Thrombosis in Patients with Myeloma Treated in the Myeloma IX and Myeloma XI Phase III Randomized Controlled Trials

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