BACKGROUND: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy.
OBJECTIVE: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM).
METHODS: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants\' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast.
RESULTS: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025.
CONCLUSIONS: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention.
BACKGROUND: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638.
UNASSIGNED: DERR1-10.2196/51368.

The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients\' work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials.

Systemic amyloid light chain, or primary amyloidosis (AL amyloidosis), is a serious medical condition that leads to the deposition of abnormal proteins called amyloid fibrils in various organs of the body. AL amyloidosis can present with different symptoms, which can make diagnosis challenging. This case report presents a clinical scenario of a 53-year-old female patient who had come in for shortness of breath and lower extremity swelling and was found to have acute on chronic pulmonary embolism. The patient had a history of systemic amyloidosis diagnosed with a kidney and duodenal biopsy. She also had a bone marrow biopsy done and was found to have IgG monoclonal gammopathy. Throughout the hospital course, patients required cautious diuretic use given the worsening kidney function. She was given intravenous anticoagulation initially and later switched to oral medication on discharge. Due to the aggressive nature of amyloidosis, a decision was made to start the patient on chemotherapy in an outpatient setting. This case presents an interesting scenario of systemic amyloidosis with concomitant monoclonal gammopathy that was complicated by acute pulmonary embolism. The case is important as it shows the different levels of amyloidosis and teaches us the benefit of taking a multidisciplinary approach to making a concrete plan for patients with advanced amyloidosis disease.

Schnitzler syndrome is a rare autoinflammatory disorder characterized by urticarial rash, joint pain, recurrent fever, leucocytosis, elevated C-reactive protein (CRP) and serum amyloid A (SAA), and monoclonal IgM or IgG gammopathy. According to the Strasbourg criteria, both urticarial rash and gammopathy are mandatorily required for the diagnosis of Schnitzler\'s syndrome. However, incomplete variants lacking either skin symptoms or monoclonal gammopathy have also been described. Here, we report a case in which the diagnosis of Schnitzler-like syndrome was made despite the absence of gammopathy, based on neutrophilic dermal inflammation, episodic and excessive increase in inflammatory parameters, and prompt response to anakinra, a soluble IL1 receptor antagonist (sIL-1RA). In addition, we detected neutrophil epitheliotropism, which is highly suggestive of autoinflammatory disease. Using whole-exome sequencing, we were unable to find a causative pathogenic mutation but did find several mutations possibly related to the inflammatory processes in this patient. This and other cases highlight that the existing Strasbourg criteria are too strict to capture Schnitzler-like syndromes that may respond well and rapidly to IL1 inhibition. Recurrent episodes of disease with normalization of inflammatory symptoms in the interval, rapid response to anakinra, and neutrophilic epitheliotropism in a lesional skin biopsy may help confirm the diagnosis of Schnitzler-like syndrome.

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.

BACKGROUND: Hyperglobulinemia is reported in 26% of canine chronic B-cell lymphocytic leukemia (B-CLL) cases. However, few cases have been characterized by protein electrophoresis and immunofixation (IF), and the incidence of a monoclonal protein (M-protein) is unknown using these techniques.
OBJECTIVE: To characterize and determine the proportion of canine B-CLL cases with an M-protein using plasma protein electrophoresis (PPE), routine and free light chain (fLC) IF, and to assess if productive B-CLL cases express MUM1/IRF4 by cell tube block (CTB).
METHODS: PPE, routine (targeting IgG, IgA, IgM, IgG4, and light chain) and fLC IF were performed using 48 dog B-CLL plasma samples from patients diagnosed via peripheral blood flow cytometry. CTB was performed on a separate cohort of 15 patients.
RESULTS: Hyperproteinemia (>7.5 g/dL) was present in 17/48 cases (35%). An M-protein was detected in 32/48 cases (67%). Of these, 19/32 cases (59%) had only complete (monoclonal heavy and light chain) M-proteins detected, 10/32 cases (31%) had both complete and fLC M-proteins detected, and 3/32 cases (9%) had only an fLC M-protein detected. IgM was the most common clonal immunoglobulin isotype detected (23 cases). CD21+ cell counts were higher in cases with detectable M-protein. Plasma fLC IF suggested β-γ region interference, likely caused by clotting proteins. All B-CLL cases consistently expressed PAX5 and did not express MUM1/IRF4.
CONCLUSIONS: Most B-CLL cases had an M-protein and were not hyperproteinemic. Most cases with paraproteins had a complete IgM monoclonal gammopathy; a subset had documented fLCs. The prognostic significance of heavy and fLC presence should be evaluated.

Multiple myeloma is characterized by the presence of M-protein (monoclonal) in blood or urine. These proteins are immunoglobulins which are produced by a clone of abnormally proliferating B-lymphocytes and/or plasma cells. To evaluate M-protein, serum protein electrophoresis (SPEP) is used where a single band, known as M-band is seen. This band is usually seen in the gamma globulin region. However, in rare entities like biclonal gammopathy, two M-bands appear simultaneously at different positions on SPEP which may be attributed to the clonal expansion of two different neoplastic cell lines. Here, we describe an atypical case of IgA-kappa multiple myeloma, where two M-bands (one in the beta region and one in the gamma globulin region) were found during SPEP. This simulated a picture of biclonal gammopathy. However the monoclonal nature of this M-protein was proved by performing immunofixation electrophoresis (IFE). Further, we put across images to explain how IFE helps in differentiating between apparent and true biclonality.

Tremors have been well-described in association with monoclonal gammopathy. We report a case of a patient with asymmetric hands tremor who responded well to levodopa-carbidopa treatment. Further workup showed an underlying gammopathy. To our knowledge, this is one of the rarest case reports of successful treatment of gammopathy-related tremors with levodopa-carbidopa. The patient was a 75-year-old male who presented to the neurology clinic for a one-year history of worsening tremors in bilateral upper extremities. A review of systems was only remarkable for mild numbness and tingling in his feet. His neurological examination was remarkable for asymmetric right more than left (R > L) resting and kinetic tremor in both upper extremities associated with mild rigidity and bradykinesia in right upper extremity and decreased bilateral ankle jerks. With the primary diagnosis of Parkinson\'s disease, he was started on levodopa-carbidopa and a neuropathy workup was requested. His follow-up visit after three months was remarkable for significant improvement of his tremors with carbidopa-levodopa. However, his blood work was consistent with a significant increase in lambda light chain levels and the presence of an M spike in serum protein electrophoresis. Based on the presentation and clinical workup, he was finally found to have both multiple myeloma and ​Waldenstrom\'s macroglobulinemia. Underlying malignancy was treated with chemotherapy and immunotherapy. Levodopa-carbidopa was discontinued after three months of chemotherapy and his tremor did not recur in one year of follow-up. Gammopathy is one of the well-known causes of tremors in the adult population. It can cause both resting and kinetic tremors in the upper extremities. It is supposed that peripheral neuropathy associated with gammopathy is the main underlying cause of tremors in these groups of patients. However, central causes are also suggested. In this case, we are led to conclude that our patient\'s tremor was centrally mediated since it responded well to dopamine replacement therapy. However, further study is needed to elucidate the role of dopamine depletion in the pathogenesis of tremors associated with gammopathies.

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The detection of monoclonal immunoglobulins is a key element in the diagnosis of monoclonal gammopathy. In clinical practice, screening and measurement of monoclonal proteins are commonly performed using capillary zone electrophoresis (CZE). Some exogenous substances, such as iodinated contrast agents, absorb incident UV light at the same wavelengths as the peptide bonds and may therefore interfere with the detection of proteins in CZE. We herein use the description of a case to illustrate that iodinated contrast agents can mask the presence of monoclonal immunoglobulins in CZE and we discuss the strategy needed to confirm this interference. Performing immunofixation, immunosubtraction, or a second CZE at a distance from the first blood sample is not only necessary to confirm the presence of an iodinated contrast media interference but also to ensure the absence of monoclonal proteins.