Waldenström’s macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a rare, malignant, hematological monoclonal gammopathy that shares several traits with multiple myeloma (MM). While the presence of elevated IgM levels is similar between the two blood disorders, WM is often also associated with lymphadenopathy, hepatosplenomegaly, and increased blood viscosity, which are absent in MM. The type of lytic lesions present also differ with infiltration of the bone marrow by small lymphocytes, plasmacytoid cells, and plasma cells, whereas MM primarily affects plasma cells. Renal involvement is also more common in MM. 

An update on the prognostication and treatment of WM was recently published. Until lately, not much was known about WM. However, new advances have identified clinical and genetic markers that can be used for disease prognostication. Further, drug therapy trials are now focusing on WM instead of extrapolating information from related B-cell lymphoid malignancies. 

Survival from WM is in the range of 5 years to more than 10 years. A pre-existing diagnosis of IgM-type monoclonal gammopathy of undetermined significance (MGUS) increases the risk of developing WM 46-fold with a transformation rate of 1.5% per year. 

While the etiology of WM has not been fully elucidated, it is believed to originate in a postgerminal center B-lymphocyte. There appear to be abnormalities in Chromosome 17 that lead to the deletion or loss of function of TP53 (p53 tumor suppressor gene), resulting in deregulation of cell growth, cell-cycle checkpoint, DNA repair and apoptosis, and reduced overall survival (OS) or time-to-treatment (TTT). 

MYD88L265P (L265P mutation in the myeloid differentiation primary response gene 88), an important biomarker, is found in more than 90% of WM patients and is associated with activation of the nuclear-factor kappa B and Janus kinase/signal transducers and activators of transcription pathways, as well as with Brutons tyrosine kinase (BTK) protein. Likewise, mutations in CXCR4, a gene that acts as a modifier of drug response in WM, are also associated with decreased OS and extramedullary organ involvement. 

The clinical presentation of WM includes nonspecific symptoms (such as fatigue, malaise, fever and/or weight loss), anemia, lymphadenopathy, hepatosplenomegaly, hyperviscosity syndrome, and neuropathy, which is attributable to autoimmune-like reactions.

The International Prognostic Staging System for WM (IPSS-WM), the most widely studied and validated risk stratification-tool for symptomatic WM patients, has demonstrated an OS rate of 87%, 68%, and 36% in low, intermediate, and high-risk groups, respectively. This is important because treatment is not warranted in asymptomatic patients. The addition of LDH testing may further improve the identification of high-risk patients. Other prognostic models are also under investigation. 

Symptom control and reduction in organ damage are goals of therapy. Rituximab monotherapy is used in newly diagnosed patients with low-risk symptomatic disease who fail steroid therapy. Rituximab use is associated in an IgM flare. Ofatumumab, a second-generation anti-CD20 monoclonal antibody, is an alternative to rituximab. In intermediate disease, rituximab-based chemoimmunotherapy is recommended, whereas in low disease burden, the preferred regimen is dexamethasone, rituximab, and cyclophosphamide. In those with a higher disease burden, including severe cytopenia and constitutional symptoms, four to six cycles of bendamustine plus rituximab are utilized. This regimen is better tolerated than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), although OS is similar.

Autologous stem-cell transplant may be an option for patients aged <70 years. Other treatment options in newly diagnosed patients include bortezomib-based regimens, which are also used in MM, and carfilzomib and ixazomib, which are both newer generation protease inhibitors. These agents have less neurotoxicity than bortezomib and are also administered in protocols along with rituximab and prednisone. 

Currently, there are no universal recommendations for maintenance therapy in WM, although the use of rituximab for this indication is being studied. Preliminary results have demonstrated improved outcomes with the use of rituximab-based maintenance therapy. 

Salvage regimens, which are indicated only for symptomatic patients, not just those with biochemical progression, include retreatment using first-line agents (if at least 3 years have passed since initiation of therapy); bendamustine + rituximab or bendamustine + ofatumumab; bortezomib combined with rituximab and prednisone; autologous or allogenic stem-cell transplant; and ibrutinib, a BTK inhibitor indicated for the management of symptomatic WM. The overall response rate with ibrutinib is 96%, especially in those with MYD88L265P/CXCR4WT. Ibrutinib offers an improvement in progression-free survival and OS over other salvage regimens, but not in complete response. Adverse effects of ibrutinib include grade 3 hematological abnormalities and atrial fibrillation. Ibrutinib is indicated only for salvage therapy; when used for this indication, it should be continued indefinitely. 

Other novel treatments, including immunomodulating drugs, are currently in various phases of clinical investigation. Their mechanisms of actions include anti-CD38, anti-CXCR4, anti-CD25, anti-CD20, anti-CD3, and anti-PD-1 activity; inhibition of Bcl-2 inhibition,  P13k delta, BTK, proteasome, exportin, P13K, Syk, HDAC1/HDAC2, mTOR, and tyrosine kinase inhibition, as well as chimeric antigen receptor t-cell therapy. 

Although WM is an uncommon disorder, it is important for pharmacists to be able to recognize the signs and symptoms of the disorder as well as know the recommended therapeutic interventions. 

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