Immunotherapy in Multiple Myeloma: Experience of the Multiple Myeloma Gimema Lazio Group
Authors: Vozella Federico , Siniscalchi Agostina , Rizzo Manuela , Za Tommaso , Antolino Giusy , Coppetelli Ugo , Piciocchi Alfonso , Andriani Alessandro , Annibali Ombretta , De Rosa Luca , Cimino Giuseppe , La Verde Giacinto , De Stefano Valerio , Cantonetti Maria , Caravita di Toritto Tommaso , Foà Robin , Petrucci Maria Teresa 
Published: October 2019

Abstract
Introduction .Treatment of multiple myeloma (MM) patients (pts) has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivatives (IMiDs). Despite the improvement of pts' outcome due to these drugs, MM remainsan incurable disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment. Almost all pts eventually relapse despite their responses to PI, IMiDs or both. Recently, one further therapeutic option for MM patients is represented bydaratumumab, an anti-CD38 monoclonal antibody approved alsofor heavily pre-treated pts who have exhausted all other therapeutic options.
Patients and Methods. We report the experience of the Multiple Myeloma GIMEMA Lazio Group in 50 relapsed/refractory MM pts treated with daratumumab as monotherapy. Twenty-nine pts (58%) were men and 21 (32%) women. According to the ISS,24 pts (48%) were ISS I, 11 (22%) ISS II, 7 (14%) ISS III and 8(16%)not evaluable. According toDurie& Salmon, 20 pts (40%) were 1 A, 2 (4%) 1 B, 12 (24%) II A, 1 (2%) II B,7 (14%) III A, 3 (6%) III B and 5 (10%) not evaluable. Isotype IgG-k was found in 21 pts (42%), IgG-λ in 13 (26%), IgA-k in 6 (12%), IgA-λ in 3 (6%), micromolecular k in 5 (10%) andmicromolecular λ in 2 (4%). Median age was 62.3 years (range, 43.1 - 85.7); 32 pts (64%) were refractory to the last line of therapy; 26 (52%) had previously received a stem cell transplant (13 single autologous, 12 tandem autologous and one an autologous followed by an allogeneic transplant). After a median follow-up from diagnosis of 54.5 months (range 1.0 - 203.0) and a median of 3 previous lines of therapy (range 2 - 8), pts received a median of 3 cycles (range 1 - 23) of daratumumab.
Results.Forty-seven pts (94%) performed at least one cycle and were evaluable for response. The overall response rate was 74%; in particular, 2 pts obtained a CR (4.2%), 3 pts a VGPR (6.3%), 17 pts a PR (36.2%) and 15 pts a SD (32%), while 10 pts (21.3%) presented a PD. After a median follow-up of 5.3 months (range 1 - 31) ,24 pts(65%) were still in response and alive, one pt (5.8%) died in PR due to post-allograft GVHD and 12 (32%) experienced a PD (1 CR, 1 VGPR, 6 PR and 4 SD). Seven (19%) pts died and 30 (81%) are still alive. With regard to the 3 pts not evaluable for response, 2 died early and 1 has not yet completed the first cycle. The median time to response, duration of response, progression-free survival and overall survival were 1.5 months (range 1.0 - 6.0), 6.7 months (95% CI, 4.14 - 14.21), 5.7 months (95% CI, 3.26 - 13.75) and 22.5 months (95% CI, 11.6 - 36.1), respectively. Daratumumab was well tolerated; the most common adverse events, of any grade, were infections in 20 pts (42.0%) and anaemia in 21 pts (44.0%), which did not lead to treatment discontinuation. Infusion-related reactionswere observed in 7pts (14.8%), grade I-II (4 pts), grade III (3 pts).
Conclusions.Daratumumab monotherapy is an effective strategy for heavily pre-treated and refractory pts with multiple myeloma, with a favorable safety profile. This treatment option needs to be considered for pts not eligible for combination therapy of daratumumab with bortezomib or lenalidomide, recently approved also in our country.

Disclosures
Vozella: Takeda Oncology; Amgen: Honoraria. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Petrucci:Takeda Oncology; Amgen; Celgene; BMS; Janssen Cilag: Honoraria, Other: Advisory Board.