Obesity and multiple myeloma: Emerging mechanisms and perspectives.

Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is also involved in the development of cardiovascular disease and type 2 diabetes mellitus. Recently, an increase in the incidence of obesity-related cancers has been reported. Multiple myeloma (MM) is the second most common hematological malignancy, after lymphoma. The aim of this review is to examine the epidemiological data on obesity and MM, assess the effect of obesity on MM outcomes, evaluate the possible mechanisms through which obesity might increase the incidence of MM and provide the effects of obesity management on MM. Current evidence indicates that obesity may have an impact on the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM and increase the prevalence of MM. However, data regarding the effect of obesity on MGUS incidence are controversial; further studies are needed to examine whether obesity affects the development of MGUS or the progression of MGUS to MM. In addition, obesity affects MM outcomes. Increased BMI is associated with decreased survival in patients with MM, while data regarding the effect of obesity on newly diagnosed MM subjects and autologous stem cell transplantation are limited. Interestingly, the obesity paradox may also apply to patients with relapsed/refractory MM who are overweight or obese, because they may have a survival advantage. The pathophysiological pathways linking obesity to MM are very complicated and include bone marrow adipose tissue; adipokines, such as adiponectin, leptin, resistin, and visfatin; inflammatory cytokines and growth factors, such as TNF-α and IL-6; hormones including insulin and the insulin-like growth factor system as well as sex hormones. In terms of the effect of pharmacological management of obesity, orlistat has been shown to alter the proliferation of MM cells, whereas no data exist on glucagon-like peptide-1 receptor agonists, naltrexone/bupropion, or phentermine/topiramate. Bariatric surgery may be associated with a reduction in the incidence of MM, however, further studies are needed.

Smouldering multiple myeloma: To seek or not to seek? To treat or not to treat. That is the question.

In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence-based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193-1206.

Early detection of multiple myeloma: A first step towards a screening programme.

Novel therapies for multiple myeloma have substantially improved the prognosis, but before patients are able to benefit from treatment, a diagnosis must have been made. The Myeloma UK laboratory working group has developed a three-part tool box to help primary care physicians to suspect myeloma despite mostly vague symptoms, to do the right tests and to derive the proper conclusions from the results. Commentary on: Drayson et al. Laboratory practice is central to earlier myeloma diagnosis; utilising a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol 2024;204:476-486.

Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of in vivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Vitamin D and monoclonal gammopathy of undetermined significance (MGUS) among U.S. Black women.

PURPOSE: Risk factors for monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor to multiple myeloma, are largely unknown. We hypothesized that low vitamin D levels might be associated with higher MGUS prevalence in a national cohort of U.S. Black women. METHODS: We screened archived serum samples (collected 2014-2017) from 3896 randomly selected participants in the Black Women's Health Study ages 50-79 for evidence of MGUS; samples had been assayed for 25-hydroxyvitamin D [25(OH)D] shortly after blood draw. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D level and MGUS status, adjusting for age, body mass index, and season of blood draw. RESULTS: We identified 334 MGUS cases (8.6%) in the study population. The adjusted OR comparing women with vitamin D deficiency (25(OH)D < 20 ng/mL) to those with 25(OH)D levels ≥ 30 ng/mL was 1.27 (95% CI: 0.95, 1.72). CONCLUSION: MGUS was more prevalent among Black women with vitamin D deficiency compared to those with 25(OH)D ≥ 30 ng/mL; however, the association was not statistically significant. Future prospective studies are warranted to clarify the possible association between vitamin D and MGUS.

Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.

BACKGROUND: Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance. METHODS: To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM. RESULTS: Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. CONCLUSION: Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Differences in the proteome within extracellular vesicles between premalignant and malignant plasma cell disorders.

BACKGROUND: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. METHODS: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography-based method and evaluated their proteome using a label-free proteomics workflow. RESULTS: In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. CONCLUSIONS: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

Decreased neutrophil function in newly diagnosed multiple myeloma patients is restored with lenalidomide therapy.

OBJECTIVES: Bacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. METHODS: Phagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay. RESULTS: PMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment. CONCLUSION: Our results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.

Renal impairment in monoclonal gammopathies and multiple myeloma.

The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.

Investigation and management of the monoclonal gammopathy of undetermined significance: A British Society for Haematology Good Practice Paper.

This Good Practice Paper provides recommendations for the diagnosis, risk stratification and management of the monoclonal gammopathy of undetermined significance (MGUS). It describes the recently recognised entity of the monoclonal gammopathy of clinical significance (MGCS), and recommends how it should be managed. The potential for targeted population screening for MGUS is also discussed.

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia.

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

Gaucher disease prevalence in 600 patients affected by monoclonal gammopathy of undetermined significance.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive inherited disorder caused by the lysosomal enzyme acid ß-glucosidase deficiency. Many patients experience a critical delay in the diagnosis of up to 8-10 years due to its rarity and variability in signs and symptoms, with the consultation of several specialists. PATIENTS AND METHODS: This prospective observational study analyzed the prevalence of GD in 600 patients with monoclonal gammopathy of uncertain significance (MGUS) from January 2018 until February 2022. RESULTS: The mean age of participants was 66 years, with a mean monoclonal component of 0.58 g/dL. In 433 MGUS patients with available data, anemia (hemoglobin level < 10 g/dL) was present in 31 patients (7%), and thrombocytopenia (platelet count <100.000/mm3 ) in 24 (5.5%). Of 600 MGUS patients tested for acid ß-glucosidase enzyme activity, 7 patients (1.2%) had activity below 2.5 nmol/h/mL. In comparison, GBA gene analysis was executed in 110 patients. It revealed 4 patients (0.7%) affected by GD (3 patients with compound heterozygous mutation and 1 with homozygous mutation), with a prevalence of 1 every 150 MGUS patients. Furthermore, 12 out of the remaining 106 evaluated patients (11%) were carriers of a single heterozygous mutation while having regular enzyme activity. CONCLUSIONS: The clinical heterogeneity of GD and frequent lack of awareness among physicians often lead to diagnostic delays and severe clinical manifestations. The role of MGUS in the presence of at least one clinical sign, such as low platelet count, organomegaly, bone pain, or bleeding tendency, could aid in initiating GD screening with DBS, thus reducing the period between symptom onset and the diagnosis of this rare disease.

Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.

An unusual case of acquired angioedema associated with monoclonal gammopathies of uncertain significance.

Acquired angioedema (AAE) is a rare disease due to the C1 esterase inhibitor (C1-INH) deficiency. Clinically, its symptoms are similar to hereditary angioedema (HAE) with hereditary C1-INH deficiency. Both conditions have the potential to cause upper airway obstruction, which can be fatal in clinical practice and thus require intense attention. Here, we'd like to discuss the clinical presentation, diagnosis and follow up of a special case of AAE associated with monoclonal gammopathies of unknown significance (MGUS) with recurrent upper airway obstruction. The patient was regularly followed up after being discharged from our ward. Measurements of C3-C4 levels were carried out by a hematological test. Due to the rarity of such a disease, especially in Chinese people, relevant diagnosis methods are missing in this patient, so the patient was only diagnosed with AAE-C1-INH associated with MGUS clinically. The latest follow up showed that he still underwent recurrent upper airway obstruction; thus, he remained in a tracheostomy state due to a lack of proper medication prophylaxis and died eventually. This unusual case reminds emergency physicians to pay attention to such disease during clinical practice, and relevant diagnosis method should be improved.

A UK consensus algorithm for early treatment modification in newly diagnosed systemic light-chain amyloidosis.

Depth of response is the critical determinant of prognosis in amyloid light-chain (AL) amyloidosis. Here, we aim to identify patients who are unlikely to improve response based on analysis of baseline characteristics and 1-month response. In a multivariate model, difference in involved amyloidogenic and uninvolved serum free light chains (dFLC) at diagnosis (dFLC >400 mg/l, odds ratio [OR] 4.051, p < 0.005) and no response at 1 month (OR 4.787, p < 0.005) were significant predictors of no improvement in response. Only 5% of patients with a dFLC of >400 mg/l and no response at 1 month improved their response (p < 0.005). We suggest that these patients should switch treatment early, subject to their functional status.

The potential role of mass spectrometry for the identification and monitoring of patients with plasma cell disorders: Where are we now and which questions remain unanswered?

Mass spectrometry (MS) techniques provide a highly sensitive methodology for the assessment and monitoring of paraproteins compared to standard electrophoretic techniques. The International Myeloma Working Group (IMWG) recently approved the use of intact light chain matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) in lieu of immunofixation in the clinical assessment of patients and the assessment of patients enrolled on clinical trials. The increased sensitivity of these assays may help to detect and monitor monoclonal proteins (MP) in many patients with previously non-measurable disease, will reduce complete response (CR) rates and increase detection of low-level MP. The ability to track the unique mass or amino acid sequence of the MP also eliminates interference from therapeutic monoclonal antibodies (tmAbs) in most patients with IgG kappa myeloma. The intact light chain assays also provide structural information about the monoclonal light chain, including the presence of N-linked glycosylation, which has been shown to be commoner on amyloidogenic light chains and may have prognostic significance in monoclonal gammopathy of undetermined significance (MGUS). In this review, we discuss these issues alongside differences in the analytical and practical aspects related to the different MS assays under development and the challenges for MS.

STAT3 is over-activated within CD163pos bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS.

Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy.We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13).Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients.In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients.