Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. Medications that modify progression risk have yet to be identified. To investigate, we leveraged machine-learning and electronic health record (EHR) data to screen for drug repurposing candidates. We extracted clinical and laboratory data from a manually curated MGUS database, containing 16,752 MGUS patients diagnosed from January 1, 2000 through December 31, 2021, prospectively maintained at Mayo Clinic. We merged this with comorbidity and medication data from the EHR. Medications were mapped to 21 drug classes of interest. The XGBoost module was then used to train a primary Cox survival model; sensitivity analyses were also performed limiting the study group to those with non-IgM MGUS and those with M-spikes >0.3 g/dl. The impact of explanatory features was quantified as hazard ratios after generating distributions using bootstrapping. Medication data were available for 12,253 patients; those without medications data were excluded. Our model achieved a good fit of the data with inverse probability of censoring weights concordance index of 0.883. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses. This work could inform subsequent prospective studies, or similar studies in other disease states.

Case report: Scleromyxedema associated with a monoclonal gammapathy: Successful treatment with intravenous immunoglobulins.

Scleromyxedema is a rare idiopathic fibromucinous disorder characterized by a generalized papular and sclerodermoid cutaneous eruption. Patients often have praraproteinemia and extracutaneous, even lethal, manifestations. Yet the prognostic and therapeutic features of scleromyxedema are poorly documented. High-dose intravenous immunoglobulin (IVIG), used either alone or in conjunction with systemic steroids and/or thalidomide, has been suggested as a first-line treatment. We report the case of a 45-year-old woman diagnosed with scleromyxedema with paraproteinemia that initially did not respond to systemic steroids, retinoids, and thalidomide but greatly improvement in terms of systemic and cutaneous symptoms after treatment with IVIG.

Reviewing the Significance of Vitamin D Substitution in Monoclonal Gammopathies.

Vitamin D is a steroid hormone that is essential for bone mineral metabolism and it has several other effects in the body, including anti-cancer actions. Vitamin D causes a reduction in cell growth by interrupting the cell cycle. Moreover, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, exerts various effects via its interaction with the vitamin D receptor on the innate and adaptive immune system, which could be relevant in the onset of tumors. Multiple myeloma is a treatable but incurable malignancy characterized by the growth of clonal plasma cells in protective niches in the bone marrow. In patients affected by multiple myeloma, vitamin D deficiency is commonly correlated with an advanced stage of the disease, greater risk of progression, the development of pathological fractures, and a worse prognosis. Changes in the vitamin D receptor often contribute to the occurrence and progress of deficiencies, which can be overcome by supplementation with vitamin D or analogues. However, in spite of the findings available in the literature, there is no clear standard of care and clinical practice varies. Further research is needed to better understand how vitamin D influences outcomes in patients with monoclonal gammopathies.

Monoclonal Gammopathy of Renal Significance (MGRS): Prospects for Treatment in Integrated Chinese and Western Medicine.

Monoclonal gammopathy of renal significance (MGRS) is a pathological state which presents with a spectrum of renal lesions. MGRS is characterized by pathogenic monoclonal immunoglobulins or light chains produced by a premalignant plasma cell or B cell clone. In view of inadequate understanding in the past, the low detection rate of MGRS often results in poor outcomes and reduces quality of life of patients. Thus, MGRS stands for a group of clinical refractory renal diseases. To date, no standard treatment strategy for MGRS is available. Current consensus suggests a clone-directed approach that aims to eradicate the offending clone, but its long-term prognosis is not clear. In this article, we discuss the diagnostic methods, highlight treatment advances, and introduce integrated Chinese and Western medicine in the management of MGRS.

Complete Remission of Advanced Hepatocellular Carcinoma Treated with Sorafenib and Concomitant Appearance of IgG4- related Diseases. A Case Report.

Sorafenib is currently the gold standard therapy for palliative treatment of advanced hepatocellular carcinoma (HCC) in patients with compensated liver disease. There are few cases reported in literature describing patients with HCC achieving a complete remission (CR) due to Sorafenib therapy. We report the case of a 62-year old patient who obtained CR despite single, long drug discontinuation and kept it without any maintenance therapy. Furthermore, this is the first case describing the onset of a likely IgG4-related retroperitoneal fibrosis and cholangitis during Sorafenib administration. Further studies are required to define the predictors of a good response to Sorafenib and to codify a therapeutic maintenance regimen for patients who achieve CR.

Acquired Fanconi syndrome secondary to light chain deposition disease associated with monoclonal gammopathy of renal significance: A case report.

RATIONALE: Renal Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. It is characterized by the impairment of renal proximal tubular function leading to normoglycemic glycosuria, aminoaciduria, hypophosphatemia, hypouricemia and proximal renal tubular acidosis. Renal impairment in monoclonal gammopathy, without fulfilling the criteria of multiple myeloma, is categorized as monoclonal gammopathy of renal significance (MGRS). PATIENT CONCERNS: A 54-year-old male presented with progressively aggravated bone pain and limitation of activity was admitted to our department. A proximal renal tubular damage was suggested by hypophosphatemia, compensated metabolic acidosis, renal glycosuria, aminoaciduria, and hypouricemia. M-protein of IgA kappa was detected by immunofixation electrophoresis. Mildly increased plasma cells were found in bone marrow cytomorphologic examination. Renal biopsy revealed diffuse linear monoclonal IgA-kappa light chain deposits along tubular basement membranes (TBMs), while lambda was negative. Electron microscopy showed granular electron-dense deposits along the outer aspect of TBMs. DIAGNOSES: The patient was diagnosed as FS induced osteomalacia secondary to monoclonal gammopathy of renal significance (MGRS) (IgA-κ type) and LCDD. INTERVENTIONS: He was treated with bortezomib, supplementation by phosphate, alkali agents, and active vitamin D. He responded well to the treatment symptomatically. OUTCOMES: We reported a rare case of adult acquired FS with hypophosphatemic osteomalacia secondary to LCDD associated with MGRS and the patient was successfully treated with bortezomib. LESSONS: Although few cases of LCDD with isolated symptoms of tubulointerstitial nephropathy, rather than glomerular symptoms have been reported. It still needs to be recognized as a differential diagnosis in monoclonal gammopathy.

Vitamin D and plasma cell dyscrasias: reviewing the significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder and precursor disease to multiple myeloma and other related cancers. While MGUS is considered a benign disorder, with a low risk of disease progression, patients have altered bone microarchitecture and an increased risk of bone fracture. In addition, alterations in immune function are regularly found to correlate with disease activity. Vitamin D, an important hormone for bone and immune health, is commonly deficient in multiple myeloma patients. However, vitamin D deficiency is also prevalent in the general population. The purpose of this review is to highlight the current understanding of vitamin D in health and disease and to parallel this with a review of the abnormalities found in plasma cell dyscrasias. While some consensus statements have advocated for vitamin D testing and routine supplementation in MGUS, there is no clear standard of care approach and clinical practice patterns vary. Further research is needed to better understand how vitamin D influences outcomes in MGUS patients.

Scleredema. A multicentre study of characteristics, comorbidities, course and therapy in 44 patients.

BACKGROUND: The prognostic and therapeutic features of scleredema are poorly documented. OBJECTIVES: To describe the characteristics of patients with scleredema regarding demographics, clinical characteristics, comorbidities, therapeutic interventions and course. METHODS: We conducted a retrospective multicentre study. RESULTS: We identified 44 patients (26 men).The mean age at diagnosis was 53.8 years. The most common associated disorders were endocrine/metabolic diseases including 30 patients suffering from diabetes, mostly type 2 diabetes. Monoclonal gammopathies were confirmed in five cases. A preceding respiratory tract infection was not a feature. Treatments with different combination or sequential modalities were used with variable results. Phototherapy (UVA1 or PUVA) was the treatment associated with higher, although partial response. Systemic corticosteroids and immunosuppressive drugs were reserved to patients with severe disease in whom phototherapy had failed or for patients with multiple myeloma. Forty-one patients were followed up (mean period: 32.2 months).Thirty-nine patients are alive, 30 with and 9 without skin disease. Two patients died of cardiovascular complications due to myeloma and severe diabetes. CONCLUSIONS: Scleredema is a chronic debilitating disease associated with diabetes and metabolic syndrome, unresponsive to various treatments but not necessarily a life-threatening condition. Although there is no definitive treatment, phototherapy should be attempted first. Treatment of primary disease including strict glycaemic control combined with physical therapy should be also employed.

Curcumin for monoclonal gammopathies. What can we hope for, what should we fear?

Over the last decades there has been an increasing interest in a possible role of curcumin on cancer. Although curcumin is considered safe for healthy people, conclusive evidence on the safety and efficacy of curcumin for patients with monoclonal gammopathies is, so far, lacking. The present paper reviews the literature on molecular, cellular and clinical effects of curcumin in an attempt to identify, reasons for optimism but also for concern. The results of this critical evaluation can be useful for both patient- selection and monitoring in the context of clinical trials. Curcumin might be helpful for some but certainly not for all patients with monoclonal gammopathies. It is important to avoid unnecessary detrimental side effects in some in order to safeguard curcumin for those that could benefit. Parameters for patient monitoring, that can be used as early warning signs and as indicators of a favorable development have therefore been suggested.

Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry study.

BACKGROUND: Information on demographics and survival of patients starting renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to multiple myeloma (MM) or light-chain deposit disease (LCDD) is scarce. The aim of this study was to describe the incidence, characteristics, causes of death and survival rates of RRT for ESRD due to MM or LCDD in the ERA-EDTA Registry. METHODS: Thirteen national registries providing data on patients who started RRT from 1986-2005 to the ERA-EDTA Registry participated. Incidence per million population (pmp) of RRT for ESRD due to MM or LCDD and other causes (non-MM) was observed overtime. Patient survival on RRT was examined, unadjusted and adjusted for age and gender. RESULTS: Of the 159 637 patients on RRT, 2453 (1.54%) had MM or LCDD. The incidence of RRT for ESRD due to MM or LCDD, adjusted for age and gender, increased from 0.70 pmp in 1986-1990 to 2.52 pmp in 2001-2005. MM and LCDD patients compared to non-MM patients were older and a higher percentage was on haemodialysis at day 91 after the start of RRT. The most common causes of death in MM and LCDD patients were malignancy (36.1%), cardiovascular causes (17.2%) and infection (14.7%). MM and LCDD patients had a 2.77 (95% CI, 2.65-2.90) higher risk of death compared to non-MM patients. The unadjusted median survival on RRT was 0.91 years in MM and LCDD patients and 4.46 years in non-MM patients. During follow-up, 35 patients were transplanted and their mean survival was 9.6 years. CONCLUSION: The incidence of RRT for ESRD due to MM or LCDD has increased over the past 20 years in Europe. The median patient survival on RRT for MM and LCDD patients was 0.91 years, compared to 4.46 years for non-MM patients. These results suggest that dialysis, and in selected cases even transplantation, should be offered to MM and LCDD patients.

Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case report.

Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.

The potential role of curcumin in patients with monoclonal gammopathy of undefined significance--its effect on paraproteinemia and the urinary N-telopeptide of type I collagen bone turnover marker.

PURPOSE: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS. EXPERIMENTAL DESIGN: Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen. RESULTS: Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen. CONCLUSION: Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation.

Long-term follow-up of a population based cohort with monoclonal proteinaemia.

Prospective studies on the risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance (MGUS) and factors predictive of survival are lacking. The Dutch Comprehensive Cancer Centre West, comprising 1.6 million inhabitants, initiated a prospective hospital-based cohort study on 1464 patients with newly diagnosed M-proteinaemia, median age 73 (17-103) years. M-protein related diagnoses, patients' characteristics, laboratory investigations, bone marrow examinations and skeletal X-rays were registered with a yearly follow-up. Main endpoints were death, or new diagnoses of multiple myeloma and non-Hodgkin lymphoma. Kaplan-Meier survival curves were compared with age- and gender-matched survival data from the total Dutch population. Cumulative malignant transformation was corrected for death using a competing risk model. Risk factors for transformation or death were analyzed by univariate and multivariate analyses. In 1007 MGUS-patients, malignant transformation was associated with rising M-protein levels, IgA and IgM isotype and occurred at a yearly rate of 0.4%. All MGUS patients survived less than a matched cohort of the Dutch population, even in the absence of M-protein-associated comorbidity. Serum albumin levels at entry appeared highly predictive for survival. M-proteinaemia is not an innocent symptom. Although malignant transformation occurs rarely, survival is shortened irrespective of comorbidity.

Acquired fanconi syndrome with osteomalacia secondary to monoclonal gammopathy of undetermined significance.

A 60-year-old woman was admitted because of multiple bone pain. Examination revealed hypophosphatemic osteomalacia and acquired Fanconi syndrome. Further exploration revealed monoclonal gammopathy of undetermined significance (MGUS) excreting urinary Bence Jones protein (kappa light chain). Renal biopsy showed non-specific tubulointerstitial nephritis, yet neither crystalline inclusions in the cytoplasm of the tubular epithelium nor myeloma casts nor amyloid deposits were found. She was treated with supplementation by phosphate, alkali agents, and vitamin D, and responded well to the treatment symptomatically and biochemically. MGUS was observed without chemotherapy. Myeloma had not developed after 10 months follow-up.

Hypophosphatemia associated with paraproteinemia: a case report and review of the literature.

The differential diagnosis for hypophosphatemia is long, and involves complex, overlapping physiological systems. Practitioners are often guilty, however, of simply supplementing phosphate without fully investigating the etiology of the problem. The purpose of this case presentation is to illustrate a case of spurious hypophosphatemia that initially led to unnecessary phosphate replacement in a woman with undiagnosed multiple myeloma. An 85-year-old African American woman was admitted to the hospital for congestive heart failure exacerbation. The patient was incidentally found to be profoundly hypophosphatemic and was also diagnosed with multiple myeloma at this hospitalization. Normal phosphorus levels were difficult to maintain despite aggressive replacement. A serum sample initially reported to have an abnormally low phosphorus concentration on the Beckman CX7 analyzer was reanalyzed with the Kodak Ektachem 700 system, revealing the phosphorus concentration to be towards the higher limit of the normal range on the same sample. We conclude that clinicians should proceed with caution before aggressively treating abnormal phosphorus levels in patients with known paraproteinemia. Conversely, unexplained phosphorus abnormalities should bring disorders associated with paraproteinemia, such as multiple myeloma, into the differential diagnosis. Knowledge of how various phosphorus assays are affected by paraproteins is essential to guiding diagnosis and treatment. We also review mechanisms of reported interference with common assays.

Subcorneal pustulosis and Pyoderma gangrenosum associated with a biclonal gammopathy.

Pyoderma gangrenosum and subcorneal pustulosis are two neutrophilic dermatoses. Their occurrence in the same patient is rare and may be related to an IgA dysglobulinemia. We report a case presenting these two conditions associated with a biclonal benign IgA and IgG gammopathy. A 67-year-old man exhibited typical pyoderma gangrenosum associated after three years duration with subcorneal pustulosis lesions, confirmed by cutaneous biopsy. Laboratory results showed a biclonal benign IgA and IgG kappa gammopathy. Therapeutic management was difficult: Pyoderma gangrenosum responded well to corticosteroids but subcorneal pustulosis management was harder and treatments were poorly effective.Pyoderma gangrenosum and subcorneal pustulosis are a part of the neutrophilic spectrum. Their association has been only reported in eleven patients. In eight cases, an IgA dysglobulinemia was associated suggesting its responsibility in the occurrence of both dermatoses. Treatments are various and not fully effective. If the Pyoderma gangrenosum usually responds to corticosteroids, the subcorneal pustulosis treatments are not well defined and often not efficient. Our case illustrates the dissociated evolution of these two dermatoses and their difficult global management. During the follow-up, a regular search for dysglobulinemia is required in order to detect malignant transformations.

Best practice in primary care pathology: review 1.

This first best practice review examines four series of common primary care questions in laboratory medicine, namely: (i) measurement and monitoring of cholesterol and of liver and muscle enzymes in patients in the context of lipid lowering drugs, (ii) diagnosis and monitoring of vitamin B12/folate deficiency, (iii) investigation and monitoring of paraprotein bands in blood, and (iv) management of Helicobacter pylori infection. The review is presented in a question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents, and evidence based medicine reviews, supplemented by MEDLINE EMBASE searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence based. They will be updated periodically to take account of new information.