Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: part 1 results of a phase I/II study.

Preclinical and clinical data demonstrate synergy between belantamab mafodotin (belamaf) and immunomodulatory drugs with limited overlapping toxicities. We investigated the safety and efficacy of belamaf with lenalidomide 25 mg on days 1-21 every 28 days and dexamethasone 40 mg weekly (belamaf-Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma. Thirty-six patients (median age, 72.5 years) were randomized to receive belamaf at three different doses (2.5, 1.9, or 1.4 mg/kg) every 8 weeks. The dosing schedule was extended to every 12 weeks to mitigate ocular toxicity. Most common grade ≥3 adverse events were fatigue (n=21, 58.3%), rash (n=6, 16.7%), diarrhea (n=8, 22.2%) and COVID-19 (n=5, 13.9%). Grade 3-4 ocular adverse events, comprising visual acuity decline from baseline and/or keratopathy, were reported in 39/216 (18.1%), 33/244 (13.5%), and 26/207 (12.6%) ophthalmological assessments in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Importantly, grade 3-4 keratopathy was identified in 9/216 (4.2%), 1/244 (0.4%) and 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated with the extended, every-12-week schedule, during which 40, 33 and 16 doses were withheld due to ocular adverse events in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Overall, the rates of very good partial response and better and complete response and better were 83.3% and 52.8%, respectively, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; six patients discontinued treatment due to infection-related death (4 cases of COVID-19, 2 cases of pneumonia) and one patient withdrew consent. Based on the toxicity/efficacy balance, the recommended phase II dose was 1.9 mg/kg every 8 weeks, extended to every 12 weeks because of toxicity. In conclusion, Belamaf-Rd, with the extended schedule for belamaf, showed important clinical activity and a significant improvement of ocular adverse events with minimal impact on vision-related functioning in an elderly, non-transplant eligible population.

Low circulating tumor cell levels correlate with favorable outcomes and distinct biological features in multiple myeloma.

There is growing interest in multiple myeloma (MM) circulating tumor cells (CTCs), but their rareness in peripheral blood (PB) and inconsistency in cutoffs question their clinical utility. Herein, we applied next-generation flow cytometry in 550 bone marrow (BM) and matched PB samples to define an optimal CTC cutoff for both transplant-eligible and transplant-ineligible newly diagnosed MM (NDMM) patients. Deep phenotyping was performed to investigate unique microenvironmental features associated with CTC dissemination. CTCs were detected in 90% of patients (median 0.01%; range: 0.0002%-12.6%) and increased levels associated with adverse features. Correlations were observed between high CTC percentages and a diffused MRI pattern, a distinct BM composition characterized by altered B-cell differentiation together with an expansion of effector cells and tumor-associated macrophages, as well as a greater phenotypic dissimilarity between BM and PB clonal cells. Progression-free survival (PFS) and overall survival (OS) gradually worsened with each logarithmic increment of CTCs. Conversely, NDMM patients without CTCs showed unprecedented outcomes, with 5-year PFS and OS rates of 83% and 97%, respectively. A cutoff of 0.02% CTCs was independent of the ISS, LDH, and cytogenetics in a multivariate analysis of risk factors for PFS. The 0.02% CTC cutoff synergized with the MGUS-like phenotype and the R-ISS for improving the risk stratification systems. MRD negativity was less frequent if CTCs were ≥0.02% at diagnosis, but whenever achieved, the poor prognosis of these patients was abrogated. This study shows the clinical utility of CTC assessment in MM and provides evidence toward a consensus cutoff for risk stratification.

Outcomes of patients with light chain (AL) amyloidosis after failure of daratumumab-based therapy.

As daratumumab use in AL amyloidosis increases, more patients will either relapse after or become refractory to daratumumab. We present the outcome of 33 patients with AL who failed on daratumumab (due to haematological relapse in 21 [64%] patients and inadequate haematological response in 12 [36%]) and received further treatment. Overall response rate in the post-daratumumab failure treatment was 55% (CR/VGPR: 14 [42%] and PR: 3 [9%] patients). Patients retreated with daratumumab and patients harbouring +1q21 had lower rates of response. Treatment of patients with AL who fail daratumumab therapy is feasible when non-cross-resistant drugs or other targeted therapies are available.

Prognostic impact of translocation t(11;14) and of other cytogenetic abnormalities in patients with AL amyloidosis in the era of contemporary therapies.

OBJECTIVES: Translocation t(11;14) is the most common cytogenetic abnormality in patients with systemic AL amyloidosis with prognostic and therapeutic relevance, which has not been clearly defined in the most recent therapeutic era. METHODS: We assessed its prognostic role in 146 newly-diagnosed patients who received novel agent-based treatment combinations. Event-free survival (EFS), a composite endpoint defined by hematological progression, start of a new treatment-line or death, and overall survival (OS) were the primary endpoints. RESULTS: Half of the patients had at least one FISH abnormality; 40% had t(11;14) which was inversely associated with other cytogenetic abnormalities. At 1, 3, and 6-month landmarks, hematologic response rates were numerically but not statistically higher in the non-t(11;14) group. Patients with t(11;14) were more frequently switched to second-line treatment within 12 months (p = .015). At median follow-up of 31.4 months, t(11;14) was associated with shorter EFS [17.1 (95% CI 3.2-10.6) vs. 27.2 months (95% CI 13.8-40.6), p = .021] and retained its prognostic significance in the multivariate model (HR:1.66, p = .029). The effect on OS was neutral, possibly due to the use of effective salvage therapies. CONCLUSIONS: Our data support the use of targeted therapies for patients with t(11;14) to avoid delays in the achievement of deep hematologic responses.

Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM). The aim of this study was to assess the effectiveness and tolerability of monotherapy with the conjugated anti-BCMA monoclonal antibody belantamab mafodotin in triple-class refractory patients with MM in real-world practice. Patients refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 monoclonal antibody received belantamab mafodotin at 2.5 mg/kg intravenously every 3 weeks. Overall, 27 patients with a median age of 65 years (range 41-81) were included. Of these, 52% were male and the median number of prior lines of treatment was 5 (4-10). The overall response rate (partial response or better) was 52%, whereas the disease control rate (stable disease or better) was 70%. The median progression-free survival (PFS) was 2 months (95%CI: 0-7), whereas the median PFS among the responders was 12 months (95%CI: 6-18). Regarding the toxicity profile, the most common toxicity was eye toxicity, in 44% of the patients. Keratopathy grade 2-3 was reported in 33.3% of the patients. In conclusion, belantamab mafodotin showed a safety and efficacy profile consistent with the results of the registrational study. Importantly, heavily pretreated patients who responded to treatment derived a substantial survival benefit.

miRNA-seq and clinical evaluation in multiple myeloma: miR-181a overexpression predicts short-term disease progression and poor post-treatment outcome.

BACKGROUND: Despite significant advances in multiple myeloma (MM) therapy, disease relapse and treatment resistance remain major obstacles in clinical management. Herein, we have studied the clinical utility of miRNAs in improving patients' risk-stratification and prognosis. METHODS: miRNA-seq was performed in CD138+ plasma cells of MM, smoldering multiple myeloma (sMM) and monoclonal gammopathy of undetermined significance (MGUS) patients. The screening MM cohort consisted of 138 patients. miRNA levels of CD138+ plasma cells were quantified by RT-qPCR following 3'-end RNA polyadenylation. Disease progression and patients' death were used as clinical end-point events. Internal validation was conducted by bootstrap analysis. Clinical net benefit on disease prognosis was assessed by decision curve analysis. Kruykov et al. 2016 served as validation cohort (n = 151). RESULTS: miRNA-seq highlighted miR-181a to be upregulated in MM vs. sMM/MGUS, and R-ISS III vs. I patients. Screening and validation cohorts confirmed the significantly higher risk for short-term progression and worse survival of the patients overexpressing miR-181a. Multivariate models integrating miR-181a with disease established markers led to superior risk-stratification and clinical benefit for MM prognosis. CONCLUSIONS: CD138+ overexpression of miR-181a was strongly correlated with inferior disease outcome and contributed to superior prediction of MM patients early progression, supporting personalised prognosis and treatment decisions.

Myeloma patients with COVID-19 have superior antibody responses compared to patients fully vaccinated with the BNT162b2 vaccine.

Patients with multiple myeloma (MM) have a suboptimal antibody response following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lower seroconversion rates following coronavirus disease 2019 (COVID-19) compared with healthy individuals. In this context, we evaluated the development of neutralising antibodies (NAbs) against SARS-CoV-2 in non-vaccinated patients with MM and COVID-19 compared with patients after vaccination with two doses of the BNT162b2 vaccine. Serum was collected either four weeks post confirmed diagnosis or four weeks post a second dose of BNT162b2. NAbs were measured with a Food and Drug Administration-approved enzyme-linked immunosorbent assay methodology. Thirty-five patients with COVID-19 and MM along with 35 matched patients were included. The two groups did not differ in age, sex, body mass index, prior lines of therapy, disease status, lymphocyte count, immunoglobulin levels and comorbidities. Patients with MM and COVID-19 showed a superior humoral response compared with vaccinated patients with MM. The median (interquartile range) NAb titre was 87·6% (71·6-94%) and 58·7% (21·4-91·8%) for COVID-19-positive and vaccinated patients, respectively (P = 0·01).Importantly, there was no difference in NAb production between COVID-19-positive and vaccinated patients who did not receive any treatment (median NAb 85·1% vs 91·7%, P = 0·14). In conclusion, our data indicate that vaccinated patients with MM on treatment without prior COVID-19 should be considered for booster vaccine doses.

Chromosome 1q21 aberrations identify ultra high-risk myeloma with prognostic and clinical implications.

Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R-ISS stage (p < .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p < .001) and OS (median 75 vs. 44 months, p < .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R-ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p < .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R-ISS-3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R-ISS-3 without +1q21, p < .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R-ISS-3 disease and +1q21 have a very poor outcome comprising an ultra-high-risk group.

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

A Cancer-Related microRNA Signature Shows Biomarker Utility in Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT-adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM.

Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis.

Growth differentiation factor-15 (GDF-15) improves prognostication in patients with cardiovascular disorders in addition to conventional cardiac markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], troponins [Tns]) and has shown prognostic value in patients with renal diseases. In patients with light chain (AL) amyloidosis, cardiac involvement is the major determinant of prognosis, and cardiac markers define prognosis, whereas biomarkers of renal involvement stratify renal risk. We explored the prognostic importance of serum level of GDF-15 in patients with AL amyloidosis in 2 independent cohorts. The prognostic value of GDF-15 level was initially evaluated in a cohort of 107 consecutive previously untreated patients with AL amyloidosis from Athens, Greece, and was then validated in a second cohort of 202 consecutive previously untreated patients from Pavia, Italy. High GDF-15 level was associated with a higher risk of early death and poor overall survival independently of NT-proBNP and high-sensitivity TnT (hsTnT) or hsTnI levels. At the 6-month landmark, reduction of GDF-15 level ≥25% was associated with improved outcome. GDF-15 level ≥4000 pg/mL was associated with a high risk of progression to dialysis, independently of renal risk defined by estimated glomerular filtration rate and proteinuria, in both cohorts; failure to reduce GDF-15 below this level was associated with increased risk at either the 3- or 6-month landmark, independently of the established renal response or progression criteria. In conclusion, GDF-15 has prognostic implications for different outcomes in patients with AL and adds prognostic information independent of that provided by cardiac and renal risk biomarkers.

Clinical characteristics and outcomes of oligosecretory and non-secretory multiple myeloma.

Secretion of monoclonal immunoglobulins (MIg) detected in the serum and/or urine is one of the typical features of multiple myeloma (MM). However, some patients secrete MIg in quantities below "measurable" (termed oligosecretory MM) and others have no detectable MIgs by standard serum and urine immunofixation (termed non-secretory MM). In a cohort of 852 consecutive patients with active myeloma, we identified 100 (11.7%) patients with oligo/non-secretory MM, including 20 (2.3%) with non-secretory MM. Compared to patients with secretory MM, these were younger, less anemic, and had less often renal dysfunction and less extensive bone marrow infiltration. Presence and extent of bone disease were similar, however, hypercalcemia was less common and more often is ISS (International Staging System)-1 and, in those with available FISH (Fluoresense In Situ Hybridization) , high-risk cytogenetics were less common. FLCs (Free Light Chains) were available in 17 patients with non-secretory MM: only 3 had normal FLC ratio; the others had abnormal ratio and 9/14 had involved FLC ≥ 100 mg/L. The 4-year OS for patients with oligo/non-secretory disease was 64% vs 58% for secretory MM. In multivariate analysis, oligo/non-secretory disease was not an independent prognostic factor per se. Thus, 12% of MM patients present with oligo/non-secretory disease at diagnosis and have different biologic characteristics but similar outcome to other MM patients.

Long PFS of more than 7 years is achieved in 9% of myeloma patients in the era of conventional chemotherapy and of first-generation novel anti-myeloma agents: a single-center experience over 20-year period.

Advances in the management of multiple myeloma (MM) have led to a significant prolongation of both progression-free (PFS) and overall survival (OS). Herein, we evaluated the characteristics of patients who achieved a PFS of at least 7 years following frontline therapy, as compared with all other patients who were treated in a single center during the same time period. Thirty-six (8.8%) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. Long PFS patients were younger (p < 0.001) and had lower ECOG performance status (p = 0.014), higher hemoglobin (p = 0.001), and higher creatinine clearance (p < 0.001) compared with the others. More patients in the long PFS group had ISS-1 or ISS-2 disease (p = 0.002) and normal pattern of marrow infiltration (p = 0.035). No patient in the long PFS group had high-risk cytogenetics at diagnosis. Long PFS patients had received more often autologous stem cell transplantation (p = 0.001) and had achieved deeper responses. The probability of achieving long PFS (≥ 7 years) for patients who managed to be progression-free at 2, 3, and 4 years was 11.6%, 13.2%, and 15.3%, respectively. Median OS in the long PFS group has not been reached yet, while in all other patients, the median OS was 4.3 years. In conclusion, our study in an unselected patient group showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years in the era of conventional chemotherapy or first-generation novel agents. We anticipate that novel treatment approaches will increase the probability of achieving a prolonged relapse-free status.

Response of an oncology unit in the midst of the COVID-19 outbreak.

Coronavirus disease 19 (COVID-19) pandemic has caused an emergency in health systems worldwide. Apart from its apparent morbidity and mortality, COVID-19 has also imposed unique challenges in the management of cancer patients. We report here measures taken by a major oncology Unit in Greece to continue operation of the department while ensuring safety of the patients and health care professionals. The efficacy of these measures could serve as guidance for Oncology departments in view of a second wave of COVID-19 cases.

Pulmonary function abnormalities are common in patients with multiple myeloma and are independently associated with worse outcome.

Pre-existing pulmonary disease may affect treatment choices, toxicity, and survival of patients with multiple myeloma (MM). However, data on the prognostic value of pulmonary function tests (PFTs) in myeloma patients' outcome, at the time of initial assessment of newly diagnosed patients, are scarce. Here, we prospectively performed PFTs in 121 newly diagnosed MM patients, before initiation of treatment, and we evaluated possible associations of lung function with their outcomes. Fifty-four patients (44.63%) had either obstructive or restrictive pulmonary function defects, even among those not reporting a history of lung disease. The survival was significantly worse in those with obstructive pulmonary defect (median OS 32.8 months) vs. those with restrictive (median OS 52.5 months) or normal lung function (median not reached, 3-year survival 76%) (p = 0.013), independently of other myeloma-related factors. Forced vital capacity (FVC) (lt) (p = 0.012), forced expiratory volume in 1 s (FEV1) (lt) (p = 0.018), peak expiratory flow (PEF) (lt/min) (p = 0.008), carbon monoxide diffusion capacity (DLCO) (p = 0.012), and expiratory/inspiratory pressures (Pe) (kPa) (p = 0.032)/(Pi) (kPa) (p = 0.023) were significantly associated with OS. Myeloma-related factors associated with survival included ISS stage (p = 0.008), hypercalcemia (p = 0.064), and high-risk cytogenetics (p = 0.004). In the multivariate analysis, only the presence of high-risk cytogenetics and presence of either or both PEF and DLCO < 65% of predicted were independent prognostic factors. We conclude that PEF and DLCO could be useful in the initial assessment of newly diagnosed MM patients as significant predictors of survival. Further research is needed to evaluate if respiratory screening should be included in the routine initial evaluation of myeloma patients, despite the presence or absence of respiratory symptoms or abnormal clinical respiratory examination.

Consolidation therapy with the combination of bortezomib and lenalidomide (VR) without dexamethasone in multiple myeloma patients after transplant: Effects on survival and bone outcomes in the absence of bisphosphonates.

Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.

Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers.

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma.

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66-75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma.