A subset of individuals with smoldering myeloma (SMM) are at a high risk of progression to symptomatic myeloma. Current efforts are focused on identifying this high-risk group and intercepting the disease process before its progression. There is no consensus on what the goal of an intervention should be, whether to aim for a cure through a high-intensity intervention or pursue immunologic disease control using the least intense approach. This systematic review summarized current evidence in support of the optimum approach. A database search of Medline/PubMed, Scopus, EMBASE, Web of Science, CINAHL, Wiley Cochrane Library, clinicaltrials.gov, and conference proceedings of ASH, EHA, ASCO, ESMO was performed. Results were presented using narrative synthesis of quantitative data. Of the 2088 identified records, a total of 10 eligible studies made up of 6 minimal-intensity clinical trials, 3 moderate-intensity trials, and 1 high-intensity trial were included in this review with a total demographic population of 588 high-risk SMM patients. Minimal intensity lenalidomide-based regimen demonstrated clinical effectiveness in delaying disease progression and improving overall survival in high-risk SMM. The single-agent monoclonal antibodies did not have any major impact on improving overall survival, although the studies were not powered to do so. There is a marked increase in the depth of response as the intensity of treatment increases without a proportional improvement in overall survival. Moderate- and high-intensity interventions yielded similar minimal residual disease negativity rates and overall survival. The minimal, moderate, and high-intensity approaches all demonstrated clinical benefits in delaying disease progression and improving overall survival in patients with high-risk SMM and increasing intensity of intervention does not necessarily translate to improved overall survival.

BACKGROUND: Smoldering multiple myeloma (SMM) is an intermediate pre-malignant condition with individuals having a distinct risk of progression to overt myeloma. The optimal management option has remained controversial due to the heterogeneous nature of the condition in which progression to overt diseases is variable. The question of who, when, and what to use for the treatment of SMM remains equivocal. We performed a systematic review of randomized controlled trials and summarized the current evidence supporting the best approach to the management of SMM.
METHODS: A comprehensive literature search of Medline/PubMed, PubMed Central, Embase, Scopus, Web of Science, Wiley Cochrane Library, CINAHL, clinicaltrial.gov, and conference proceedings of ASCO, ASH, EHA, and ESMO was performed on October 25, 2020. Synthesis of the result was done using narrative analysis.
RESULTS: Of the total 1560 identified records, 10 eligible studies involving 1157 patients made up of 580 in the intervention group and 577 in the control group were included in this review. Three early trials of melphalan and prednisone fail to demonstrate any significant impact on disease progression with major toxicities reported. Three trials on bisphosphonate monotherapy show reduced skeletal-related events without any clinical effect on disease progression. Lenalidomide monotherapy or as part of a combination therapy demonstrates superiority in delaying disease progression over observation. Only Lenalidomide and dexamethasone combination demonstrated superior overall survival over observation across the trials.
CONCLUSIONS: Trials of lenalidomide in a less intensive approach has shown promise in delaying disease progression and should be investigated further in clinical trials.

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of \"monoclonal gammopathy of undetermined significance-like\", in which patients never progress during their lifetimes, to \"early multiple myeloma\", in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a \"split personality\" makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.

We have reported an extremely rare case of a frontal convexity tumor diagnosed as IgG4-related disease (IgG4-RD) with unique neuroradiological images.
A 64-year-old man with a history of monoclonal gammopathy of undetermined significance and conservative treatment had presented with a left facial spasm. Computed tomography showed a high-density round tumor with perifocal edema in the right frontal convexity. Magnetic resonance imaging demonstrated unique findings, including low signal intensity on T1- and T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted images, with slight gadolinium enhancement. The tumor was totally removed via right frontal craniotomy. It had been located in the subdural space, was not adherent to the dura, and was less vascular than meningiomas. Histological investigation demonstrated plasma cells that were strongly positive for IgG4 and contained κ and λ light chains at a ratio of 1.5:1. The serum IgG4 level was elevated. The tumor met the diagnostic criteria for IgG4-RD. The patient was followed up for 3 years during postoperative adjuvant steroid therapy. The steroid therapy was discontinued, and during the next 4 years, neither tumor recurrence nor symptoms were observed.
Intracranial IgG4-RD with smoldering monoclonal gammopathy of undetermined significance is extremely rare. We reviewed the differential diagnosis of plasma cell granuloma and plasmacytoma, therapeutic implications, and clinical outcomes. Complete resection of a conspicuous and solitary IgG4-RD lesion in the frontal convexity is simple and could provide a cure with less-aggressive adjuvant therapy.

Introduction: Monoclonal antibodies (MoAbs) are rapidly changing the therapeutic scenario of multiple myeloma. Most of the available data, however, come from studies performed in patients with relapsed or refractory disease.Area covered: Here, the most recent results from clinical trials that have investigated (or are investigating) efficacy and safety of MoAbs as front-line treatments in both transplant-eligible and not-eligible patients with newly diagnosed multiple myeloma, as well as in smoldering myeloma, are reviewed. PubMed reported articles before 28 March 2020, and abstracts presented at the last ASCO, ASH, EHA, and IMW meetings were considered. Among others, pertinent data regarding daratumumab, isatuximab, elotuzumab, and pembrolizumab will be analyzed.Expert opinion: Introduction of MoAbs as first-line therapy will likely provide a significant improvement in the clinical outcome of patients with multiple myeloma. This will also require an appropriate re-positioning of salvage therapies. The role of MoAbs in smoldering myeloma appears to be promising, but adequate follow-up is needed.

All patients who develop multiple myeloma have a preceding asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM). During the past decade, significant progress has been made in the classification and risk stratification of SMM.
This review summarizes current clinical challenges and discusses available models for risk stratification in the context of SMM. Owing to several novel, more effective, and less toxic drugs, these aspects are becoming increasingly important to identify patients eligible for early treatment. However, all proposed criteria were built around indirect markers of disease burden and therefore are generally able to identify a fraction of patients with SMM in whom transformation to multiple myeloma and genomic subclonal diversification are already happening. In contrast, next-generation sequencing approaches have the potential to identify myeloma precursor disease that will progress even before the major clonal expansion and progression, providing a potential base for more effective treatment and better precision regarding the optimal timing of treatment initiation.
Owing to modern technologies, in the near future, prognostic models derived from genomic signatures independent of the disease burden will allow better identification of the optimal timing to treat a plasma cell clonal disorder at the very early stages, when the chances of eradication are higher.

BACKGROUND: Scleredema is a rare sclerodermoid skin condition characterized by diffuse symmetrical thickening of the upper part of the body. Its association with monoclonal gammopathy and myeloma was recently described; very few cases have been reported to date.
METHODS: A 66-year-old Sri Lankan woman who had been followed in a dermatology unit for 34 years with diffuse systemic sclerosis presented with an acute exacerbation of the skin disease. Absence of Raynaud\'s phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibodies test results led to reevaluation for the possibility of scleredema. Skin biopsies from four body sites showed normal epidermis and thickened reticular dermis with swollen collagen bundles separated from one another by clear spaces, resulting in fenestration. The skin appendages were not atrophied or bound down. Alcian blue staining showed interstitial mucin deposition. Serum protein electrophoresis demonstrated an abnormal monoclonal band in the β-region with a paraprotein level of 8.9 g/dl. Immunofixation showed an abnormal band in the γ-region consisting of immunoglobulin A and κ. Bone marrow biopsy revealed abnormal monoclonal plasma cells (15%) with multinuclearity. There was no evidence of end organ damage, and whole-body magnetic resonance imaging did not reveal any evidence of bone involvement. The patient\'s diagnosis was revised as scleredema type 2 associated with IgA-κ, and she was referred to a hemato-oncologist for chemotherapy, which led to significant improvement in the skin condition.
CONCLUSIONS: Scleredema is a rare disorder that has an enigmatic, rare association with monoclonal gammopathy. Dermatologists should be aware of this rare but important association.

CME: Multiple Myeloma - a Review Abstract. Multiple myeloma accounts for 1 % of all malignancies, and its incidence increases with age. Both the symptoms and the course of the disease are heterogeneous. While some patients experience unspecific complaints, e.g. malaise or lethargy, others might present with emergency situations like hypercalcemia, spinal cord compression or hyperviscosity, so that an urgent therapy initiation is crucial. The aim of this article is to review the most common initial symptoms, typical emergencies, as well as diagnostics and therapy of multiple myeloma.
Zusammenfassung. Das Multiple Myelom macht 1 % aller Malignome aus, wobei die Inzidenz mit zunehmendem Alter steigt. Das Krankheitsbild verläuft sehr heterogen und die Symptome sind vielgestaltig. Während sich einige Patienten mit unspezifischen Beschwerden,wie Müdigkeit, Lethargie und Infektneigung präsentieren, gibt es Notfallsituationen wie die Hyperkalziämie, die Rückenmarkskompression oder das Hyperviskositätssyndrom, die einer sofortigen Therapieeinleitung bedürfen. Ziel dieses Artikels ist es, einen Überblick über Symptome und Notfallsituationen, die wichtigsten Abklärungsstrategien und die Therapie zu geben.