Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group

Waldenström macroglobulinaemia (WM) is an indolent B‐cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab‐induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib‐ and bortezomib‐based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work‐up and therapy of WM to assist Australian clinicians in the management of this disease.     

Bone Marrow Histology in Waldenström's Macroglobulinaemia

Bone marrow biopsies of 137 patients with Waldenström's macroglobulinaemia (WM), 26 with non-secretory immunocytoma and 32 with benign monoclonal gammopathy were processed for histologic evaluation. Bone marrow involvement was found in 110 (80%) initially, and in 24 (18%) in sequential biopsies. 3 types were distinguished: lymphoplasmacytoid (47%), lymphoplasmacytic (42%) and polymorphous (11%) with median survivals of 74, 25 and 12 months, respectively. When grouped according to the tumour cell mass in the biopsies, the median survivals were 55, 21 and 8 months for < 20 vol%, 20–50 vol% and > 50 vol% respectively; in each subtype, the tumour cell mass correlated with the disease progression. 6 clinical variables were also found prognostically significant. These results demonstrate that (i) 98% of patients with WM have bone marrow involvement; (ii) the lymph node sub-classification is applicable to the bone marrow and has both clinical and prognostic significance; (iii) patients may be staged according to the tumour cell burden in the bone marrow biopsy.     

Monoclonal gammopathy of undetermined significance

Significant advances have been made in our understanding of the natural history, pathogenesis, mechanisms of progression and prognosis of monoclonal gammopathy of undetermined significance (MGUS). Although the overall incidence of MGUS progression is 1 per year, it is now possible to more accurately predict the risk of progression based on a new risk-stratification model. However, it is still hard to design chemopreventive trials given that the absolute risk of progression per year is low, even in the high-risk group. Therefore, further improvements in estimating the risk of progression are needed. Roughly 50% of MGUS may originate from primary translocation events at the heavy-chain immunoglobulin locus at chromosome 14q32. In most of the remaining MGUS patients, the initiating event is associated with genomic instability that results in hyperdiploidy of certain odd numbered chromosomes. Cytogenetically distinct subtypes of MGUS may carry significant differences in the risk of progression to malignancy. New markers, such as measures of bone marrow angiogenesis and circulating plasma cells may be additional prognostic factors. A better understanding of the mechanisms underlying the transition of normal plasma cells to the MGUS phenotype, and the transition of MGUS to myeloma or related malignancy, will help identify new risk factors for progression and new targets for chemopreventive interventions.     

Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by a serum monoclonal protein <30 g/l, <10% plasma cells in the bone marrow, and absence of end-organ damage (CRAB-hypercalcaemia, renal insufficiency, anaemia, or bone lesions). MGUS is present in 3% of persons >50 years and in 5% >70 years of age. The risk of progression to multiple myeloma (MM) or a related disorder is 1% per year. Patients with risk factors consisting of an abnormal serum free light chain ratio, non-immunoglobulin G (IgG) MGUS, and an elevated serum M protein >/=15 g/l had a risk of progression at 20 years of 58%, compared with 37% with two risk factors present, 21% with one risk factor present, and 5% when none of the risk factors were present. Smouldering (asymptomatic) multiple myeloma is characterized by having a serum IgG or IgA monoclonal protein of 30 g/l or higher and/or 10% or more plasma cells in the bone marrow but no evidence of end-organ damage. The cumulative probability of progression to active MM or amyloidosis was 51% at 5 years, 66% at 10 years and 73% at 15 years; the median time to progression was 4.8 years.     

Malignant Evolution of Asymptomatic Monoclonal IgM after Seven and Fifteen Years in Two Siblings of a Patient with Waldenström's Macroglobulinemia

ABSTRACT. This paper reports a rare familial occurrence of Waldenström's macroglobulinemia (WM) in siblings (two brothers and one sister). Examination of the siblings of a patient suffering from WM in 1965 showed that a brother and a sister had an “asymptomatic” monoclonal IgM in their sera without clinical or hematological features. Follow-up demonstrated a malignant transformation into WM after 7 years in the brother and after 15 years in the sister. This unusual incidence makes the true existence of asymptomatic gammopathies of IgM class questionable.     

Serum Neopterin and β2-Microglobulin Concentrations in Monoclonal Gammopathies

ABSTRACT Serum neopterin and β₂-microglobulin concentrations were investigated in 46 patients with multiple myeloma and in 28 patients with asymptomatic monoclonal gammopathy followed for long periods (median 9.6 years) and showing an absence of evolution. Seventy-two per cent of the patients with multiple myeloma showed β₂-microglobulin concentrations higher than 3 mg/1 with a mean of 6.84 mg/1, whereas all the patients with asymptomatic monoclonal gammopathies had concentrations lower than 3 mg/1 with a mean of 1.64 mg/1. Concerning serum neopterin concentrations, 91% of the patients with multiple myeloma had values with in pathological limits (>8 nmol/1) with a mean of 34 nmol/1, whereas all but one of the patients with asymptomatic monoclonal gammopathy had normal values with a mean of 5.19 nmol/1. The differences thus observed in these two groups of patients are highly significant (p<0.001). Serum neopterin concentration, unrelated to renal insufficiency, seems to be useful in the differentiation of malignant or benign asymptomatic monoclonal gammopathies.     

Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.     

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia

Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenström macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. We carried out a large retrospective study in 825 newly diagnosed WM patients, of who 113 (14%) developed symptomatic hyperviscosity. The median serum IgM level at the time of symptomatic hyperviscosity was 61·8 g/l (range 31–124 g/l). Forty‐four patients (36%) had symptomatic hyperviscosity at the time of WM diagnosis. A serum IgM level >60 g/l at diagnosis was associated with a median time to symptomatic hyperviscosity of 3 months, whereas the median time for patients with serum IgM level of 50·01–60 g/l was approximately 3 years. Adjusting for other clinical factors, the odds of developing symptomatic hyperviscosity were 370‐fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival (P = 0·12). The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.     

Severe Anemia Due to Cold Agglutinin Syndrome in a COVID-19 Patient with IgM Monoclonal Gammopathy of Undetermined Significance Successfully Treated with Corticosteroids

Secondary cold agglutinin syndrome (CAS) is autoimmune hemolytic anemia secondary to infections and lymphoid disorder. We here report the first Asian case of CAS secondary to novel coronavirus disease 2019 (COVID-19). A 72-year-old Japanese woman presented with a 2-week history of dyspnea and cough, and laboratory data revealed severe hemolytic anemia with a hemoglobin level of 4.7 g/dL. She was diagnosed with COVID-19, CAS, and monoclonal gammopathy of undetermined significance (MGUS). The anemia responded to corticosteroids administered for COVID-19 and required maintenance therapy. Although corticosteroids are not a standard therapy for CAS, they might be effective for CAS secondary to COVID-19 complicated with MGUS.     

Monoclonal gammopathy‐associated pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti‐myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy‐associated PRCA.     

A risk-stratification model based on the initial concentration of the serum monoclonal protein and MYD88 mutation status identifies a subset of patients with IgM monoclonal gammopathy of undetermined significance at high risk of progression to Waldenström macroglobulinaemia or other lymphoproliferative disorders

IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1–2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80–2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0–273·3, P = 0·012 and HR 24·4, 95% CI 2·2–275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.     

Waldenström macroglobulinaemia: the key questions

In this review, the key issues that pertain to Waldenström disease are discussed in a concise question‐and‐answer format. Diagnosis, prognosis, and indications for state‐of‐the‐art therapy are updated. Current therapies presented at the 7th International Workshop for Waldenström Macroglobulinaemia are included.     

Renal disease related to Waldenström macroglobulinaemia: incidence,pathology and clinical outcomes

The incidence and prognostic impact of nephropathy related to Waldenström macroglobulinaemia (WM) is currently unknown. We performed a retrospective study to assess biopsy‐confirmed WM‐related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5·1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis (n = 11, 25%), monoclonal‐IgM deposition disease/cryoglobulinaemia (n = 10, 23%), lymphoplasmacytic lymphoma infiltration (n = 8, 18%), light‐chain deposition disease (n = 4, 9%) and light‐chain cast nephropathy (n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy (TMA) (n = 3, 7%), minimal change disease (n = 2, 5%), membranous nephropathy (n = 1, 2%) and crystal‐storing tubulopathy (n = 1, 2%). The median overall survival in patients with biopsy‐confirmed WM‐related nephropathy was 11·5 years, shorter than for the rest of the cohort (16 years, P = 0·03). Survival was better in patients with stable or improved renal function after treatment (P = 0·05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome.     

Response and survival for primary therapy combination regimens and maintenance rituximab in Waldenström macroglobulinaemia

Waldenström macroglobulinaemia (WM) is a rare and incurable lymphoma. Comparative studies evaluating the efficacy of primary therapy in symptomatic WM patients have not been performed. In this study, we compared response and survival outcomes in WM patients who received primary therapy with cyclophosphamide‐dexamethasone‐rituximab (CDR), bortezomib‐dexamethasone‐rituximab (BDR) and bendamustine‐rituximab (Benda‐R), as well as maintenance rituximab following primary therapy. Analyses were adjusted for relevant clinical factors associated with response and survival. Maintenance rituximab was analysed as a time‐varying covariate. Our study included 182 patients, of which 57 (31%) received Benda‐R, 87 (48%) BDR and 38 (21%) CDR; 116 (64%) received maintenance rituximab. The median time to best response was shorter for Benda‐R and BDR than CDR (18, 20 and 30 months, respectively). Benda‐R and BDR were associated with better median progression‐free survival (PFS) than CDR (5·5, 5·8 and 4·8 years, respectively), and better 10‐year overall survival rates (OS; 95%, 96% and 81%, respectively). Maintenance rituximab was associated with higher rates of major response (97% vs. 68%), and better median PFS (6·8 years vs. 2·8 years) and 10‐year OS rate (84% vs. 66%) when compared to not receiving maintenance. Benda‐R, BDR and maintenance rituximab associate with higher response rates and longer survival in WM patients than CDR and no maintenance, respectively.     

Familial monoclonal gammopathy: hyper-responsive B cells in unaffected family members

Background: In Iceland, eight families have been identified with multiple cases of monoclonal gammopathies (MG) and other lymphoproliferative diseases. In one of these families with several cases of monoclonal gammopathy of undetermined significance (MGUS) and Waldenströms macroglobulinemia, in vitro stimulation with poke‐weed mitogen revealed hyper‐responsive B cells showing increased immunoglobulin production in one‐third of disease‐free family members. Design and methods: In this study, the families were further traced and the list of names produced was compared with The Icelandic Cancer Registry (ICR) to find all recent cases of lymphoproliferative diseases. First‐degree relatives and descendants older than 20 yrs of age (n = 350) were selected for screening for paraprotein. Selected family members were tested for B‐cell hyper‐responsiveness and the lymphocyte phenotype was analysed by flow cytometry. Results: Comparison of the total list of 4370 family members with the ICR revealed 22 new cases and screening for serum paraprotein identified nine new cases of MG, eight being first‐degree relatives of known probands. Sixty cases of lymphoproliferative diseases are currently known within the eight families, five of them containing both IgG/A and IgM disorders. Twelve hyper‐responders (HR) were identified in four families, eight from one family, of whom four were known already. Stimulated B cells from HR had a significantly higher proportion of CD27⁺ memory/plasma cells than controls. Conclusion: Identification of new affected family members by screening confirms a hereditary predisposition to B‐cell proliferative diseases. Contrary to most studies, IgG/A and IgM disorders occurred together in five families. In four families, enhanced B‐cell responsiveness was found in healthy subjects clustered around cases.     

Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance

The possible relationships between biochemical measurements and both densitometric and radiographic indexes of skeletal fragility were evaluated in 65 postmenopausal women with monoclonal gammopathy of undetermined significance (MGUS). There was a significantly higher prevalence of vertebral fractures in the MGUS group compared with a control population (P < or = 0.001). The MGUS patients were then grouped according to the presence or absence of at least one mild vertebral fracture. Patients with fractures (Fx, n=34) were older (62.8 +/- 6.1 years), with long-standing disease (8.8 +/- 7.1 years) when compared with those without fractures (NFx, n=31; 59.7 +/- 5.0 years, P < or = 0.05 and 5.8 +/- 4.1 years, P < or = 0.05). The receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio was higher in Fx compared with NFx (0.092 +/- 0.018 vs. 0.082 +/- 0.020; P < or = 0.05). Lumbar spine (0.811 +/- 0.14 vs. 0.956 +/- 0.12 g/cm2), femoral neck (0.660 +/- 0.09 vs. 0.747 +/- 0.10 g/cm2) and total bone mineral density (BMD) (0.788 +/- 0.11 vs. 0.884 +/- 0.11 g/cm2) were lower (all P < or = 0.001) in FxMGUS compared with Nfx patients. Receiver operating characteristic curves identified lumbar BMD as the variable that best predicted vertebral fractures (area under the curve 0.817; 95% confidence interval, 0.713-0.921). This study provides an indication for the measurement of BMD in MGUS patients, as a means of predicting vertebral fractures, especially in those that are asymptomatic. Patients with prevalent fractures should undergo pharmacological treatment to prevent further fractures.