Venous thromboembolism prophylaxis and multiple myeloma patients in real-life: Results of a large survey and clinical guidance recommendations from the IFM group.

Venous thromboembolism (VTE) remains a critical issue in the management of patients with multiple myeloma (MM), particularly when immunomodulatory drugs (IMiDs) combined with dexamethasone therapy are being prescribed as first-line and relapse therapy. One possible explanation for the persistent high rates of VTE, is the use of inappropriate thromboprophylaxis strategies for patients starting antimyeloma treatment. To tackle the issue, the Intergroupe francophone du myélome (IFM) offered convenient guidance for VTE thromboprophylaxis in MM patients initiating systemic therapy. This guidance is mainly supported by the results of a large survey on the clinical habits regarding VTE of physicians who are substantially involved in daily care of MM patients. VTE prophylaxis should be considered for all patients treated with IMiDs in combination with dexamethasone, in the absence of significant comorbidities, such as renal failure or bleeding risk. Anticoagulant should be preferred to antiplatelet agents for thromboprophylaxis. Despite the absence of large randomized controlled trials comparing those attitudes/options, available data on direct oral anticoagulants, which are already used in daily management of MM patients, are consistent with their potential usefulness for VTE prophylaxis in such patients. However, in order to implement a personalized continuous improvement strategy, clinicians must to be organized to collect all the data regarding this management. In other situations, thromboprophylaxis should be evaluated by using risk models and after careful evaluation of the risk/benefit ratio.

Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA.

In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P < 0.0001) and frail (NR vs 30.4 months; HR, 0.62; P = 0.003). Improved rates of complete response or better and minimal residual disease (10-5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.

Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial.

PURPOSE: Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile. PATIENTS AND METHODS: IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose. RESULTS: Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response. CONCLUSIONS: The MTD dose of carfilzomib was 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.

Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study.

The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism-PE, or symptomatic proximal or distal deep vein thrombosis-DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.