Outcome of Soft-Tissue Plasmocytomas in Newly Diagnosed Multiple Myeloma Patients Treated with New Drugs
Authors: Montefusco Vittorio , Gay Francesca , Spada Stefano , De Paoli Lorenzo , Di Raimondo Francesco , Ribolla Rossella , Musolino Caterina , Patriarca Francesca , Musto Pellegrino , Galieni Piero , Cavo Michele , Ballanti Stelvio , Nozzoli Chiara , Cascavilla Nicola , Ben-Yehuda Dina , Nagler Arnon , Hajek Roman , Offidani Massimo , Liberati Anna Marina , Corradini Paolo , Boccadoro Mario 
Published: October 2019

Abstract
Introduction
Multiple myeloma (MM) can be associated with paraskeletal (PP) or extramedullary (EMP) plasmocytomas (PL). Although PLs are relatively frequent, even at diagnosis, our knowledge on the subject mainly relies on small case series or single center experiences. Remarkably, little is known regarding the role of new drugs on MM with PL.
Aim
To perform a meta-analysis of 8 EMN-GIMEMA studies focused on the description of PLs characteristics, clinical outcome, and response to new drugs. The trials involved in this meta-analysis have the following identification codes: EUDRACT 2005-00473041, NCT01093196, NCT01063179, NCT01091831, NCT01857115, NCT01190787, NCT00551928, NCT01346787.
Patients
A total of 2332 newly diagnosed MM patients have been included in the analysis, and 267 (11.4%) had a PL, defined as PP in 243 (10.4%), EMP in 12 (0.5%), and not classified in 12 (0.5%) patients. PLs were evaluated with different techniques as PET, CT, NMR or physical examination accordingly to their site and local guidelines. PP and EMP were single in 195, and multiple in 60 cases, and their median size was 4 cm (range 1-26 cm). Median age at diagnosis was 68 years (range 18-87) in PL, and 69 years (range 25-91) in non-PL patients; male patients were 149 (55.8%) in PL and 1007 (48.8) in non-PL patients. ISS stage in PL and non-PL patients was as follows: stage I in 119 (44.6%) and 682 (33.0%), stage II in 89 (33.3%) and 792 (38.3%), stage III in 38 (14.2%) and 508 (24.6%), unknown in 21 (7.8%) and 83 (4.0%) patients, respectively. Cytogenetics was available in 166 PL, and 1528 non-PL patients, and high risk status, defined as having t(4;14) or t(14;16) or del(17p), was observed in 51 (30.7%) PL, and 446 (21.6%) non-PL patients. PL and non-PL patients received treatment with the following drugs: bortezomib in 65 (24.3%) and 598 (29.0%), lenalidomide in 182 (68.1%) and 1366 (66.1%), and carfilzomib in 20 (7.5%) and 101 (4.9%), respectively. Autologous stem cell transplantation (ASCT) was performed in 112 (41.9%) PL and 782 (37.9) non-PL patients. PL and non-PL patients received maintenance in 108 (40.4%) and 815 (39.5%), continuous treatment in 128 (47.9%) and 1007 (48.7%), and fixed-duration treatment in 31 (11.6%) and 243 (11.7%) cases, respectively.
Results
With a median follow-up of 62 months (IQ range 34-75) in PL and 65 months (IQ range 40-77) in non-PL patients, 4-years overall survival (OS) was 56% in PL and 67% in non-PL patients (p<0.001). In multivariate analysis for OS the presence of PL confers a HR 1.41 (95% CI, 1.17-1.71), high risk cytogenetics a HR 1.68 (95% CI, 1.44-1.96), ISS III vs I HR 2.36 (95% CI, 1.98-2.82), while ASCT a HR 0.78 (95% CI, 0.63-0.98). Four-years OS was not affected by the PL size, both considering a 3 cm threshold (58% >3 cm PL, 53% ≤3 cm PL vs 67% in non-PL), and a 5 cm threshold (55% >5 cm PL, 57% ≤5 cm PL vs 67% in non-PL), neither by the number of PLs (58% single PL, 50% multiple PLs vs 67% in non-PL), or the onset site (57% PP, 55% EMP vs 67% in non-PL). Four-years OS in PL patients treated with either bortezomib or carfilzomib was 44%; it was 56% in patients treated with lenalidomide; in non-PL patients was 62% when treated with bortezomib or carfilzomib, or 65% when treated with lenalidomide. Four-year progression-free survival (PFS) was 26% in PL and 27% in non-PL patients. In patients that received maintenance, the 4-years PFS from maintenance start was 24% in PL and 30% in non-PL patients. When considering the PFS-2, i.e. the PFS calculated from the treatment start to the time of second relapse/progression, the median time was 42.3 months (95% CI, 36.3 - 51.5) in PL and 46.4 months (95% CI, 44.1 - 48.9) in non-PL patients.
Conclusions
Our meta-analysis studied the largest number of newly diagnosed MM patients with PL so far reported. We observed that in patients treated with new generation therapies incorporating new drugs, the detrimental effect of PL at diagnosis is limited. The 4-years OS is modestly reduced for PL patients, while we observed that PSF and PFS-2 were similar in PL and non-PL patients, suggesting that effective treatment can overcome the unfavorable prognostic significance of PLs. We also observed that lenalidomide is effective in patients with MM and PL, as are bortezomib and carfilzomib.

Disclosures
Montefusco: Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Gay:Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. De Paoli:Gilead: Other: Advisory Board; Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Patriarca:Janssen: Other: advisory role; Celgene: Other: advisory role & travel, accommodations, expenses; MSD Italy: Other: advisory role; Medac: Other: travel, accommodations, expenses; Jazz: Other: travel, accommodations, expenses. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ballanti:BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Corradini:Gilead: Honoraria, Other: Advisory Board & Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer. Boccadoro:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.