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.

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Immune-Pathogenesis of Myeloma.

This research indicates that monoclonal gammopathy of undetermined significance (MGUS) and myeloma may stem from chronic immune activation and inflammation, causing immune dysfunction and spatial immune exclusion. As the conditions progress, a shift toward myeloma involves ongoing immune impairment, affecting both innate and adaptive immunity. Intriguingly, even in advanced myeloma stages, susceptibility to immune effector cells persists. This insight highlights the intricate interplay between immune responses and the development of these conditions, paving the way for potential therapeutic interventions targeting immune modulation in the management of MGUS and myeloma.

Resolution of dysglycaemia after treatment of monoclonal gammopathy of endocrine significance.

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

The progress in multiple myeloma.

Multiple myeloma (MM) is a neoplastic disease characterized by the proliferation of clonal plasma cells. This disease arises from an initial asymptomatic stage known as monoclonal gammopathy of unknown significance (MGUS). The clinical phenotype that lies between MGUS and MM is commonly known as smoldering multiple myeloma (SMM). In individuals with MGUS and SMM, the risk of progression to MM persists constantly. In MGUS, the progression rate to MM or a related malignancy is around 1% per year, while in SMM, the progression rate to MM is approximately 10% per year. Recently, myeloma was defined as a clonal proliferation of malignant plasma cells that results in end organ damage or myeloma-defining events. MM is a genetically complex disease that exhibits clinical and biological diversity. Currently, the revised International Staging System (R-ISS) is used for prognostication in newly diagnosed patients. For transplant-eligible patients with newly diagnosed MM, the standard of care treatment (SoC) regimen is induction therapy, followed by ASCT and maintenance therapy. In general, the recommended induction therapy is a triplet or quadruplet-agent therapy consisting of a proteasome inhibitor, an immunomodulatory compound, and/or a CD38 antibody in combination with dexamethasone. Myeloma patients who are ineligible for a transplant are typically treated with a triplet combination, which necessitates specialized knowledge of treatment adverse effects. Although the prognosis for patients with MM has significantly improved over time due to advances in treatment, the disease remains incurable and relapses are common. Because various immunotherapeutic agents, new drugs and combinations have become available, selecting the most effective treatment for patients with relapsed/refractory MM needs both art and science.

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.

Investigation and Management of Immunoglobulin M- and Waldenström-Associated Peripheral Neuropathies.

The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are associated with IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia. Establishing a causal link between a paraprotein and neuropathy can be challenging but is necessary to adopt an appropriate therapeutic approach. The most common type of IgM-PN is Antimyelin-Associated-Glycoprotein neuropathy, but half of the cases are of other causes. Progressive functional impairment is an indication for treatment, even when the underlying disorder is IgM MGUS, involving either rituximab monotherapy or combination chemotherapy to achieve clinical stabilization.

Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance-Like Phenotype in Patients With Monoclonal Gammopathies.

PURPOSE: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated. PATIENTS AND METHODS: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis. RESULTS: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival. CONCLUSION: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Monoclonal Gammopathy of Undetermined Significance: A Comprehensive Review.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia with a predominate rise of the IgG immunoglobulin fraction without end-organ damage, often diagnosed incidentally. Despite its progression into various subsequent forms of hematological malignancies, MGUS remains underdiagnosed. A literature search was conducted using the Medline, Cochrane, Embase, and Google Scholar databases, including articles published until December 2022. Keywords used encompassed "Monoclonal Gammopathy of Undetermined Significance," "Plasma Cell dyscrasia," "Monoclonal gammopathy of renal significance," and "IgM Monoclonal gammopathy of Undetermined Significance," This study aimed to conduct a critical review to update knowledge regarding the pathophysiology, risk factors, clinical features, diagnostic protocols, complications, and current and novel treatments for MGUS. We recommend a multidisciplinary approach to manage MGUS due to the complexity of the illness's etiology, diagnosis, and therapy. This comprehensive review also highlights future prospects, such as developing screening protocols for at-risk populations, prevention of disease progression by early diagnosis through genome-wide association studies, and management using Daratumumab and NSAIDs.

Patient and provider-level drivers of healthcare utilization related to a diagnosis of a precancerous condition: monoclonal gammopathy of undetermined significance (MGUS).

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma. This qualitative study described patient (n = 14) experiences and healthcare providers' (n = 8) opinions and practices concerning care for patients with MGUS in the US. METHODS: Semi-structured, in-depth interviews were analyzed using thematic analysis. RESULTS: We identified six overarching themes related to the care pathway for patients with MGUS: (1) Process of MGUS diagnosis, (2) Providers' explanations, (3) Patients' understanding, (4) Impact of the diagnosis, (5) Follow-up/management, and (6) Factors influencing healthcare utilization. Patients demonstrated a basic understanding of MGUS. However, some patients felt anxiety around the diagnosis, which may affect other aspects of their lives. Non-hematologist providers report having less MGUS-specific knowledge. Older age, high-risk MGUS, and insurance coverage/healthcare costs influenced healthcare utilization. CONCLUSION: Patients with MGUS may have difficulty processing this premalignant diagnosis. Non-hematologist providers may have gaps in knowledge around specific care for patients with MGUS.

The immune system in multiple myeloma and precursor states: Lessons and implications for immunotherapy and interception.

Multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) are distinct disorders that likely originate in the setting of chronic immune activation. Evolution of these lesions is impacted by cross-talk with both innate and adaptive immune systems of the host. Harnessing the immune system may, therefore, be an attractive strategy to prevent clinical malignancy. While clinical MM is characterized by both regional and systemic immune suppression and paresis, immune-based approaches, particularly redirecting T cells have shown remarkable efficacy in MM patients. Optimal application and sequencing of these new immune therapies and their integration into clinical MM management may depend on the underlying immune status, in turn impacted by host, tumor, and environmental features. Immune therapies carry the potential to achieve durable unmaintained responses and cures in MM.

Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment.

Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized.

Monoclonal gammopathies of clinical significance (MGCS): In pursuit of optimal treatment.

Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.

Smoldering multiple myeloma current treatment algorithms.

Smoldering multiple myeloma (SMM) is an asymptomatic condition that occupies a space between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) along the spectrum of clonal plasma cell proliferative disorders. It is not a biologic intermediate stage between MGUS and MM, but rather represents a heterogeneous clinically defined condition in which some patients (approximately two-thirds) have MGUS (pre-malignancy), and some (approximately one-third) have MM (biologic malignancy). Unfortunately, no single pathologic or molecular feature can reliably distinguish these two groups of patients. For purposes of practice and clinical trials, specific risk factors are used to identify patients with SMM in whom malignant transformation has already likely occurred (high risk SMM). Patients with newly diagnosed high risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials. Patients with low risk SMM should be observed without therapy every 3-4 months.

Differences in Hospital, Emergency Room and Outpatient Visits Among Adults With and Without Monoclonal Gammopathy of Undetermined Significance.

INTRODUCTION: This study evaluated the impact of receiving a monoclonal gammopathy of undetermined significance (MGUS) diagnosis on healthcare utilization from patients at a community-based multispecialty provider organization. METHODS: A cohort of patients with MGUS (n = 429) were matched on sex, age, and length of enrollment to a cohort of patients without MGUS (n = 1286). Healthcare utilization was assessed: 1-12 months before, 1 month before and after, and 1-12 months after diagnosis/index date. Multivariable conditional Poisson models compared change in utilization of each service in patients with and without MGUS. RESULTS: During the 2 months around diagnosis/index date, the rates of emergency room, hospital and outpatient visits were higher for patients with MGUS than patients without MGUS. In the year before MGUS diagnosis, the association was still elevated, although attenuated. CONCLUSION: Understanding the care of MGUS patients is important given that multiple myeloma patients with a pre-existing MGUS diagnosis may have a better prognosis.

Efficacy of SARS-CoV-2 vaccination in patients with monoclonal gammopathies: A cross sectional study.

SARS-CoV-2 vaccination is the most effective strategy to protect individuals with haematologic malignancies against severe COVID-19, while eliciting limited vaccine responses. We characterized the humoral responses following 3 mo after mRNA-based vaccines in individuals at different plasma-cell disease stages: monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma on first-line therapy (MM), compared with a healthy population. Plasma samples from uninfected MM patients showed lower SARS-CoV-2-specific antibody levels and neutralization capacity compared with MGUS, SMM, and healthy individuals. Importantly, COVID-19 recovered MM individuals presented significantly higher plasma neutralization capacity compared with their uninfected counterparts, highlighting that hybrid immunity elicit stronger immunity even in this immunocompromised population. No differences in the vaccine-induced humoral responses were observed between uninfected MGUS, SMM and healthy individuals. In conclusion, MGUS and SMM patients could be SARS-CoV-2 vaccinated following the vaccine recommendations for the general population, whereas a tailored monitoring of the vaccine-induced immune responses should be considered in uninfected MM patients.

When a Monoclonal Gammopathy Is Not Multiple Myeloma.

Our knowledge of monoclonal gammopathies is continuously evolving. Once accepted as a possible precursor condition to multiple myeloma, monoclonal gammopathies as an entity are now associated with many renal, neurologic, and dermatologic disorders of clinical significance. This change has created a challenge for patients and clinicians, as a monoclonal gammopathy may be a harbinger not of multiple myeloma but of other lymphoproliferative disorders such as light-chain amyloidosis and Waldenström macroglobulinemia. Early recognition of monoclonal gammopathies along with a careful workup are essential in determining the next steps in the care of a given patient. Recognition has become all the more important as we understand how to triage the 4% to 9% of patients with monoclonal gammopathies depending on age, with the goal of limiting overdiagnosis and misdiagnosis. In this review, we focus on treatment strategies for patients with monoclonal gammopathies that are not multiple myeloma, including smoldering multiple myeloma, light-chain amyloidosis, and Waldenström macroglobulinemia.

Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors.

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0-121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25-0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04-115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS.

Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy : Breaking a dangerous bond.

Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1-3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since.The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.

Patients With Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance.

BACKGROUND: Multiple myeloma (MM) is a malignant plasma-cell disease that arises on the basis of a so-called monoclonal gammopathy of undetermined significance (MGUS). The median age at disease onset is over 70. In Germany, there are approximately eight new cases per 100 000 inhabitants per year, or about 6000 new patients nationwide each year. METHODS: To prepare this clinical practice guideline, a systematic literature review was carried out in medical databases (MEDLINE, CENTRAL), guideline databases (GIN), and the search portal of the German Institute for Quality and Efficiency in Health Care (IQWiG). The recommendations to be issued were based on two international guidelines, 40 dossier evaluations and systematic reviews, 10 randomized controlled trials, and 37 observational studies and finalized in a structured consensus process. RESULTS: Because of its prognostic relevance, the use of the International Staging System (ISS) is recommended to stage MM and related plasma-cell neoplasms. When symptomatic MM is diagnosed, it is recommended to determine the extent of skeletal involvement by whole-body computed tomography. The indications for treatment shall be determined on the basis of the SLiMCRAB criteria; in all patients with MM it is recommended to include the biological (rather than chronological) age in the decisionmaking process. In suitable patients, it is recommended that initial treatment includes high-dose therapy, followed by main - tenance treatment. Even without high-dose treatment, a median progression-free survival of more than three years can be achieved with combination therapies. For the treatment of relapse, combinations of three drugs are more effective than doublet regimens with a median progression-free survival ranging from 10 to 45 months, depending on the study and prior therapy. Following anti-myeloma therapy, it is recommended to promptly offer physical exercise adapted to individual abilities to all patients who have the potential for rehabilitation, so that their quality of life can be sustained and improved. CONCLUSION: This new clinical practice guideline addresses, in particular, the modalities of care that can be offered in addition to systemic antineoplastic therapy. In view of the significant recent advances in the treatment of myeloma, affected patients' quality of life now largely depends on optimized interdisciplinary care.