Real-world Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma in the Novel Therapeutic Era: A study of the Greco-Israeli Collaborative Myeloma Working Group

Macrofocal Multiple Myeloma (MFMM) was described as a distinct entity of Multiple Myeloma (MM), characterized by young age (≤40), multiple lytic lesions, limited bone marrow (BM) infiltration, absence of anemia, renal insufficiency or hypercalcemia, and favorable prognosis. Our aim was to investigate the incidence, characteristics and outcome of a large cohort of patients, regardless of age, meeting the criteria of MFMM and treated mainly with novel therapies. Patients were considered to have MFMM if BM infiltration was <20% and they had multiple lytic lesions without anemia, renal insufficiency or hypercalcemia; among 4650 MM patients (3%) registered in the MM databases of Greek and Israeli centers during 2001-2017, we identified 140 patients with MFMM (M/F: 93/47, median age: 61, range: 26-89, IgG: 86, IgA: 12, light chain: 21, IgD: 4, non-secretory: 16, IgM: 1). Twice the number of patients with typical MM treated during the same period were used for comparisons; 60% of MFMM patients were <65 years, whereas only 7/140 were ≤40 years; 68% had good performance status and 70% had advanced bone disease. Plasmacytomas present at diagnosis or during disease course were more common in MFMM compared with standard myeloma (68% vs. 15%; p<0.05). Solitary bone plasmacytoma (SBP) preceded MFMM diagnosis in 14%. Adverse prognostic parameters (i.e. high LDH, advanced age, high β2 microglobulin, high risk cytogenetics) and immunoparesis were infrequent in patients with MFMM compared with controls (p<0.05). According to the International staging system (ISS) 4% of patients with MFMM were stratified in advanced stage (ISS3) whereas none of the patients was classified in the revised-ISS3, both displaying significant difference compared with controls (ISS3:29% and R-ISS3:13%; p<0.05); 90% of patients with MFMM received novel drugs, mainly bortezomib-based (PI-based) regimens and 47% underwent autologous transplantation upfront; 90% achieved an objective response (ORR) and 70% had at least very good partial response (vgPR), both significantly higher compared with typical myeloma (p<0.05). After a median follow-up of 52 months, 33 patients have died (disease progression:19/33). Early deaths (i.e. <12 months) were uncommon (5% of patients). Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (p<0.001); PI-based therapy upfront, was the only independent predictor for OS in the multivariate analysis (HR: 3.9; p<0.001). In conclusion, MFMM is a distinct entity characterized by limited bone marrow involvement, advanced bone disease and frequent development of plasmacytomas. In an appreciable number of patients, SBP precedes MFMM diagnosis suggesting a different natural history of MFMM; MFMM may occur regardless of age and it has less often adverse prognostic features. Patients with MFMM enjoy high response rates and prolonged OS when treated with PI-based therapies.