High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.

ABSTRACT: Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

The Rory Morrison WMUK Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder.

National registries are used globally to characterise patient demographics, treatment choices and mortality to inform and improve clinical management. Waldenström macroglobulinaemia (WM) is a rare, treatment-responsive B-cell lymphoproliferative disorder with diverse clinical features and variable outcomes. To prospectively chart changes in the management of WM in the UK, the Rory Morrison Registry (RMR) was developed to systematically collect real-world data. Here we describe the development of the RMR, demonstrate its feasibility and describe preliminary observations. The RMR was devised as a collaborative project between patients and clinicians, under the auspices of the UK Charity for WM in 2016. Patients may be registered after the point of diagnosis and those with historic diagnosis were also eligible. Data collection fields were compiled by focus groups of clinicians, patients, industry and commissioning partners. The RMR launched in November 2017 and as of March 2022, there were 22 participating centres and 1305 patients registered. Median follow-up was 6.4 years, five-year overall survival 90.7% (95% confidence interval [CI] 88.4%-92.5%) and 10-year overall survival 79.3% (95% CI 75.7%-82.4%). There has been a clear evolution in treatments including a rapid growth in the use of Bruton's tyrosine kinase inhibitors in relapsed disease since their availability in the UK.

Monoclonal Gammopathy of Undetermined Significance.

Monoclonal gammopathy of undetermined significance (MGUS) is of considerable clinical importance to primary care physicians given its high prevalence in the general population. MGUS has a variable but lifelong risk for progression to hematologic cancer, such as multiple myeloma, Waldenström macroglobulinemia, or light-chain amyloidosis. In addition, MGUS has been associated with several nonmalignant yet symptomatic disorders that require therapy directed toward eliminating the monoclonal gammopathy. Thus, it is important not only to understand the essentials of diagnosing and monitoring patients with MGUS but also to recognize when to refer patients with MGUS to a specialist.

Diagnosis and management of Waldenström macroglobulinaemia-A British Society for Haematology guideline.

SCOPE: The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. METHODOLOGY: This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström('s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(-related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents.

Primary therapy and relative survival in patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia: a population-based study in the Netherlands, 1989-2018.

It is unclear how treatment advances impacted the population-level survival of patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM). Therefore, we assessed trends in first-line therapy and relative survival (RS) among patients with LPL/WM diagnosed in the Netherlands between 1989 and 2018 (N = 6232; median age, 70 years; 61% males) using data from the nationwide Netherlands Cancer Registry. Patients were grouped into three age groups (<65, 66-75 and >75 years) and four calendar periods. Overall, treatment with anti-neoplastic agents within 1 year post-diagnosis gradually decreased over time, following a broader application of an initial watch-and-wait approach. Approximately 40% of patients received anti-neoplastic therapy during 2011-2018. Furthermore, use of chemotherapy alone decreased over time, following an increased application of chemoimmunotherapy. Detailed data among 1596 patients diagnosed during 2014-2018 revealed that dexamethasone-rituximab-cyclophosphamide was the most frequently applied regimen; its use increased from 14% to 39% between 2014 and 2018. The 5-year RS increased significantly over time, particularly since the introduction of rituximab in the early-mid 2000s. The 5-year RS during 1989-1995 was 75%, 65%, and 46% across the age groups compared to 93%, 85%, and 79% during 2011-2018. However, the survival improvement was less pronounced after 2011. Collectively, the impressive survival improvement may be accounted for by broader application of rituximab-containing therapy. The lack of survival improvement in the post-rituximab era warrants studies across multiple lines of therapy to further improve survival in LPL/WM.

IgM monoclonal gammopathies of clinical significance: diagnosis and management.

IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.

Does early disease progression predict survival after first line-treatment of Waldenström macroglobulinemia?

In symptomatic Waldenström macroglobulinemia (sWM) patients, prognosis is assessed with the international prognostic scoring system (IPSSWM). In follicular lymphoma and other B-cell and T-cell lymphomas, disease progression within 24 months (POD24) or (in patients without POD24) after 24 months has been proposed as the start date for stratifying subsequent survival. In the present report, we assessed in a large series of 472 sWM patients, the prognostic value of this new dynamic endpoint already reported in many other lymphomas subtypes. The 3 year subsequent survival for patients with POD24 was 75% and 93% for patients without POD24. In sWM patients, departure from the proportional hazards assumption complicated this analysis. In patients without POD24, the median subsequent progression-free survival time of 43 months accounted for favorable outcome, whereas survival after progression was not influenced by the time to progression. In addition, sensitivity analysis showed that the baseline IPSSWM score also influenced survival after POD24. In sWM patients, we conclude that the apparent difference in survival after POD24 or the 24 months time-point (in patients without POD24) is mainly explained by the prolonged subsequent progression free survival of latter patients. Indeed, the mortality after progression is not influenced by the time to this event.

Post-relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto-HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto-HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto-HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto-HCT between 2007 and 2017. The primary endpoint was post-relapse overall survival (PR-OS). Secondary endpoints were to identify factors prognostic of PR-OS. Of the 48 patients with WM who underwent auto-HCT, 22 (46%) experienced relapse following auto-HCT. Median PR-OS of relapsed WM patients after auto-HCT (n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months-NR). Among patients who relapsed <1 year versus ≥1 year from auto-HCT, the median PR-OS was 18.4 months (95%CI: 0.8-NR) months and NR (95%CI: 17.5-NR), respectively (p = 0.06). Of note, disease status at the time of transplant, CR/VGPR versus partial remission did not appear to impact PR-OS. The median PR-OS was significantly longer in patients who received ibrutinib in the post-transplant setting compared to those who did not (NR vs. 18.4 months, 95%CI: 9.1-NR, p = 0.02). On univariable analysis, the presence of complex karyotype (RR = 4.87, 95% CI = 1.22-19.53) and a higher number of prior lines of therapy (RR = 1.81, 95% CI = 1.23-2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto-HCT and provides a benchmark for future trials evaluating survival following auto-HCT relapse.

How I treat Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM). The disease may have an asymptomatic phase, or patients may present with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM. Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions. Specific criteria that define symptomatic disease that needs treatment offer clinical guidance. The treatment of WM has evolved rapidly, with treatment options that include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors. The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient's age. With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy. In this review, we focus on different clinical scenarios and discuss treatment options, based on the available data.

Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia.

Comparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab-based frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status.

Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas.

OPINION STATEMENT: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.

Efficacy and safety of plasmapheresis in symptomatic hyperviscosity and cast nephropathy: A Multicenter Experience in Turkey.

BACKGROUND AND OBJECTIVES: Cast nephropathy (CN) and hyperviscosity (HV), which we encounter in plasma cell diseases, are serious clinical manifestations that increase mortality and morbidity if not managed well in the early period. Therapeutic plasma exchange (TPE) procedures based on the removal of patient plasma is a frequently preferred treatment modality. TPE is recommended at varying levels of evidence for the treatment of CN and HV in plasma cell disorders. MATERIAL AND METHODS: A total of 61 patients, 50 with multipl myeloma (MM) and 10 with Waldenström macroglobulinemia (WM), who underwent TPE for CN and HV, were included in our multicenter, and retrospective study. RESULTS: A statistically significant decrease was found in all disease-related biochemical markers, which were measured 1 week after the application of TPE added to standard medical treatment (IgG; p < 0.001, IgM; p = 0.004, IgA; p = 0.14, kappa light chain; p < 0.001, lambda light chain; p < 0.001, ß-2 microglobulin; p < 0.001, total protein; p < 0.001, albumin; p < 0.001, LDH; p = 0.02, creatine; p < 0.001, hemoglobin; p = 0.010). Clinically, all 11 patients who underwent TPE for HV responded. While a partial response (PR: 80 %) was obtained in 40 of 50 MM patients with CN, no response was obtained in 10 patients (non-response: 20 %). CONCLUSION: In conclusion, it was observed that TPE reduced all biochemical markers related to HV and CN, while making a significant contribution to clinical improvement. We believe that adding TPE to the standard treatment in this patient group will reduce mortality and morbidity in the early period and have a positive effect on survival in the long term.

Cause-specific mortality in individuals with lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia, 2000-2016.

Data on cause-specific mortality after lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinaemia (WM) are lacking. We identified causes of death amongst 7289 adults diagnosed with incident first primary LPL (n = 3108) or WM (n = 4181) during 2000-2016 in 17 USA population-based cancer registries. Based on 3132 deaths, 16-year cumulative mortality was 23·2% for lymphomas, 8·4% for non-lymphoma cancers and 14·7% for non-cancer causes for patients aged <65 years at diagnosis of LPL/WM, versus 33·4%, 11·2% and 48·7%, respectively, for those aged ≥75 years. Compared with the general population, patients with LPL/WM had a 20% higher risk of death due to non-cancer causes (n = 1341 deaths, standardised mortality ratio [SMR] 1·2, 95% confidence interval [CI] 1·1-1·2), most commonly from infectious (n = 188; SMR 1·8, 95% CI 1·6-2·1), respiratory (n = 143; SMR 1·2, 95% CI 1·0-1·4), and digestive (n = 80; SMR 1·8, 95% CI 1·4-2·2) diseases, but no excess mortality from cardiovascular diseases (n = 477, SMR 1·1, 95% CI 1·0-1·1). Risks were highest for non-cancer causes within 1 year of diagnosis (n = 239; SMR<1year 1·3, 95% CI 1·2-1·5), declining thereafter (n = 522; SMR≥5years 1·1, 95% CI 1·1-1·2). Myelodysplastic syndrome/acute myeloid leukaemia deaths were notably increased (n = 46; SMR 4·4, 95% CI 3·2-5·9), whereas solid neoplasm deaths were only elevated among ≥5-year survivors (n = 145; SMR≥5years 1·3, 95% CI 1·1-1·5). This work identifies new areas for optimising care and reducing mortality for patients with LPL/WM.

Detection of the MYD88L265P and CXCR4S338X mutations by cell-free DNA in Waldenström macroglobulinemia.

We aimed to detect the MYD88L265P and CXCR4S338X mutations in cell-free DNA (cfDNA) in patients with Waldenström macroglobulinemia (WM). We collected peripheral blood and paired bone marrow aspirates from 27 WM patients (including 16 patients with newly diagnosed WM, 3 patients with WM in relapse and 8 patients with WM during treatment). cfDNA was extracted from peripheral blood using a QIAamp Circulating Nucleic Acid Kit. The MYD88L265P and CXCR4S338X mutations were detected by real-time allele-specific PCR (AS-PCR) in cfDNA and genomic DNA (gDNA) extracted from bone marrow aspirates. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was determined using a serial dilution of 10%, 2%, 0.4% and 0.08% MYD88L265P cfDNA in wild-type cfDNA. Among the 27 patients, MYD88L265P was detected in 88.9% of them in gDNA and in 85.2% of them in cfDNA, with a concordance rate of 96.3%. The concordance rates were 93.8%, 100% and 100% in patients with newly diagnosed WM, patients with WM in relapse and patients with WM during treatment, respectively. The sensitivity of real-time AS-PCR for detecting MYD88L265P in cfDNA was 0.4%. CXCR4S338X was detected in 6.3% of the 16 newly diagnosed WM patients in both gDNA and cfDNA, with a concordance rate of 100.0%. It is feasible to apply cfDNA to detect MYD88L265P and CXCR4S338X in WM patients with a high concordance rate.

Outcome of stem cell transplantation for Waldenström's macroglobulinemia: analysis of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Lymphoma Working Group.

The role of stem cell transplantation (SCT) for patients with Waldenström's macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7-46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0-93.4%) and 70.8% (95% CI, 53.0-82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5-68.6%) and 45.0% (95% CI, 26.3-62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM.

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P = .002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P = .028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Neuropathies and paraproteins.

PURPOSE OF REVIEW: There is an increasingly recognized association between haematological and neurological disease. This is especially true in the peripheral nervous system in which, to an extent, proof of a link is easier to achieve. The most sensitive low level paraprotein detection methods should always be employed in which a paraprotein is suspected. Peripheral nerves can be damaged not only by the immunological targeting of the myelin by the paraprotein, but by deposition (light chain amyloid and cryoglobulins) or direct infiltration (neurolymphomatosis). This has resulted in other defined paraprotein-related disease pathogeneses. RECENT FINDINGS: Our opportunities for treating these patients are greater not only through better recognition of disease but also treatments introduced from haematological research. Beyond rituximab, combination therapies, proteasome inhibition and novel biological treatments are being described in haematological practice with early efficacy in neurology. Important developments here should be exploited in neurology to improve outcomes. SUMMARY: This review of the current literature focuses not only on the long-term outcome studies in anti-myelin-associated glycoprotein neuropathy, but developments in the diagnosis and treatment of monoclonal gammopathy of undetermined significance and Waldenström's Macroglobulinaemia.

Diagnostic framing of IgM monoclonal gammopathy: Focus on Waldenström macroglobulinemia.

The finding of an IgM monoclonal gammopathy often represents a diagnostic challenge. In fact, there are many pathological disorders associated with this condition, each of which has distinctive characteristics and requires specific clinical, instrumental, and laboratory assessments to set the appropriate treatment. This review has two aims. Firstly, to provide a framework of the broad spectrum of IgM-associated disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2) Waldenström macroglobulinemia (WM); (3) IgM-related disorders (among which hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease, cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4) IgM-secreting multiple myeloma (IgM-MM); and (5) other lymphoproliferative disorders which may be associated with IgM (such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and B-cell non Hodgkin lymphoma). Secondly, to give a detailed insight regarding diagnosis and treatment of WM.

Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in >90% of patients and is found in the majority of IgM monoclonal gammopathy of undetermined significance patients. RISK STRATIFICATION: Age, hemoglobin level, platelet count, ß2 microglobulin, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogs are active but usage is declining for less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Potential for stem cell transplantation should be considered in selected younger patients. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, fludarabine, thalidomide, everolimus, ibrutinib, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.