Association of routine hematological parameters with the development of monoclonal gammopathies: a case-control study of 134,740 patients : Resubmitted to annals of Hematology 26 March 2024.

The diagnosis of multiple myeloma requires detection of paraproteinemia and confirmation of monoclonal bone marrow infiltration, along with signs of end-organ damage. Despite the increasing prevalence, serum paraproteinemia is not routinely measured. We examined the relationship between alterations in routine hematological parameters and the development of paraproteinemia in a case-control study. Data was retrieved from a laboratory database in the capital region of Denmark between 01/01/2012 and 31/12/2022. Patients were included if they had a test for paraproteinemia (n = 134,740) and at least one prior hematological parameter (white blood cells, hemoglobin and platelet count) with a minimum follow-up of 1 year.Between 96,999 and 103,590 patients were included in each of the three hematological groups. We found white blood cell count and the presence of paraproteinemia followed an inverse J-shaped curve, with the highest presence below 3 × 109/L and above > 9 × 109/L. The adjusted OR below and above the nadir of 4 × 109/L was 1.61 (95% CI 1.25; 2.08, p < 0.0001) and 1.03 (95% CI 1.03; 1.04, p < 0.0001). Hemoglobin levels were inversely associated the presence of paraproteinemia, with the highest association below 6 mmol/L with an OR of 1.30 (95% CI 1.28; 1.32, p < 0.0001) adjusted for age and gender. Platelet count followed a U-shaped curve with the highest association at < 100 × 109/L. The adjusted OR below and above the nadir of 250 × 109/L was 1.13 (95% CI 1.10; 1.17, p < 0.0001) and 1.10 (95% CI 1.08; 1.12, p < 0.0001) respectively. In conclusion, all three parameters showed significant association with later paraproteinemia.

Paraproteinaemic keratopathy simulating a crystalline keratopathy.

BACKGROUND: Paraproteinemic keratopathy is a rare disorder characterized by the bilateral accumulation of polychromatic deposits diffusely in all corneal layers together or not with diffuse or patchy pseudo lipid deposits. We present an atypical case of paraproteinemic keratopathy which lead to an initial misdiagnosis of infectious crystalline keratopathy. CASE PRESENTATION: a 69-year-old woman with an asymptomatic keratopathy detected during a cataract intervention. Slit-lamp examination revealed several hyper refringent subepithelial foci with fern-shaped branches, resembling crystalline keratopathy, in her left eye. Anterior segment optical coherence tomography revealed exclusively subepithelial hyperreflective lesions limited to the anterior stroma. The progressive bilateralization and progression of the condition prompted us to include other entities with crystalline corneal deposits in our differential diagnosis. Hematological analysis showed a high number of free Kappa light chains. Despite the typical clinical appearance of crystalline keratopathy, the atypical evolution and test results led us to consider that monoclonal gammopathy could be the cause of this entity. CONCLUSIONS: Paraproteinemic keratopathy may present in its early stages as a unilateral subepithelial crystalline keratopathy. Thus, it must always be taken into account in the differential diagnosis of any crystalline keratopathy, particularly when there are no predisposing factors for an infectious crystalline keratopathy. Early recognition of this rare entity is important to address the associated potentially serious systemic disease.

Outcomes of kidney transplantation in patients with myeloma and amyloidosis in the USA.

BACKGROUND: Recent improvement in treatment and patient survival has opened the eligibility of kidney transplantation to patients who developed end-stage kidney disease (ESKD) from plasma cell dyscrasias (PCDs). Data on clinical outcomes in this population are lacking. METHODS: We conducted a retrospective study of United Network for Organ Sharing/Organ Procurement and Transplantation Network dataset (2006-2018) to compare patient and graft outcomes of kidney transplant recipients with ESKD due to PCD versus other causes. RESULTS: Among 168 369 adult first kidney transplant recipients, 0.22-0.43% per year had PCD as the cause of ESKD. The PCD group had worse survival than the non-PCD group for both living and deceased donor types {adjusted hazard ratio [aHR] 2.24 [95% confidence interval (CI) 1.67-2.99] and aHR 1.40 [95% CI 1.08-1.83], respectively}. The PCD group had worse survival than the diabetes group, but only among living donors [aHR 1.87 (95% CI 1.37-2.53) versus aHR 1.16 (95% CI 0.89-1.2)]. Graft survival in patients with PCD were worse than non-PCD in both living and deceased donors [aHR 1.72 (95% CI 1.91-2.56) and aHR 1.30 (95% CI 1.03-1.66)]. Patient and graft survival were worse in amyloidosis but not statistically different in multiple myeloma compared with the non-PCD group. CONCLUSION: The study data are crucial when determining kidney transplant eligibility and when discussing transplant risks in patients with PCD.

Kidney transplantation in patients with multiple myeloma: narrative analysis and review of the last two decades.

There have been significant advances in the treatment of multiple myeloma in the last two decades. Approximately 25% of patients with newly diagnosed myeloma have some degree of kidney impairment. During the course of illness, nearly 50% of myeloma patients will develop kidney disease. Moreover, ∼10% of myeloma patients have advanced kidney disease requiring dialysis at presentation. Hemodialysis is associated with a significantly reduced overall survival (OS). In the setting of prolonged long-term OS due to the use of newer immunotherapeutic agents in the treatment of myeloma, patients with myeloma and advanced kidney disease may benefit from more aggressive management with kidney transplantation (KTx). Unfortunately, most data regarding outcomes of KTx in patients with myeloma come from single-center case series. With the advent of novel treatment choices, it remains unclear if outcomes of kidney transplant recipients with myeloma have improved in recent years. In this descriptive systematic review, we coalesced published patient data over the last 20 years to help inform clinicians and patients on expected hematologic and KTx outcomes in this complex population. We further discuss the future of KTx in patients with paraproteinemia.

Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies.

BACKGROUND AND PURPOSE: To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies. METHODS: Neurofilament light chain (NfL) and total tau (T-tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain-Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease-free controls and 59 other controls. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. RESULTS: Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease-free controls. Patients with MMN had higher NfL levels in plasma vs. disease-free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS). T-tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light chain levels in CSF and plasma in patients with GBS correlated with GBS-ds, as higher levels were associated with inability to run after 6 and 12 months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome. CONCLUSIONS: Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies.

Prevalence and Clinical Characteristics of Paraproteinemia Associated with Chronic Myeloid Leukemia.

INTRODUCTION: Data regarding the prevalence of paraproteinemia in patients with chronic myeloid leukemia (CML) are lacking. METHODS: To evaluate for the prevalence of paraproteinemia, we undertook this cross-sectional study among consecutive chronic-phase CML patients. Complete blood count, chemistry, immunoglobulins, serum-free light chains, serum-protein electrophoresis and immunofixation were collected. Further analyses evaluated whether various patient-, disease-, and treatment-related variables are associated with paraproteinemia. RESULTS: One hundred patients, median age 63.5 (IQR 48.1-72) years were recruited. Median time from CML diagnosis to enrollment was 6.3 (IQR 2.3-11.3) years. Monoclonal protein was detected in 8 patients (8%), diagnosed with smoldering multiple myeloma (SMM, n = 2) and low-risk monoclonal gammopathy of undetermined significance (MGUS, n = 6). Six patients were on tyrosine kinase inhibitor treatment, 2 were in treatment-free remission. The only covariate associated with paraproteinemia was the presence of anemia, albeit with borderline statistical significance in univariate analysis (p = 0.053) and when adjusted for age (p = 0.056). CONCLUSIONS: In this largest study so far describing the prevalence of paraproteinemia among CML patients, we found MGUS prevalence to be higher than the 3.2% expected prevalence in the general population above 50 years and a non-negligible prevalence of SMM (2%). Screening for paraproteinemia in CML patients, especially in the presence of anemia, should be considered.

POEMS Syndrome Diagnosis in a Patient with Mixed Polyneuropathy: Case Report.

POEMS syndrome is a rare condition of paraneoplasic origin characterized by the presence of a sensorimotor polyneuropathy associated with the presence of a proliferative disorder of plasmatic monoclonal cells and overproduction of vascular endothelial growth factor. The acronym "POEMS" represents multisystem findings including polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes; nevertheless, clinical presentation is heterogeneous. We describe a clinical case, the diagnostic and therapeutic approach in a patient with sensorimotor polyneuropathy in whom POEMS syndrome was diagnosed; to understand this pathology, its clinical and paraclinical manifestations in order to make a diagnosis or to avoid a delayed one and to provide an adequate treatment.

POEMS syndrome: A multisystem clonal disorder.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome is a rare condition defined by monoclonal plasma cell disorder, peripheral neuropathy, and other systemic symptoms. The pathophysiology of POEMS syndrome is unknown, but the overproduction of vascular endothelial growth factor (VEGF) appears to be an important contributory element. The diagnosis of POEMS syndrome requires the presence of both mandatory criteria (ie, polyneuropathy and a monoclonal plasma cell disorder), at least one major criterion (ie, osteosclerotic bone lesions, Castleman disease, or elevated serum or plasma levels of vascular endothelial growth factor), and at least one of the six minor criteria. POEMS syndrome lacks a standard treatment, but patients with limited sclerotic bone lesions are typically treated with radiation therapy. In contrast, those with widespread lesions receive chemotherapy and hematopoietic stem cell transplantation.

Disease progression and defects in primary hemostasis as major cause of bleeding in multiple myeloma.

BACKGROUND AND OBJECTIVES: In patients with multiple myeloma (MM), unexpected bleeding complications remain a major issue. Since routine coagulation parameters are often inconspicuous, diagnosis and treatment of the underlying coagulation disorders are challenging. PATIENTS AND METHODS: In our single-center observational study, we analyzed 164 patients with MM for coagulation disorders and bleeding complications. RESULTS: Prolonged closure times (CTs), measured by PFA-100, were the most common, abnormal coagulation test, found in 66% of bleeding patients vs 5% in non-bleeding, followed by qualitative defects of von Willebrand factor (VWF:CB/VWF:Ag ratios), found in 34% vs 1% in the non-bleeding group. Increased serum free light chains (SFLC) and SFLC ratios were significantly associated with prolonged CTs and acquired von Willebrand syndrome (AVWS). Prolonged CTs and AVWS were associated with disease progression, determined by dynamics of SFLC ratios (P < .001), serum creatinine level (P = .013), Beta-2 microglobulin (P = .03), LDH (P = .016), and bone marrow infiltration (P < .001). Of note, response to myeloma therapy was frequently correlated with normalization of coagulation parameters. CONCLUSIONS: Bleeding complications in MM are predominantly caused by defects in primary hemostasis and associated with disease progression. In a peri-interventional workup, determination of CTs and VWF:CB/VWF:Ag ratios are of significant importance to assess bleeding risk.

Epidemiological and clinical characteristics and outcome of monoclonal gammopathy of renal significance-related lesions in Latin America.

BACKGROUND: Monoclonal gammopathy of renal significance (MGRS)-related lesions are infrequent entities. There are no publications on these disorders in Latin America (LA). The aim of this study was to describe epidemiological and clinical characteristics of these patients in LA. METHODS: We performed a multicentre retrospective study. Patients with diagnosis of MGRS between 2012 and 2018 were included. Epidemiological and clinical data were collected from clinical records. RESULTS: Twenty-seven patients from Chile, Argentina, Ecuador and Uruguay were included. Half debuted with a nephrotic syndrome, and 32% required dialysis. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits was found in 33%, amyloidosis in 26% and monoclonal immunoglobulin deposition disease also in 26%. The immunoglobulin most frequently found in renal biopsies was IgG kappa. In 67% a paraprotein was found. Twenty patients received an anti-plasma cell regimen, and 3 a rituximab-based regimen (IgM-MGRS). Renal response (RR) was achieved in 56%. Early treatment (≤3 months) was associated with higher RR (75% vs 43%). Three patients relapsed within 21.5 months, and 3 progressed: 1 to multiple myeloma, 1 to systemic amyloidosis and another to systemic light-chain deposition disease. Two patients died, both due to infection during induction treatment. CONCLUSION: There was a higher than expected frequency of patients requiring dialysis. The most common MGRS-related lesion was PGNMD. Early treatment was associated with better response. As a rare disease, increasing awareness and promoting early diagnosis are necessary in LA to improve outcomes. SUMMARY AT A GLANCE A collection of 27 cases of MGRS from Latin America with information on epidemiology, clinical characteristics, treatment and outcome of patients diagnosed of MGRS-related renal lesions.

Carl Freiherr von Rokitansky's Manual and Rudolf Virchow's criticism: The controversial subject of Rokitansky's doctrine of crases and dyscrases and the groundwork for modern humoral pathology.

For Rokitansky, pathological anatomy was not only a descriptive but also an explanatory science. Since the changes in the solidis (morphological conditions) did not always adequately explain the cause of death, Rokitansky considered that the answers to his research questions were to be found in a combination of solidar pathology and humoral pathology. Many reviewers claim that Rokitansky had fallen back into the "old" humoral pathology. However, Rokitansky's approach to humoral pathology also included the analysis of blood, blood plasma, blood serum, secretions, excretions, lymph and exudates in pathological anatomy. In his research, Rokitansky referred to "the oxidation of protein to fiber", "illnesses of the protein" and "illnesses of the fibrin". Rokitansky postulated that the progression of a disease was determined by the different forms of protein and fibrin in the blood. From his point of view, diseased blood components (dyscrasias) influence the tissue in its cellular and intercellular dimensions. He sought to generate awareness of this interaction in his Krasenlehre, which was criticised by Rudolf Virchow. Only in the past thirty years has research confirmed the visionary dimension of Rokitansky's humoral pathology.

Kidney diseases associated with Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoma characterized by lymphoplasmacytic cell infiltration in the bone marrow and other organs and the presence of a monoclonal immunoglobulin M protein in the serum. Although uncommon, several kidney diseases have been associated with WM. In addition to kidney diseases related to lymphoplasmacytic lymphoma infiltration, a variety of glomerular and tubular lesions have been described in patients with WM. Immunoglobulin light chain (AL) amyloidosis and cryoglobulinemic glomerulonephritis are the two predominant glomerular pathologies seen in WM. In this article we review the kidney diseases associated with WM. We also briefly review some nephrotoxicities of novel chemotherapeutic and targeted therapies used for the treatment of WM.

Tubulointerstitial nephritis with monotypic lympho-plasmacytic infiltrates in a patient with primary Sjögren's syndrome accompanied by IgA-type monoclonal gammopathy.

BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

Laboratory Abnormalities in Polyneuropathy and Electrophysiological Correlations.

To study the frequency of laboratory test abnormalities, and electrophysiological correlations, we performed a retrospective chart review of 226 patients with polyneuropathy. The frequency of laboratory test abnormalities, and correlations with electrophysiological findings were explored. Abnormal glucose handling tests were the most common findings (54%), followed by paraproteinemia (21%) and anemia (21%). The frequencies of paraproteinemia and anemia in our cohort were significantly higher than previously reported. In addition, several laboratory abnormalities correlated with electrophysiological findings of median neuropathy at the wrist, expanding current knowledge about the deleterious effects of various metabolic and hematologic derangements at this site.

Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies.

The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.

Frequent laboratory abnormalities in CIDP patients.

INTRODUCTION: The role of screening laboratory tests in chronic inflammatory demyelinating polyneuropathy (CIDP) is currently unknown. The objectives of this study are to explore common laboratory test abnormalities in CIDP patients. METHODS: CIDP subjects attending the Neuromuscular Clinic between 01/2013 and 12/2014 were evaluated. Demographic data, clinical history, physical examination, and laboratory test results were extracted from their charts. RESULTS: Seventy-nine charts were reviewed. Mean age was 61 ± 11 years. Most (84%) CIDP patients had laboratory test abnormalities; the most frequent were paraproteinemia (29%) and elevated HbA1C (28%) and creatine kinase (27%). Additional abnormalities included anemia in 19%, and elevated anti-neutrophil cytoplasmic antibody, erythrocyte sedimentation rate, and urate in 17%, elevated antinuclear antibodies, rheumatoid factor, and thyroid-stimulating hormone in 11%, and abnormal C3 in 10%. CONCLUSIONS: Laboratory test abnormalities were found in most CIDP patients. The most common were paraproteinemia, higher than expected frequency of diabetes, and unexpected CK elevation. Additional abnormalities included anemia, high urate levels, and common biomarkers for vasculitic neuropathies. Muscle Nerve 53: 862-865, 2016.

Paraproteinemic neuropathies.

The paraproteinemias are a heterogeneous group of disorders in which monoclonal plasma cells cause the proliferation of monoclonal proteins. They are of importance to clinicians because they often occur in association with neuropathies. Neurologists play a particularly important role when the neuropathy is the presenting feature, in which case they may uncover clinical, laboratory, radiologic, electrodiagnostic, or biopsy findings that lead to identification of the underlying paraproteinemia. The frequency of neuropathies in these patients, and the extent to which such neuropathies dominate the clinical picture, varies significantly between the different paraproteinemias. Treatments may be aimed specifically at the neuropathy, or against the underlying hematologic disorder. In all patients with paraproteinemias, the neurologist can work collaboratively with the hematologist to formulate therapeutic plans and goals and can provide follow-up and monitoring to determine the response of the neuropathy to treatment.

Multiple myeloma after kidney transplantation.

BACKGROUND: Data regarding multiple myeloma (MM) that develops after kidney transplantation (KTx) are scarce. The outcomes of these patients were evaluated in a retrospective study. METHODS: Patients with newly diagnosed MM after KTx were selected. Patients with a diagnosis of MM or those who received treatment for monoclonal gammopathy of renal significance (MGRS) prior to KTx were excluded. RESULTS: Between 2001 and 2012, seven patients developed MM after KTx. Reasons for ESRD included ADPKD (1), C1q nephropathy (1), MPGN (2), hypertensive nephrosclerosis (2), and chronic interstitial nephritis (1). Before KTx, only four patients had monoclonal protein studies, four had monoclonal gammopathy of undermined significance (MGUS), and two of them had clonal plasma cells in bone marrow. Median follow-up after MM was 70 months (range 19-100). Median survival was 80 months. Median time from KTx to MM was 72 months (range 3-204 months). The Kidney allograft failed in four patients due to monoclonal protein-related renal disease. Five patients received chemotherapy: bortezomib (n = 3), lenalidomide (n = 2), melphalan (n = 1), thalidomide (n = 1), pomalidomide (n = 1), and high-dose dexamethasone (n = 1). Three patients received ASCT. CONCLUSION: Multiple myeloma after KTx is rare. Most patients who develop MM had MGUS prior to KTx. There is significant renal involvement in these patients. Survival is not worse when compared to MM without KTx. Further work is needed to identify the best treatment options for these patients.

The effect of paraprotein on platelet aggregation.

BACKGROUND: Some patients with paraproteinemia have platelet aggregation disorders and the aim of this study was to examine disturbance of platelet aggregation in healthy blood donors by isolated paraprotein in vitro. METHODS: Using Rivanol, paraprotein was separated from the serum of ten patients with paraproteinemia, who had decreased platelet aggregation with several inducers. Platelet aggregation in ten healthy donors was measured with and without addition of the isolated induced paraprotein. The test was repeated with added human immunoglobulins for intravenous use. RESULTS: Average of maximal levels of platelet aggregation has been significantly decreased in plasma rich in platelets (PRP) of healthy donors after addition of paraprotein when inducers are used: adenosine diphosphate (ADP) (P = 0.007), collagen (COL) (P = 0.008), ristocetin (RIS) (P = 0.001), and epinephrine (EPI) (P = 0.002). Average of latent time of platelet aggregation was significantly prolonged in healthy donors after addition of paraprotein with inducers: COL (P = 0.008), RIS (P = 0.008) and EPI (P = 0.006) while addition of human immunoglobulins caused no change in platelet aggregation. In comparison, when human immunoglobulins were added, maximal platelet aggregation and latent time did not change significantly. Paraprotein isolated from patients with paraproteinamia, who had decrease platelet aggregation, had significantly decreased platelet aggregation when added to PRP of healthy donors, in vitro. CONCLUSION: Platelet aggregation was not significantly changed was confirmed with addition of human immunoglobulins.