Obesity and multiple myeloma: Emerging mechanisms and perspectives.

Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is also involved in the development of cardiovascular disease and type 2 diabetes mellitus. Recently, an increase in the incidence of obesity-related cancers has been reported. Multiple myeloma (MM) is the second most common hematological malignancy, after lymphoma. The aim of this review is to examine the epidemiological data on obesity and MM, assess the effect of obesity on MM outcomes, evaluate the possible mechanisms through which obesity might increase the incidence of MM and provide the effects of obesity management on MM. Current evidence indicates that obesity may have an impact on the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM and increase the prevalence of MM. However, data regarding the effect of obesity on MGUS incidence are controversial; further studies are needed to examine whether obesity affects the development of MGUS or the progression of MGUS to MM. In addition, obesity affects MM outcomes. Increased BMI is associated with decreased survival in patients with MM, while data regarding the effect of obesity on newly diagnosed MM subjects and autologous stem cell transplantation are limited. Interestingly, the obesity paradox may also apply to patients with relapsed/refractory MM who are overweight or obese, because they may have a survival advantage. The pathophysiological pathways linking obesity to MM are very complicated and include bone marrow adipose tissue; adipokines, such as adiponectin, leptin, resistin, and visfatin; inflammatory cytokines and growth factors, such as TNF-α and IL-6; hormones including insulin and the insulin-like growth factor system as well as sex hormones. In terms of the effect of pharmacological management of obesity, orlistat has been shown to alter the proliferation of MM cells, whereas no data exist on glucagon-like peptide-1 receptor agonists, naltrexone/bupropion, or phentermine/topiramate. Bariatric surgery may be associated with a reduction in the incidence of MM, however, further studies are needed.

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.

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.

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.

Management of multiple myeloma-related renal impairment: recommendations from the International Myeloma Working Group.

Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.

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.

Improved survival of patients with primary plasma cell leukemia with VRd or daratumumab-based quadruplets: A multicenter study by the Greek myeloma study group.

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) versus previous anti-myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow-up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/µL, independently predicted OS (p < .05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL.

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.

Immune response and adverse events after vaccination against SARS-CoV-2 in adult patients with transfusion-dependent thalassaemia.

Patients with transfusion-dependent thalassaemia (TDT) are considered an at increased-risk population for severe and/or morbid coronavirus disease 2019 (COVID-19) infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population.

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.

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.

SARS-CoV-2 humoral responses following booster BNT162b2 vaccination in patients with B-cell malignancies.

Patients with B-cell malignancies have suboptimal immune responses to SARS-CoV-2 vaccination and are a high-risk population for severe COVID19 disease. We evaluated the effect of a third booster BNT162b2 vaccine on the kinetics of anti- SARS-CoV-2 neutralizing antibody (NAbs) titers in patients with B-cell malignancies. Patients with NHL (n = 54) Waldenström's macroglobulinemia (n = 90) and chronic lymphocytic leukemia (n = 49) enrolled in the ongoing NCT04743388 study and compared against matched healthy controls. All patient groups had significantly lower NAbs compared to controls at all time points. 1 month post the third dose (M1P3D) NAbs increased significantly compared to previous time points (median NAbs 77.9%, p < .05 for all comparisons) in all patients. NAbs ≥ 50% were seen in 59.1% of patients, 34.5% of patients with suboptimal responses post-second dose, elicited a protective NAb titer ≥50%. Active treatment, rituximab, and BTKi treatment were the most important prognostic factors for a poor NAb response at 1MP3D; only 25.8% of patients on active treatment had NAbs ≥ 50%. No significant between-group differences were observed. Patients with B-cell malignancies have inferior humoral responses against SARS-CoV-2 and booster dose enhances the NAb response in a proportion of these patients.