When Waldenström macroglobulinemia hits the kidney: Description of a case series and management of a "rare in rare" scenario.

BACKGROUND: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. CASE: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). CONCLUSION: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.

Hospitalization-based epidemiology of systemic and cardiac amyloidosis in the Veneto Region, Italy.

AIM: Defining the epidemiology of systemic and cardiac amyloidosis (CA) is a contemporary challenge. The present study aimed to estimate incidence and time trends in amyloidosis-related hospitalizations (AH) in Veneto Region (5 million inhabitants, Northeastern Italy). METHODS: International Classification of Diseases (ICD-9) codes were used to identify AH in Veneto from 2010 to 2020. AH were defined as any hospitalization with a discharge summary reporting an ICD-9 code for systemic amyloidosis. Hospitalization for CA was defined as records with ICD-9 code for systemic amyloidosis and ICD-9 code for heart failure,cardiomyopathy or arrhythmia. Hospital/outpatient encounters for carpal tunnel syndrome (CTS) surgeries also were extracted. AH incidence was estimated using a buffer of 5 years. RESULTS: In the time range 2015-2020, the incidence rate of AH was 23.5 cases per 106 (95% confidence interval, CI, 21.8; 25.3), mainly affecting patients>65 years (76.2%) and males (63.5%), with a progressively increasing trend (percent annual increase 17%, 95% CI 12; 22%). The 10 year prevalence of AH in 2020 was 124.5 per 106 (95% CI 114.9; 134.8). In 2020, annual hospitalized prevalent cases of CA were about 70% of all cases (159/228), mainly patients >65 years and males. Among patients with multiple CTS surgeries, a subsequent code for cardiac disease was found in 913 after a median of 3.9 years, more frequently in men than in women (463/6.526 7.1% versus 450/11.406 3.9%). CONCLUSIONS: In Veneto, we recorded a significantly increasing trend in the incidence of AH, with concordant increasing prevalence estimates.

Thromboembolic and Bleeding Events in Transthyretin Amyloidosis and Coagulation System Abnormalities: A Review.

Transthyretin amyloidosis (ATTR) is a group of diseases caused by the deposition of insoluble fibrils derived from misfolded transthyretin, which compromises the structure and function of various organs, including the heart. Thromboembolic events and increased bleeding risk are among the most important complications of ATTR, though the underlying mechanisms are not yet fully understood. Transthyretin plays a complex role in the coagulation cascade, contributing to the activation and regulation of the coagulation and fibrinolytic systems. The prevalence of atrial fibrillation, cardiac mechanical dysfunction, and atrial myopathy in patients with ATTR may contribute to thrombosis, though such events may also occur in patients with a normal sinus rhythm and rarely in properly anticoagulated patients. Haemorrhagic events are modest and mainly linked to perivascular amyloid deposits with consequent capillary fragility and coagulation anomalies, such as labile international-normalised ratio during anticoagulant therapy. Therefore, it is paramount to carefully stratify the thrombotic and haemorrhagic risks, especially when initiating anticoagulant therapy. Our review aims to ascertain the prevalence of thromboembolic and haemorrhagic events in ATTR and identify potential risk factors and predictors and their impact on antithrombotic therapy.

Tixagevimab/Cilgavimab as pre-exposure prophylaxis against SARS-CoV-2 in patients with hematological malignancies.

The approved combination of Tixagevimab/Cilgavimab has been shown to decrease the rate of symptomatic SARS-CoV-2 infection in patients at increased risk of inadequate response to vaccination. However, Tixagevimab/Cilgavimab was tested in a few studies that included patients with hematological malignancies, even if this population has shown an increased risk of unfavorable outcomes following infection (with high rates of hospitalization, intensive care unit admission, and mortality) and poor significant immunization following vaccines. We performed a real-life prospective cohort study to evaluate the rate of SARS-CoV-2 infection following pre-exposure prophylaxis with Tixagevimab/Cilgavimab in anti-spike seronegative patients compared to a cohort of seropositive patients who were observed or received a fourth vaccine dose. We recruited 103 patients with a mean age of 67 years: 35 (34%) received Tixagevimab/Cilgavimab and were followed from March 17, 2022, until November 15, 2022. After a median follow-up of 4.24 months, the 3-month cumulative incidence of infection was 20% versus 12% in the Tixagevimab/Cilgavimab and observation/vaccine groups respectively (HR 1.57; 95% CI: 0.65-3.56; p = 0.34). In this study, we report our experience with Tixagevimab/Cilgavimab and a tailored approach to SARS-CoV-2 infection prevention in patients with hematological malignancies during the SARS-CoV-2 omicron surge.

Chest pain in cardiac amyloidosis: occurrence, causes and prognostic significance.

BACKGROUND: Chest pain is experienced by patients with cardiac amyloidosis (CA), but a systematic investigation of its frequency, underlying etiologies and clinical significance is lacking. METHODS: Clinical, echocardiographic, laboratory characteristics, available coronary arteries imaging and endomyocardial biopsy (EMB) findings of 174 patients with CA (n = 104 with transthyretin, ATTR; n = 70 with light chains, AL) were analyzed. RESULTS: Chest pain was reported in 66 (38%) CA patients. Compared to those without, patients with chest pain had more frequently a history of coronary artery disease (CAD) (27% vs 15%, p = 0.048) and heart failure (HF) symptoms (62% vs 43%, p = 0.015), higher high sensitivity troponin I (hs-cTnI, 101 vs 65 ng/L, p = 0.032) and higher brain natriuretic peptide (597 vs 407 ng/L, p = 0.024). Among CA patients with chest pain undergoing coronary arteries imaging (n = 37), obstructive CAD was detected in 14 (38%), 13 of whom with ATTR-CA. Of these 37 patients, EMB was available in 10 and vascular/perivascular amyloid deposition was detected in 4/5 (80%) of AL-CA patients and 1/5 ATTR-CA. Among patients with suspected acute coronary syndrome (n = 22), obstructive CAD was detected in 9/17 (53%) ATTR-CA and 0/5 AL-CA; hs-cTnI levels were similar between those with and without obstructive CAD. During a follow-up of 17 (8-34) months, chest pain was a significant predictor of HF hospitalization (HR1.86, 95% CI 1.02-3.39, p = 0.042), even after adjustment for CA subtype and CAD. CONCLUSION: Chest pain is a common symptom in patients with CA, reflects a more advanced cardiac impairment and predicts future HF hospitalization. The etiology of chest pain seems to differ, with obstructive CAD more frequent in ATTR-CA whilst amyloid vascular/perivascular involvement more common in AL-CA.

Light-chain cardiac amyloidosis for the non-expert: pearls and pitfalls.

Cardiac amyloidosis (CA) is an uncommon, progressive, and fatal disease; the two main forms that can affect the heart are transthyretin CA and light chain CA (AL-CA). AL-CA is a medical urgency for which a diagnostic delay can be catastrophic for patients' outcome. In this manuscript, we focus on the pearls and pitfalls that are relevant to achieve a correct diagnosis and to avoid diagnostic and therapeutical delays. Through the aid of three unfortunate clinical cases, some fundamental diagnostic aspects are addressed, including the following: first, a negative bone scintigraphy does not exclude CA, with patients with AL-CA frequently showing no or mild cardiac uptake, and its execution should not delay hematological tests; second, fat pad biopsy does not have a 100% sensitivity for AL amyloidosis and, if negative, further investigations should be performed, particularly if the pre-test probability is high. Third, Congo Red staining is not sufficient to reach a definitive diagnosis and amyloid fibrils typing with mass spectrometry, immunohistochemistry, or immunoelectron microscopy is crucial. To achieve a timely and correct diagnosis, all the necessary investigations must be performed, always considering the yield and diagnostic accuracy of each examination.

Peripheral neuropathy as clinical onset of monoclonal IgM/k-related amyloidosis.

AIM: Neuropathy is a frequent complication of Waldenström's macroglobulinemia (WM), the most common being a demyelinating polyneuropathy with anti-myelin associated glycoprotein (MAG) antibodies, but also cryoglobulins, vasculitis, neurolymphomatosis, and amyloidosis. We describe a patient with IgM/kappa WM who presented with a severe, not length-dependent, peripheral neuropathy as clinical onset of IgM/kappa-related amyloidosis. METHODS: A 69-year-old woman came to our attention for weight loss, gait imbalance and sensory loss at upper limbs. In her medical history, she was in hematological follow-up for WM, and had undergone left carpal tunnel release. At neurological evaluation she had weakness and loss of sensation at upper limbs up to the elbows, more at the left side, gait was unsteady with right foot drop. Hypotrophy and areflexia were present at four limbs. Sensory loss and vibration sense were dramatically reduced. She underwent extensive diagnostic workup. RESULTS: Laboratory workup revealed an IgM/kappa monoclonal paraprotein of 16 g/L and increased NT-proBNP; anti-MAG antibodies were absent. Bone marrow biopsy demonstrated a population of neoplastic B-lymphocytes. Total-body CT scan and echocardiogram were negative. Neurophysiology revealed a symmetric, no length dependent sensory-motor polyneuropathy Periumbilical fat biopsy was positive for amyloid. Sural nerve biopsy detected amyloid in the wall of an epineurial vein. CONCLUSIONS: This case report describes a rare and unusual manifestation of IgM-related AL amyloidosis in WM. The patient presented with a subacute clinically asymmetric neuropathy with no pain or dysautonomic features as clinical onset of IgM/kappa-related amyloidosis. Sural nerve biopsy was crucial for the diagnosis.

CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma.

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and ß-catenin signaling. CK1α is a negative regulator of the Wnt/ß-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM-MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/ß-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments.

Dealing With High-Risk AL Amyloidosis Patients: A Single Hematologic Center Experience.

PURPOSE: To assess the feasibility and the results of Bortezomib-based treatment of "high-risk" AL-amyloidosis patients in a hematology ward. METHODS: We report on 52 high-risk amyloidosis patients treated with first-line bortezomib-based chemotherapy. RESULTS: At day 30 from the beginning of the therapy, 23 patients (44%) achieved a hematological response (complete response plus very good partial response); 14 patients (27%) achieved a partial response; 15 patients (29%) were non-responders. After a median follow-up of 28.5 months, the survival rates were 18/23 (78%) for responders; 9/14 (64%) for partial responders and 3/15 (20%) for nonresponders with a median overall survival of 43, 24 and 11 months, respectively (log-rank test: P < .001). NHYA class I-II, NTproBNP < 6500 ng/L, the hematologic response, and the partial hematological response at day 30 independently predicted the survival. There has been no significant difference (P = .173) in survival between revised Mayo stage III and IV patients although there was a trend toward a better prognosis for Mayo stage III. A suboptimal hematological response at day 30 allowed a later organ response in 12/14 patients (85%) even without therapy change and no modification of the hematological status. CONCLUSIONS: These results show that high-risk AL-amyloidosis patients can be managed safely and effectively in a hematology ward. A partial hematologic response may herald a later better response, organ response, and can allow a subsequent second-line therapy and a good survival.

Treatment Induced Cytotoxic T-Cell Modulation in Multiple Myeloma Patients.

The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors. Since genetic lesions are necessary but not sufficient for Multiple Myeloma (MM) evolution, several authors hypothesized that immune dysfunction involving both B and T cell counterparts plays a key role in the pathogenesis of the disease. The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma into immune system shaping. A large series of 976 bone marrow samples from 735 patients affected by PCD was studied by flow analysis to identify discrete immune subsets. Treated MM samples displayed a reduction of CD4+ cells (p<0.0001) and an increase of CD8+ (p<0.0001), CD8+/DR+ (p<0.0001) and CD3+/CD57+ (p<0.0001) cells. Although these findings were to some extent demonstrated also following bortezomib treatment, a more pronounced cytotoxic polarization was shown after exposure to autologous stem cell transplantation (ASCT) and Lenalidomide (Len) treatment. As a matter of fact, samples of patients who received ASCT (n=110) and Len (n=118) were characterized, towards untreated patients (n=138 and n=130, respectively), by higher levels of CD8+ (p<0.0001 and p<0.0001, respectively), CD8+/DR+ (p=0.0252 and p=0.0001, respectively) and CD3+/CD57+ cells (p<0.0001 and p=0.0006, respectively) and lower levels of CD4+ lymphocytes (p<0.0001 and p=0.0005, respectively). We demonstrated that active MM patients are characterized by a relevant T cell modulation and that most of these changes are therapy-related. Current Myeloma treatments, notably ASCT and Len treatments, polarize immune system towards a dominant cytotoxic response, likely contributing to the anti-Myeloma effect of these regimens.

High rate of profound clonal and renal responses with daratumumab treatment in heavily pre-treated patients with light chain (AL) amyloidosis and high bone marrow plasma cell infiltrate.

Daratumumab demonstrated activity in the treatment of AL amyloidosis in two recently concluded phase II clinical trials in relapsed and refractory patients. Its role in upfront therapy is under evaluation in a phase III study. In this report we evaluated the safety and efficacy of 28-day cycles of daratumumab (single agent or combined with bortezomib or lenalidomide) in 72 previously treated patients with multiple myeloma and AL amyloidosis. Fifty (69%) were refractory to the last line of therapy. After eight infusions of daratumumab, 59 patients (82%) achieved a hematologic response, with 12 (16%) complete responses (CRs) and 30 (42%) very good partial responses (VGPRs). After 16 infusions, the quality of response improved with 22 patients (30%) achieving CR and 21 (29%) attaining VGPR. Cardiac response was observed in 11 of 37 evaluable patients (29%) and renal response in 23 of 38 patients (60%). Daratumumab is highly effective in heavily pretreated patients with relapsed/refractory AL amyloidosis and high bone marrow plasma cell burden. Renal responses, which are usually rare in this setting, were frequently observed.

Is vitamin D deficiency a risk factor for osteonecrosis of the jaw in patients with cancer? A matched case-control study.

PURPOSE: A previous case-control histomorphometric study showed higher odds of osteomalacia in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Vitamin D deficiency causes osteomalacia and may therefore be involved in the pathogenesis of BRONJ. The present case-control study aimed at testing such hypothesis. MATERIALS AND METHODS: BRONJ+ and BRONJ- patients treated with bisphosphonates were matched by sex (same) and age (within 5 years). Serum 25-hydroxy-vitamin D (25-OH-D), parathyroid hormone, bone alkaline phosphatase, total procollagen type 1 amino-terminal propeptide, carboxy-terminal collagen crosslinks, Dickkopf WNT signaling pathway inhibitor 1 and sclerostin were measured. RESULTS: The main outcome was vitamin D deficiency defined as 25-OH-D < 50 nmol/l. A total of 51 BRONJ+ and 73 BRONJ- patients were studied. The frequency (95% CI) of vitamin D deficiency was 59% (45%-72%) in BRONJ+ and 62% (48%-75%) in BRONJ- patients. This amounts to a difference of -3% (-22%-16%, p = 0.77) for BRONJ+ patients. Serum 25-hydroxy-vitamin D and parathyroid hormone were similar in BRONJ+ and BRONJ- patients. Among the bone metabolism markers, only sclerostin differed between the two groups, being higher in BRONJ+ patients. CONCLUSION: The present matched case-control study suggests that vitamin D deficiency is not a risk factor for BRONJ.

Whole-body low-dose CT recognizes two distinct patterns of lytic lesions in multiple myeloma patients with different disease metabolism at PET/MRI.

We evaluated differences in density and 18F-FDG PET/MRI features of lytic bone lesions (LBLs) identified by whole-body low-dose CT (WB-LDCT) in patients affected by newly diagnosed multiple myeloma (MM). In 18 MM patients, 135 unequivocal LBLs identified by WB-LDCT were characterized for inner density (negative or positive Hounsfield unit (HU)), where negative density (HU < 0) characterizes normal yellow marrow whereas positive HU correlates with tissue-like infiltrative pattern. The same LBLs were analyzed by 18F-FDG PET/DWI-MRI, registering DWI signal with ADC and SUV max values. According to HU, 35 lesions had a negative density (- 56.94 ± 31.87 HU) while 100 lesions presented positive density (44.87 ± 23.89 HU). In seven patients, only positive HU LBLs were demonstrated whereas in eight patients, both positive and negative HU LBLs were detected. Intriguingly, in three patients (16%), only negative HU LBLs were shown. At 18F-FDG PET/DWI-MRI analysis, negative HU LBLs presented low ADC values (360.69 ± 154.38 × 10-6 mm2/s) and low SUV max values (1.69 ± 0.56), consistent with fatty marrow, whereas positive HU LBLs showed an infiltrative pattern, characterized by higher ADC (mean 868.46 ± 207.67 × 10-6 mm2/s) and SUV max (mean 5.04 ± 1.94) values. Surprisingly, histology of negative HU LBLs documented infiltration by neoplastic plasma cells scattered among adipocytes. In conclusion, two different patterns of LBLs were detected by WB-LDCT in MM patients. Both types of lesions were indicative for active disease, although only positive HU LBL were captured by 18F-FDG PET/DWI-MRI imaging, indicating that WB-LDCT adds specific information.