Despina Fotiou

Cardiac and renal complications of carfilzomib in patients with multiple myeloma

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m2. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m2) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m2) was associated with a 2‐year progression to dialysis rate of 0% compared to 9% for a ratio of 31‐99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2‐year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib‐based therapy was more effective than lenalidomide‐based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.

A review of the venous thrombotic issues associated with multiple myeloma

ABSTRACT Introduction: Patients with multiple myeloma (MM) have an increased risk of venous thromboembolic (VTE) complications. The first reports of high VTE rates date back to 1999 but became more apparent with the introduction of novel agents in the treatment of MM and mostly with immunomodulatory drugs (IMiDs; thalidomide, lenalidomide and pomalidomide). Areas covered: Currently thromboprophylaxis is recommended for patients who receive IMiDs-based regimens and the type of thrombophrophylaxis is based on patient-, disease- and treatment-related risk factors. Making the distinction between the intrinsic risk of thrombosis in MM and the effect of therapy is crucial. The use of aspirin, low molecular weight heparins and warfarin are the recommended drugs but despite their appropriate use the rates of VTE are not completely eliminated. Expert commentary: Research into biomarkers of increased coagulability and their incorporation in risk assessment models could identify patients most likely to benefit from thromboprophylaxis but such models are not widely used in myeloma.

Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib

Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival.

The addition of IMiDs on daratumumab refractory multiple myeloma patients can overcome refractoriness in both agents

TO THE EDITOR: The survival of myeloma patients has doubled in the past decade, but patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis.[1][1] Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising new

Growth Differentiation Factor 15 Is a New Biomarker for Survival and Renal Outcomes in Light Chain (AL) 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.

Outcomes of newly diagnosed myeloma patients requiring dialysis: renal recovery, importance of rapid response and survival benefit

About 50% of newly diagnosed mutilple myeloma (MM) patients (NDMM) have some degree of renal impairment (RI) at presentation, up to 20% have severe acute kidney injury (AKI) and ~1–5% may require extrarenal dialysis, whereas severe RI is associated with high risk of early death and other complications.1, 2 Immediate effective anti-myeloma therapy and vigorous supportive care are the cornerstones of management.2, 3 However, there are limited data focusing specifically on the management and outcomes of MM patients requiring dialysis as a consequence of MM, mostly including small numbers of patients on dialysis.4, 5, 6, 7, 8 Moreover, the use of high cut-off hemodialysis to rapidly reduce the load of nephrotoxic light chains may provide some additional benefit in patients requiring dialysis when treated with bortezomib-based therapies, but the reported results of two randomized studies are controversial.9, 10 Thus, we analyzed the outcomes of 52 consecutive NDMM with RI requiring dialysis, which were managed and treated in a single center, to provide data on response to therapy, dialysis discontinuation and survival in unselected patients, outside the context of clinical trials.

Evaluation of minimal residual disease using next-generation flow cytometry in patients with AL amyloidosis

Evaluation of minimal residual disease using next-generation flow cytometry in patients with AL amyloidosis Efstathios Kastritis , Ioannis V. Kostopoulos , Evangelos Terpos, Bruno Paiva, Despina Fotiou, Maria Gavriatopoulou, Nikolaos Kanellias, Dimitrios C. Ziogas, Maria Roussou, Magdalini Migkou, Evangelos Eleutherakis-Papaiakovou, Ioannis P. Trougakos, Ourania Tsitsilonis and Meletios A. Dimopoulos

Increased circulating VCAM-1 correlates with advanced disease and poor survival in patients with multiple myeloma: reduction by post-bortezomib and lenalidomide treatment

Circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins were prospectively measured in 145 newly-diagnosed patients with symptomatic myeloma (NDMM), 61 patients with asymptomatic/smoldering myeloma (SMM), 47 with monoclonal gammopathy of undetermined significance (MGUS) and 87 multiple myeloma (MM) patients at first relapse who received lenalidomide- or bortezomib-based treatment (RD, n=47; or VD, n=40). Patients with NDMM had increased VCAM-1 and ICAM-1 compared with MGUS and SMM patients. Elevated VCAM-1 correlated with ISS-3 and was independently associated with inferior overall survival (OS) (45 months for patients with VCAM-1 >median vs 75 months, P=0.001). MM patients at first relapse had increased levels of ICAM-1 and L-selectin, even compared with NDMM patients and had increased levels of VCAM-1 compared with MGUS and SMM. Both VD and RD reduced dramatically serum VCAM-1 after four cycles of therapy, but only VD reduced serum ICAM-1, irrespective of response to therapy. The reduction of VCAM-1 was more pronounced after RD than after VD. Our study provides evidence for the prognostic value of VCAM-1 in myeloma patients, suggesting that VCAM-1 could be a suitable target for the development of anti-myeloma therapies. Furthermore, the reduction of VCAM-1 and ICAM-1 by RD and VD supports the inhibitory effect of these drugs on the adhesion of MM cells to stromal cells.

Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies

Liquid biopsyis being integrated into cancer diagnostics with profound therapeutic implications. However, its role in Waldenström’s Macroglobulinemia (WM) and IgM monoclonal gammopathies is still unclear. In this study, we evaluated the role of peripheral blood (PB) cell-free DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 of patients with IgM monoclonal gammopathies. Paired bone marrow (BM) tumor DNA (tDNA) and PB cfDNA samples from 98 patients (9 MGUS, 45 with WM in remission, 44 with smoldering WM, newly diagnosed or relapsed WM) and 10 controls with non-IgM monoclonal gammopathies were analyzed. Regarding MYD88L265P mutation, 76 patients had paired tDNA and cfDNA informative samples. Among patients with WM in remission, 65% harbored the MYD88L265P mutation, whereas the corresponding percentage among smoldering/newly diagnosed or relapsed WM was 92%. The overall concordance rate was 94% (72/76). For CXCR4 mutations, 65 patients had paired informative tDNA and cfDNA samples. The overall concordance rate was 90% (59/65). All controls had wild-type MYD88 and CXCR4. In conclusion, PB cfDNA is a useful, minimally invasive, cost-effective, and time-effective tool for the identification of the presence of MYD88 and CXCR4 mutations in patients with IgM monoclonal gammopathies avoiding unnecessary BM assessment.