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.

Small RNA-seq and clinical evaluation of tRNA-derived fragments in multiple myeloma: Loss of mitochondrial i-tRFHisGTG results in patients' poor treatment outcome.

Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA-derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM-related tRFs in ameliorating MM prognosis and risk stratification. Small RNA-seq was performed to profile tRFs in bone marrow CD138+ plasma cells, revealing the significant deregulation of the mitochondrial internal tRFHisGTG (mt-i-tRFHisGTG) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRFHisGTG levels were quantified by RT-qPCR. Disease progression was assessed as clinical end-point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt-i-tRFHisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short-term disease progression following first-line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt-i-tRFHisGTG-fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease-established markers. Notably, our study highlighted mt-i-tRFHisGTG loss as a powerful independent indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.

Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin.

Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

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 25mg on days 1-21 every 28 days and dexamethasone 40mg weekly (belamaf-Rd) in transplant ineligible patients with newly diagnosed multiple myeloma. 36 patients (median age 72.5 years) were randomized to receive belamaf at three different doses (2.5/1.9/1.4 mg/kg) every 8 weeks (q8w). Dosing schedule was extended to every 12 weeks (q12w) to account for ocular toxicity. Most common ≥ Grade (Gr) 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%). Gr 3-4 ocular adverse events (OAEs), comprising of visual acuity decline from baseline and/or keratopathy, were reported in 39/216(18.1%)/ 33/244(13.5%)/ 26/207(12.6%) ophthalmological assessments in cohorts 2.5/1.9/1.4 mg/kg. Importantly, Gr 3-4 keratopathy was identified in 9/216 (4.2%)/ 1/244(0.4%)/ 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated in the extended q12w schedule, where dose holds due to OAEs were 40, 33 and 16 in cohorts 2.5/1.9/1.4. Overall, ≥VGPR and ≥CR rates were 83.3% and 52.8%, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; 6 patients discontinued treatment due to infection-related death (n=4 COVID-19, n=2 pneumonia) and 1 patient withdrew consent. Based on toxicity/efficacy balance, the recommended phase 2 dose was 1.9 mg/kg q8w, extended to q12w for toxicity. Belamaf-Rd, with the extended schedule for belamaf, has shown important clinical activity and a significant improvement of OAEs with minimal impact on vision-related functioning in an elderly, non-transplant eligible population.

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide-exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA.

The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide-based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow-up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid responses along with a favorable effect on bone metabolism.

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.

Central nervous system multiple myeloma: A real-world multi-institutional study of the Greek Myeloma Study Group.

Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM). We identified 54/4352 MM patients (1.2%), who developed CNS-MM between 2000 and 2022. A matched-control group of MM patients without CNS-MM was used for comparisons. Median age was 63 years. Median time to CNS-MM was 28 months; 6/54 experienced CNS-MM at MM diagnosis. Abnormal lactate dehydrogenase (LDH), high-risk cytogenetics, and extramedullary involvement (EMI), that is, soft tissue plasmacytomas and/or plasma cell leukemia (PCL), were more frequent in CNS-MM versus controls (p < .05); 13/54 had PCL at CNS-MM. The majority had leptomeningeal infiltration (LMI) (66%); 26% had CNS-MM without systemic myeloma; EMI was the strongest predictor for CNS-MM (OR: 6.3). Median overall survival (OS) of CNS-MM patients versus controls was 43 months (95% CI: 32-54) versus 60 months (95% CI: 38-82) (p < .001); treatment of CNS-MM included mainly bortezomib/thalidomide/chemotherapy whereas 20% received novel drugs/immunotherapy combinations; 28 patients underwent cerebrospinal fluid infusions; EMI was the strongest negative predictor for post CNS-MM OS (p = .005; HR: 2.9). Treatment after 2016 predicted significantly for OS (p = .002; HR: 0.27). Median post CNS-MM OS was 4 months (95% CI: 2.6-5.4); in patients treated after 2016 median OS was 12 months. In conclusion, we have demonstrated in this large real-world series that survival of CNS-MM remains poor; however, there is a positive impact of treatment after 2016, related to the efficacy of modern anti-myeloma therapy; EMI significantly increases the probability to develop CNS-MM and the risk of post CNS-MM death, indicating a potential need for CNS prophylaxis for those patients.

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.

miRNA-seq identification and clinical validation of CD138+ and circulating miR-25 in treatment response of multiple myeloma.

BACKGROUND: Despite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients' management. METHODS: miRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69). Two external datasets (Kryukov et al. cohort n = 149; MMRF CoMMpass study n = 760) served as institutional-independent validation cohorts. Patients' mortality and disease progression were assessed as clinical endpoints. Internal validation was performed by bootstrap analysis. Clinical benefit was estimated by decision curve analysis. RESULTS: miRNA-seq highlighted miR-25 of CD138+ plasma cells to be upregulated in MM vs. sMM, R-ISS II/III vs. R-ISS I, and in progressed compared to progression-free patients. The analysis of our screening cohort highlighted that CD138+ miR-25 levels were correlated with short-term progression (HR = 2.729; p = 0.009) and poor survival (HR = 4.581; p = 0.004) of the patients; which was confirmed by Kryukov et al. cohort (HR = 1.878; p = 0.005) and MMRF CoMMpass study (HR = 1.414; p = 0.039) validation cohorts. Moreover, multivariate miR-25-fitted models contributed to superior risk-stratification and clinical benefit in MM prognostication. Finally, elevated miR-25 circulating levels were correlated with poor survival of MM patients (HR = 5.435; p = 0.021), serving as a potent non-invasive molecular prognostic tool. CONCLUSIONS: Our study identified miR-25 overexpression as a powerful independent predictor of poor treatment outcome and post-treatment progression, aiding towards modern non-invasive disease prognosis and personalized treatment decisions.

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.

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia: Patient outcomes and impact of bendamustine dosing.

Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800-999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m2 had poorer PFS outcomes compared with those who received ≥600 mg/m2 (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.

Metabolomics Point out the Effects of Carfilzomib on Aromatic Amino Acid Biosynthesis and Degradation.

(1) Carfilzomib (Cfz) is an antineoplastic agent indicated for the treatment of multiple myeloma. However, its beneficial action is attenuated by the occurrence of cardiotoxicity and nephrotoxicity as the most common adverse effects. Presently, there is well-established knowledge on the pathomechanisms related to these side effects; however, the research on the metabolic alterations provoked by the drug is limited. (2) An in vivo simulation of Cfz-induced toxicity was developed in (i) Cfz-treated and (ii) control mice. An RP-HRMS-based protocol and an advanced statistical treatment were used to investigate the impact of Cfz on the non-polar metabolome. (3) The differential analysis classified the Cfz-treated and control mice and resulted in a significant number of identified biomarkers with AUC > 0.9. The drug impaired the biosynthesis and degradation of aromatic amino acids (AAA) and led to alterations of uremic toxins in the renal and urine levels. Furthermore, the renal degradation of tryptophan was affected, inducing its degradation via the kynurenine pathway. (4) The renal levels of metabolites showed impaired excretion and degradation of AAAs. Cfz was, finally, correlated with the biosynthesis of renal dopamine, explaining the biochemical causes of water and ion retention and the increase in systolic pressure.

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.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study.

BACKGROUND: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma. METHODS: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis. INTERPRETATION: A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma. FUNDING: Amgen and Janssen.

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.

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Comparison of MRI Features of Fat Fraction and ADC for Early Treatment Response Assessment in Participants with Multiple Myeloma.

Background An imaging-based predictor of response could provide prognostic information early during treatment course in patients with multiple myeloma (MM). Purpose To investigate if very early changes in bone marrow relative fat fraction (rFF) and apparent diffusion coefficient (ADC) histogram metrics, occurring after one cycle of induction therapy in participants with newly diagnosed MM, could help predict overall best response status. Materials and Methods This prospective study included participants with MM who were enrolled between August 2014 and December 2017. Histogram metrics were extracted from ADC and rFF maps from MRI examinations performed before treatment and after the first treatment cycle. Participants were categorized into the very good partial response (VGPR) or better group and the less than VGPR group per the International Myeloma Working Group response criteria. ADC and rFF map metrics for predicting treatment response were compared using the Wilcoxon rank test, and the false discovery rate (FDR) was used to correct for multiple comparisons. Results A total of 23 participants (mean age, 65 years ± 11 [SD]; 13 men) were evaluated. There was no evidence of a difference in ADC metrics between the two responder groups after correcting for multiple comparisons. The rFF histogram changes between pretreatment MRI and MRI after the first treatment cycle (ΔrFF) that provided significant differences between the VGPR or better and less than VGPR groups were as follows: ΔrFF_10th Percentile (median, 0.5 [95% CI: 0, 1] vs -2.5 [95% CI: -5.1, 0.1], respectively), ΔrFF_90th Percentile (median, 2 [95% CI: 1, 6.8] vs -0.5 [95% CI: -1, 0]), ΔrFF_Mean (median, 3.4 [95% CI: 0.3, 7.6] vs -1.1 [95% CI: -1.8, -0.7]), and ΔrFF_Root Mean Squared (median, 3.2 [95% CI: 0.3, 6.1] vs -0.7 [95% CI: -1.3, -0.4]) (FDR-adjusted P = .03 for all), and the latter two also presented mean group increases in the VGPR or better group that were above the upper 95% CI limit for repeatability. Conclusion Very early changes in bone marrow relative fat fraction histogram metrics, calculated from MRI examination at baseline and after only one cycle of induction therapy, may help to predict very good partial response or better in participants with newly diagnosed multiple myeloma. © RSNA, 2022 Online supplemental material is available for this article.

Diabetes mellitus and multiple myeloma; common features of two distinct entities.

Diabetes mellitus (DM) has attained the status of a global pandemic. Cardiovascular disease (CV) was the leading cause of morbidity in people with type 2 DM, however, a transition from CV to cancer as the leading contributor to DM related death has been observed lately. Multiple myeloma (MM) is the second most common haematological malignancy. Obesity is a common risk factor for both DM and MM. Although data are limited, studies have shown that DM might be associated with increased risk for the development of MM. The presence of DM might affect the course of patients with MM, since hyperglycemia may have an impact on both the efficacy and the adverse effects of antimyeloma therapy. In parallel, DM and MM share common clinical presentations, such as nephropathy, neuropathy, and CV. In terms of antidiabetic medications, metformin might present a synergistic effect with antimyeloma drugs and also prevent some of the adverse effects of these drugs; pioglitazone might have favourable effects when given as add on treatment in people with relapsed or refractory MM. No clinically important interactions have been observed between antidiabetic agents and the most commonly used antimyeloma drugs. Further data are needed to examine the effect of all classes of antidiabetic medication on MM and its complications. A baseline assessment of risk factors for glucose intolerance and close monitoring of glucose levels during therapy is strongly suggested for patients with MM.

Late-onset hematological complications post COVID-19: An emerging medical problem for the hematologist.

Coronavirus disease 19 (COVID-19) is considered a multisystemic disease. Several studies have reported persistent symptoms or late-onset complications after acute COVID-19, including post-COVID-19 hematological disorders. COVID-19-induced coagulopathy, an immunothrombotic state, has been linked to thromboembolic and hemorrhagic events. Late-onset thrombocytopenia related to immune system dysregulation has also been reported as a rare manifestation post COVID-19. Close monitoring of laboratory dynamics is considered essential to identify timely abnormal values that need further investigation, providing supportive care whenever indicated. The role of hematologists is essential in terms of the multidisciplinary approach of long COVID-19. This review summarizes all the available evidence on post-acute COVID-19 hematological complications.