Pharmaceuticals, Inc, , July; Treon, S.P., Tripsas, C.K., Meid, K., Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström’s macroglobulinemia (2014) Blood, 124, pp. 503-510; Siegel, D.S., Kaufman, J.L., Raje, N.S., Updated results from a multicenter, open-label, dose-escalation phase 1b/2 study of single-agent oprozomib in patients with Waldenström macroglobulinemia (WM) (2014) Blood, 124, p. 1715; Dimopoulos, M.A., Zomas, A., Viniou, N.A., Treatment of Waldenstrom’s macroglobulinemia with thalidomide (2001) J Clin Oncol, 19, pp. 3596-3601; Treon, S.P., Soumeral, J.D., Branagan, A.R., Thalidomide and rituximab in Waldenstrom macroglobulinemia (2008) Blood, 112, pp. 4452-4457; Treon, S.P., Soumerai, J.D., Branagan, A.R., Lenalidomide and rituximab in Waldenstrom’s macroglobulinemia (2009) Clin Cancer Res, 15, pp. 355-360; Fouquet, G., Guidez, S., Petillon, M.O., Lenalidomide is safe and active in Waldenstrom macroglobulinemia (2015) Am J Hematol, 90 (11), pp. 1055-1059. , Nov, Epub 2015 Oct 6; Leleu, X., Jia, X., Runnels, J., The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia (2007) Blood, 110, pp. 4417-4426; Vesole, S., Jia, X., Roccaro, A., RAD001 exerts anti-tumor activity in Waldenstrom macroglobulinemia [abstract] (2009) Blood ASH Annu Meet Abstr, 114, p. 3732. , New Orleans, Louisiana; Treon, S.P., Tripsas, C.K., Meid, K., Prospective, multicenter study of the mTor inhibitor everolimus (RAD001) as primary therapy in Waldenstrom’s macroglobulinemia (2013) Blood, 122, p. 1822. , New Orleans, Louisiana; Ghobrial, I.M., Witzig, T.E., Gertz, M., Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia (2014) Am J Hematol, 89, pp. 237-242; Ghobrial, I.M., Boswell, E.N., Banwait, R., Phase I trial of everolimus and rituximab or everolimus, bortezomib and rituximab in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia [abstract] (2011) Blood ASH Annu Meet Abstr, 118, p. 2705. , San Diego, California; Kastritis, E., Terpos, E., Dimopoulos MA emerging drugs for Waldenström’s macroglobulinemia (2011) Expert Opin Emerg Drugs, 16, pp. 45-57; Ghobrial, I.M., Roccaro, A., Hong, F., Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia (2010) Clin Cancer Res, 16, pp. 1033-1041; Ghobrial, I.M., Siegel, D., Vij, R., MLN0128 (INK128), an investigational oral dual TORC1/2 inhibitor, in patients (pts) with relapsed or refractory multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), or Waldenstrom macroglobulinemia (WM): preliminary results from a phase 1 Dose-Escalation Study [abstract] (2012) Blood ASH Annu Meet Abstr, 120, p. 4038. , Atlanta, Georgia; Ghobrial, I.M., Moreau, P., Harris, B., A multicenter phase II study of single-agent enzastaurin in previously treated Waldenstrom macroglobulinemia (2012) Clin Cancer Res, 18 (18), pp. 5043-5050; Kahl, B.S., Byrd, J., Flinn, I.W., Clinical Safety and Activity in a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma [abstract] (2010) Blood ASH Annu Meet Abstr, 116, p. 1777. , Orlando, Florida; Yang, G., Zhou, Y., Liu, X., A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia (2013) Blood, 122, pp. 1222-1232; Treon, S.P., Tripsas, C.K., Meid, K., Ibrutinib in previously treated Waldenström’s macroglobulinemia (2015) N Engl J Med, 372, pp. 1430-1440; US Prescribing Information (2015) Pharmacyclics, Inc, , Jan; (2015) IMBRUVICA® (ibrutinib) now approved to treat Waldenstrom’s macroglobulinemia in Europe, ,, Available from:, Oct; Roccaro, A.M., Sacco, A., Jia, X., microRNA-dependent modulation of histone acetylation in Waldenstrom macroglobulinemia (2010) Blood, 116, pp. 1506-1514; Grant, S., Targeting Waldenstrom macroglobulinemia with histone deacetylase inhibitors (2011) Leuk Lymphoma, 52 (9), pp. 1623-1625; Ghobrial, I.M., Campigotto, F., Murphy, T.J., Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia (2013) Blood, 121, pp. 1296-1303; Ghobrial, I.M., Poon, T., Rourke, M., Phase II Trial of Single Agent Panobinostat (LBH589) In relapsed or relapsed/refractory Waldenstrom macroglobulinemia [abstract] (2010) Blood (ASH Annu Meet Abstr), 116, p. 3952. , Orlando, Florida; Tamburini, J., Levy, V., Chaleteix, C., Fludarabine plus cyclophosphamide in Waldenstrom’s macroglobulinemia: results in 49 patients (2005) Leukemia, 19, pp. 1831-1834; Laurencet, F.M., Zulian, G.B., Guetty-Alberto, M., Cladribine with cyclophosphamide and prednisone in the management of low-grade lymphoproliferative malignancies (1999) Br J Cancer, 79, pp. 1215-1219; Van Den Neste, E., Louviaux, I., Michaux, J.L., Phase I/II study of 2-chloro-2ʹ-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma (2000) Leukemia, 14, pp. 1136-1142; Treon, S.P., Branagan, A.R., Ioakimidis, L., Long-term outcomes to fludarabine and rituximab in Waldenstrom macroglobulinemia (2009) Blood, 113, pp. 3673-3678; Tam, C.S., Wolf, M., Prince, H.M., Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma (2006) Cancer, 106, pp. 2412-2420; Leblond, V., Johnson, S., Chevret, S., Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma (2013) J Clin Oncol, 31, pp. 301-307; Dhodapkar, M.V., Jacobson, J.L., Gertz, M.A., Prognostic factors and response to fludarabine therapy in patients with Waldenstrom macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003) (2001) Blood, 98, pp. 41-48; Carney, D.A., Westerman, D.A., Tam, C.S., Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy (2010) Leukemia, 24, pp. 2056-2062; Laszlo, D., Andreola, G., Rigacci, L., Rituximab and subcutaneous 2-chloro-2ʹ-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study (2010) J Clin Oncol, 28, pp. 2233-2238; (2015) Study of the glutaminase inhibitor CB-839 in hematological tumors, ,, cited, Jun, Available from:; Davids, M.S., Seymour, J.F., Gerecitano, J.F., Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses (2014) J Clin Oncol, 32, p. 8522; Cao, Y., Yang, G., Hunter, Z.R., The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 Wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinemia cells (2015) Br J Haematol, 170 (1), pp. 134-138. , Jul; Treon, S.P., Yang, G., Hanzis, C., Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenstrom macroglobulinaemia (2011) Br J Haematol, 154, pp. 223-228; Weber, D., Treon, S.P., Emmanouilides, C., Uniform response criteria in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia (2003) Semin Oncol, 30, pp. 127-131; Owen, R.G., Kyle, R.A., Stone, M.J., Response assessment in Waldenstrom macroglobulinaemia: update from the VIth international workshop (2013) Br J Haematol, 160, pp. 171-176; Gertz, M.A., Reeder, C.B., Kyle, R.A., Stem cell transplant for Waldenstrom macroglobulinemia: an underutilized technique (2012) Bone Marrow Transplant, 47, pp. 1147-1153; Gertz, M.A., Rue, M., Blood, E., Multicenter phase 2 trial of rituximab for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98) (2004) Leuk Lymphoma, 45, pp. 2047-2055; Usmani, S., Sexton, R., Crowley, J., Autologous stem cell transplantation as a care option in Waldenstrom’s macroglobulinemia (2011) Clin Lymphoma Myeloma Leuk, 11, pp. 139-142; Kyriakou, C., Canals, C., Cornelissen, J.J., Allogeneic stem-cell transplantation in patients with Waldenstrom macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (2010) J Clin Oncol, 28, pp. 4926-4934; Castillo, J.J., Gustine, J., Meid, K., Histological transformation to diffuse large B-cell lymphoma in patients with Waldenstrom macroglobulinemia (2016) Am J Hematol, 91 (10), pp. 1032-1035. , Oct, Epub 2016 Jul 27; Xu, L., Hunter, Z.R., Tsakmaklis, N., Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom macroglobulinemia (2016) Br J Haematol, 172 (5), pp. 735-744. , Mar, Epub 2015 Dec 13; Poulain, S., Roumier, C., Venet-Caillault, A., Genomic Landscape of CXCR4 Mutations in Waldenstrom macroglobulinemia (2016) Clin Cancer Res, 22 (6), pp. 1480-1488. , Mar, Epub 2015 Oct 21