Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group
Authors: Katodritou Eirini , Kastritis Efstathios , Gatt Moshe E. , Cohen Yael C , Avivi Irit , Pouli Anastasia , Lalayianni Avgi , Lavi Noa , Delibasi Sossana , Kyrtsonis Marie-Christine , Michael Michalis D , Suriu Celia , Zektser Miri , Tzarfati Katrin Herzog , Vadikolia Chrysanthi , Maltezas Dimitrios , Zikos Panagiotis , Ganzel Chezi , Vaxman Iuliana , Aviv Ariel , Christoforidou Anna , Gavriatopoulou Maria , Shaulov Adir , Verrou Evgenia , Papanota Aristea-Maria , Fakinos Gabriel , Gkioka Annita Ioanna , Palaska Vasiliki , Triantafyllou Theodora , Konstantinidou Pavlina , Anagnostopoulos Achilles , Terpos Evangelos , Dimopoulos Meletios A 
Published: October 2019

Abstract
Macrofocal Multiple Myeloma (MFMM) has been described as a distinct entity of Multiple Myeloma (MM) characterized by young age, lytic lesions and limited bone marrow infiltration by clonal plasma cells (BMPCs), in the absence of other features of symptomatic MM (i.e. anemia, renal insufficiency and hypercalcemia). Few case studies have indicated a possible favorable prognosis of MFMM patients compared to patients with typical symptomatic MM. Our aim was to investigate the incidence, characteristics and outcome of patients with MFMM, under the light of modern therapeutic approach of MM. MFMM definition required: clonal BMPCs <20%, multiple lytic lesions, absence of anemia, renal insufficiency and hypercalcemia and 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). Most of patients with MFMM (60%) were <65 years; 68% had performance status 0-2 according to Eastern Cooperative group (ECOG) scale; 70% had advanced bone disease (>3 lytic lesions). In 20/140 (14%) patients bone plasmacytomas preceded MM diagnosis. In 95/140 (68%) patients bone, soft tissue or mixed plasmacytomas in multiple locations, were present at diagnosis or during MFMM course and this was significantly more frequent compared with standard MM. Median BMPCs infiltration was 14% (range 0-19%); immunoparesis was less common in MFMM (55% vs. 90% in standard MM). Elevated lactate dehydrogenase (LDH) and β2 microglobulin (β2Μ) ≥ 3.5mg/L were found in 9% and 20% of patients, respectively. Cytogenetics by fluorescence in situ hybridization (FISH) were available in 60% of patients and high-risk features were found in 11%; overall, adverse prognostic parameters (i.e. high LDH, advanced age, high β2Μ, high risk cytogenetics) were less common in patients with MFMM compared with others (p<0.05). According to the International staging system (ISS) patients were stratified as follows: ISS1:71%, ISS2: 25% and ISS3: 4%. Per Revised ISS the distribution was R-ISS1: 54%, RISS2: 46%, no R-ISS3). Induction therapy included novel agents in 90% of patients (bortezomib-based: 61%, thalidomide-based: 14%, bortezomib-lenalidomide-dexamethasone: 4%, lenalidomide-based: 11%); 47% underwent autologous transplantation (ASCT) upfront and 13% at 1st relapse. An objective response (ORR) was achieved in 90%: 70% had at least very good partial response (vgPR), 21% partial response, 6% stable disease and 3% had progressive disease; ORR and achievement of ≥vgPR were significantly higher compared with typical MM (p<0.05). After a median follow up of 52 months (95% CI: 40-64), 33 patients have died (MM progression: 19, lung infection: 8, other causes: 6). Early deaths (<12 months) observed in 5% of patients; 53 patients received 2nd line therapy (proteasome inhibitor-based or lenalidomide-dexamethasone: 79%) and 5 patients received only radiotherapy for plasmacytomas; early relapse (<12 months) was less common in MFMM compared with standard MM (p<0.05). Progression-free survival (PFS) and overall survival (OS) were 46 months (95% CI: 40-52) and 129 months (95% CI: 79-178) respectively, both significantly longer compared with typical MM treated during the same period (p<0.001). In the univariate analysis age <65, early stage disease (ISS1, R-ISS1), 1st line treatment with proteasome inhibitor (PI)-based regimens, ASCT, and standard risk cytogenetics predicted positively for OS in MFMM patients; treatment with PI-based therapies was the only independent predictor for OS in the multivariate analysis (HR: 3.9; p<0.001). In conclusion, MFMM is a rare entity of MM characterized by limited bone marrow infiltration, extended bone lesions and frequent presence of plasmacytomas, prior or during the diagnosis or the course of the disease. MFMM patients are younger have less often adverse prognostic features compared with standard MM and achieve high quality responses when treated with novel therapies. Treatment with PI-based regimens was the strongest predictor for OS in MFMM indicating that it is probably the best therapeutic option for these patients.

Disclosures
Kastritis: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.