Chapter 108: Macroglobulinemia

SUMMARY

Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig) M secreting lymphoplasmacytic cells. MYD88 and CXCR4 somatic mutations are present in more than 90% and 30% to 35% of WM patients, respectively, and affect disease presentation, treatment outcome, and/or overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin of less than 100 g/L, platelets less than 100 × 10⁹/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before administration of rituximab in those with high serum IgM levels to preempt a symptomatic IgM flare. The treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Initial treatments include rituximab alone or combined with alkylating agents (bendamustine, cyclophosphamide); proteasome inhibitors (bortezomib, carfilzomib, ixazomib); nucleoside analogues (fludarabine, cladribine); and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib). In patients with relapsed or treatment-resistant disease, an alternative frontline regimen, a BTK inhibitor (if not used previously) or an autologous stem cell transplantation can be considered.

Acronyms and Abbreviations

AL, light chain amyloidosis; APRIL, a proliferation inducing ligand; BDR, bortezimid, dexamethasone and rituximab; BR, bendamustine and rituximab; BTK, Bruton tyrosine kinase; CaRD, carfilzomib, rituximab, dexamethasone; CD16, FcγRIIIa receptor; CD40L, CD40 ligand; CDR, complement determination region; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; cp, centipoises; CT, computed tomography; EMN, European myeloma network; ERK, extracellular signal-related kinase; FDA, Federal Drug Administration; GM1, ganglioside M1; GM2, ganglioside M2; HCV, hepatitis C virus; Ig, immunoglobulin; IgMκ, Immunoglobulin M kappa light chain; IL, interleukin; IκB, inhibitor of kappa B; κ, kappa light chain; IPSSWM, international prognostic scoring system for Waldenstrom's macroglobulinaemia; IRAK interleukin 1 receptor associated kinase; LPL, lymphoplasmacytic lymphoma; MAG, myelin-associated glycoprotein; MGUS, Monoclonal gammopathy of undetermined significance; MMP8, matrix metalloproteinase 8; NF-κB, nuclear factor kappa B; PET, positron emission tomography; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes; PCR, polymerase chain reaction; R-CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab; R-CP, cyclophosphamide, prednisone, and rituximab; R-CVP, cyclophosphamide, vincristine, prednisone, and rituximab; sCD27, soluble CD27; SDF, stromal cell derived factor; SCT, stem cell transplantation; SEER, surveillance epidemiology and end results; TLR, toll-like receptor; US, United States; VLA, very late antigen; WGS, whole genome sequencing; WHIM, warts, hypoammoglobil, infections and myelkathexis; WHO, World Health Organization; WM, Waldenström macroglobulinemia; WT, “wild type”;.