Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials

Abstract

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs (IMiDs) are at high venous thrombosis (VTE) risk, but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n=1936) and Myeloma XI (n=4358), phase III randomized controlled trials for NDMM, treating transplant-eligible and ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, compared to CTD (cyclophosphamide, thalidomide and dexamethasone), transplant-eligible patients randomized to CVAD induction (cyclophosphamide, vincristine, doxorubicin and dexamethasone) had higher VTE risk (22.5%(n=121/538) vs 16.1%(n=89/554), aHR:1.46,95%CI:1.11-1.93). For transplant-ineligible patients, compared to MP (melphalan and prednisolone), patients randomized to CTDa (attenuated CTD) induction had higher VTE risk (16.0%(n=68/425) vs 4.1%(n=17/419), aHR:4.25,95%CI:2.50-7.20). In Myeloma XI, there was no difference in VTE or arterial thrombosis risk between transplant-eligible pathways, CRD (cyclophosphamide, lenalidomide and dexamethasone) and CTD (VTE:12.2%(n=124/1014) vs 13.2%(n=133/1008), aHR:0.92,95%CI:0.72-1.18; arterial events:1.2%(n=12/1014) vs 1.5%(n=15/1008), aHR:0.80,95%CI:0.37-1.70). For transplant-ineligible patients, there was no difference in VTEs between CRDa (attenuated CRD) and CTDa (10.4%(n=95/916) vs 10.7%(n=97/910), aHR:0.97, 95%CI:0.73-1.29). However, arterial risk was higher with CRDa than CTDa (3.1%(n=28/916) vs 1.6%(n=15/910), aHR:1.91,95%CI:1.02-3.57). Thrombotic events occurred almost entirely within 6m of treatment initiation. Thrombosis was not associated with inferior progression-free or overall survival (OS), apart from inferior OS for patients with arterial events (aHR:1.53, 95%CI:1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated IMWG thrombosis prevention recommendations and compared to Myeloma IX, more patients were on thromboprophylaxis (80.5% vs 22.3%) with lower VTE rates for identical regimens (CTD:13.2% vs 16.1%, CTDa:10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting new approaches are needed.

Does aspirin prevent venous thromboembolism?

“…30,31 In newly diagnosed multiple myeloma, the VTE rate is estimated to be at least 10% with the majority of events occurring in the first 6 months of induction. 32 A systematic review of 6 studies, encompassing 1125 patients receiving lenalidomidebased therapy, demonstrated a 10.7% total risk of VTE with aspirin compared with 1.4% with LMWH in multiple myeloma patients. 33 More evidence is needed to determine the best strategy to reduce the risk of arterial and venous thrombosis in myeloma patients starting immunomodulatory drugs.…”

A Real-Life Survey of Venous Thromboembolic Events Occurring in Myeloma Patients Treated in Third Line with Second-Generation Novel Agents

“…A retrospective French study conducted on 236 patients treated with an IMiDs-based regimen demonstrated that only 43% high-risk and 34% low-risk patients received a thrombo-prophylaxis [19]. Another study evaluated 80 MM cases with treatment-related VTE with 85% of them classified as high risk, but only 19% had received an appropriate prophylaxis according to IMWG [50]. The failure to adhere to the recommendations of the guidelines was also recorded in the context of controlled clinical studies: the English study Myeloma XI included treatment with IMiDs at diagnosis, an assessment of the thrombotic risk in accordance with the IMWG guidelines and consequently a prophylaxis with LMWH for high risk patients and with ASA for low risk patients.…”

“…The failure to adhere to the recommendations of the guidelines was also recorded in the context of controlled clinical studies: the English study Myeloma XI included treatment with IMiDs at diagnosis, an assessment of the thrombotic risk in accordance with the IMWG guidelines and consequently a prophylaxis with LMWH for high risk patients and with ASA for low risk patients. Despite these recommendations, almost 20% of patients did not receive any prophylaxis and 23% of patients classified as high risk underwent prophylaxis with ASA rather than LMWH [ 50 ]. A recent review has confirmed that ASA was the most frequent prophylaxis in patients treated with lenalidomide, no matter the individual risk assessment [ 44 ] and the most recent guidelines from NICE (National Institute for Health and Care Excellence) suggest that in patients with myeloma who are receiving treatment with thalidomide, lenalidomide or pomalidomide and steroids, it is possible to choose either aspirin or prophylactic dose of LMWH (NICE 2018 ).…”

“…Concerning ixazomib, elotuzumab and daratumumab, VTE is not reported as an adverse event for these drugs; thus, no thromboprophylaxis is currently recommended [5,7,48]. However, recommendations on next generation myeloma drugs are derived from clinical trials where patients are selected and do not fully reflect the heterogeneity of patients in the real-life setting, in the presence of multiple risk factors for VTE [17,[48][49][50].…”

Evolution or revolution in multiple myeloma therapy and the role of the UK

“…Despite extensive use of systemic anticoagulants thromboembolic events remain a problem particularly in IMiD-treated patients. 84 Happily, despite the trend to ever more intensive therapy quality of life does not appear to be adversely affected. 22,85 Longer survivals have meant that extra-medullary disease (EMD) is seen more often, usually as a late finding, often containing a new clone of the disease, and these progressions are frequently difficult to manage.…”