Deborah Martinez-Baños

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.

Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.

Aspirin as thromboprophylaxis in myeloma

Thrombosis is a frequent complication in patients with multiple myeloma [1]. Symptomatic thrombosis, generally occurring early in the course of treatment, has been reported in the context of thalidomide and corticosteroids in 17% of the cases [2]; alkylating agents can substantially increase the frequency to 28% [3–5]. Up to this writing, there are no completed randomised studies that address the best antithrombotic therapy for patients with multiple myeloma. Therefore, clinicians have adopted prophylaxis according to indirect data from clinical trials that have not been primarily designed for this purpose. For example, in patients with previously untreated symptomatic myeloma that received thalidomide with dexamethasone, thrombosis occurred in 25% of the first 24 patients including those who were treated with warfarin 1 mg PO daily. Therefore, the 16 subsequent patients received full dose warfarin or low-molecular weight heparin with no further thrombosis [6]. Although the endpoint of this study was not thromboprophylaxis at all, the evidence suggests that full dose anticoagulation with warfarin or LMWH is effective against thrombosis related to thalidomide/dexamethasone. We published the results of low-dose aspirin as thromboprophylaxis in three series of MM patients that were treated with thalidomide or lenalidomide in combination with other drugs [7]. The first cohort was treated with clarithromycin, thalidomide and dexamethasone. Midway through the trial, 9% of thromboembolic events were reported; in consequence, low-dose aspirin (81 mg) was instituted. This approach negated the occurrence of any further thrombosis. The second cohort compared thalidomide/dexamethasone (arm A) to dexamethasone alone (arm B). Mandated low-dose aspirin was prescribed only to arm A patients. Thrombotic events were similar in both arms. The third cohort received clarithromycin, lenalidomide and dexamethasone and mandated low-dose aspirin, nine patients developed thrombosis and five of them were clearly associated to aspirin interruption or poor compliance. We proposed that aspirin may be an adequate agent for prophylaxis. Conclusions from this publication emphasise the need for prospective, randomised studies to address the different strategies of anticoagulation prophylaxis for these patients, as well as evaluate risk groups before initiating therapy. Because of the lack of appropriate evidence to address this issue, recommendations in myeloma patients receiving thalidomide or lenalidomide have recently been published derived from data reported in thrombosis and cancer, thrombosis and plasma cell dyscrasia, thrombosis and immunomodulatory drugs and prophylaxis in non-myeloma patients (other medical and surgical conditions) and the available data about prophylaxis in myeloma patients treated with IMIDs [8], as well as a review of thalidomide for treatment of multiple myeloma [9]. In summary, the panel proposed a risk assessment model where clinicians should define (1) individual risk factors for thrombosis associated with IMIDs treatment (age, history of VTE, central venous catheter, immobilisation, surgery, inherited thrombophilia, and co-morbidities (infections, diabetes, cardiac disease); and (2) myeloma-related risk factors (diagnosis and hyperviscosity). The panel accepted aspirin as an adequate prophylaxis for patients with

Thalidomide, Intravenous Cyclophosphamide and Dexamethasone (ThaCyDex) in Newly Diagnosed Multiple Myeloma: Response to Therapy, Time to Progression and Survival

dexamethasone [Rd]) trials demonstrated superior overall survival (OS) with carfilzomib-based regimens in patients with relapsed or refractory multiple myeloma (RRMM) compared with standard therapies. Patients: Baseline disease and patient characteristics were generally balanced between the treatment groups in patients with RRMM with prior autologous stem cell transplant (ASCT) in ASPIRE (n1⁄4446) and ENDEAVOR (n1⁄4538). Main Outcomes Measures: OS was evaluated based on prior ASCT status in patients with RRMM in this subgroup ad-hoc analysis of ENDEAVOR and ASPIRE. Results: In ENDEAVOR, a consistent OS benefit was observed for Kd56 versus Vd across ASCT subgroups, with a more evident benefit in the no prior transplant groups. In ASPIRE, patients with prior ASCT treated with KRd had an 11.4-month improvement in median OS and, for those with first relapse after ASCT, an 18.6month improvement in median OS (58 months versus 39 months; HR1⁄40.71 [0.48, 1.0]). Consistent with previous reports, adverse events in the updated safety analysis were comparable between patients with and without prior ASCT (Hari et al, Leukemia 2017 Apr 25). Conclusions: The results of this subgroup ad-hoc analysis suggest carfilzomib-based regimens led to clinically meaningful improvements in survival for patients with prior ASCT. For patients who were treated at first relapse, more differences were observed for Kd56 versus Vd in transplant-ineligible patients and KRd versus Rd after ASCT. The ASPIRE and ENDEAVOR studies were supported by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.