Daratumumab after Allogeneic Hematopoietic Stem Cell Transplantation in Multiple Myeloma: Safety and Efficacy. a Retrospective Study from the Cmwp EBMT
Authors: Vincent Laure , Gras Luuk , Ceballos Patrice , Finke Jürgen , Passweg Jakob , Robin Marie , Rosinol Laura , Minnema Monique C. , Teipel Raphael , Van Deosum JA , Haenel Mathias , Lenain Pascal , Forcade Edouard , Koenecke Christian , Ducastelle Sophie , Sanz Jaime , Schroyens Wilfried , Zuckerman Tsila , Ladetto Marco , Koster Linda , de Wreede Liesbeth C. , Hayden Patrick J , Schönland Stefan , Yakoub-Agha Ibrahim , Beksac Meral 
Published: February 2021

BACKGROUND
Allogeneic stem cell transplantation (allo-HSCT) is a treatment option for high-risk multiple myeloma (MM), especially in patients who relapse early following auto-HSCT. Though there is a proven graft versus myeloma effect, relapse remains common. Daratumumab (Dara) is a humanized monoclonal anti-CD38 antibody approved for both newly diagnosed and relapsed MM. Its mechanisms of action include direct anti-MM activity (CDC, ADCC, ADCP, apoptosis induction) and indirect anti-MM activity depleting CD38+ immunosuppressive regulatory cellsand promoting T-cell expansion and activation. The combination of its mechanism of action and lack of toxicity makes Dara a good candidate for use in the post-allo-HSCT setting. However, its immune effects (decrease in CD38-positive immune suppressor cells, including Tregs, NK cells, regulatory B cells, and myeloid-derived suppressor cells) may interfere with post-allo anti-MM effects. Nikolaenko et al (Clin Lymph Myeloma Leuk 2020) reported that aGVHD developed in five (15%) of 34 patients given Dara (mostly in combination) as treatment for post-allo relapse and the median PFS was 4.5 months.
METHODS
We performed a retrospective study to evaluate the safety and efficacy of Dara post-allo-HSCT). Patients with MM having received at least one Dara infusion at any time after allo-HSCT were included. Key exclusion criteria were plasma cell leukemia and AL amyloidosis.
RESULTS
A total of 121 patients who received Dara after a first allo-HSCT were identified in the EBMT database. The year of allo-HSCT ranged from 2004 to 2019, median 2014. Allo-HSCT was performed at a median (range) of 34 (6-172) months after the diagnosis of myeloma. The stem cell source was PB in 89%, 37% were matched related donor and 39% matched unrelated donor. Conditioning was reduced intensity in 72% and myeloablative in 28%. Disease status at allo-HSCT was CR in 9%, VGPR in 35 %, PR in 43%, SD/MR in 7% and progression in 6%.
The median age (range) at the first Dara infusion was 55 (32-71) yrs with a male to female distribution of 70/51. Dara was administered either alone (n=70) or in combination with other anti-myeloma directed therapy (n=51). The first dose of Dara was given at a median (range) of 30 (1-173) months post-allo-HSCT. Fifteen patients started Dara in the first 6 months after allo-HSCT, 50% of patients in the first 2.5 years, 22% in 2.5 to 5 years, and 28% more than five years after allo-HSCT.
Among patients with available data, 45% had at least one serious infection: bacteremia 22% (including 15% ³ grade 3), septic shock 5% (all ³ grade 3), pneumonia 31% (including 21% ³ grade 3), urine infections 7%, CMV reactivation 7% and EBV reactivation 6%.
In the first 100 days after starting Dara, aGVHD worsened in 2% (0-4%). The incidence of cGvHD within two years was 5% (1-9%).
Dara had been stopped due to adverse events in 10% (95% CI 5-16%) by 24 months. At the same timepoint, 70% (60-79%) of patients had stopped because of progression.
The best response to Dara was sCR/CR in 11%, VGPR in 12%, PR in 25%, SD/MR in 20% and progression in 33%. The best response was obtained at a median of 81 days (min-max 7-851 days) after starting Dara. The proportion of at least stable disease was higher when DLI treatment (n=37) was given pre-Dara.
The median follow-up from the first dose of Dara was 26.8 months (95% CI 22.3 to 31.1). After starting Dara, the median PFS was 6.5 months, the median TTNT 19.3 months and median OS 21.6 months.
Extra-medullary progression post-Dara was observed in 43% of patients for whom there was available data. Bone plasmacytomas were reported in 63%, soft tissues in 33% and both in 4% of cases.
In total 13% of patients received a median of two DLI after starting Dara. 47% of patients received other anti-myeloma medications after Dara and 26% received radiotherapy.
CONCLUSIONS
The use of Dara post-allo-HSCT resulted in stable disease or better in 67% of patients. As reported previously, infections appeared to be common. Compared to the recently published data from Nikolaenko et al, there were fewer cases of aGVHD post-Dara in this retrospective analysis. The PFS were similar in both studies (4.5 vs. 6.5 months) as well as OS (17,4 v 21,6 months). A high proportion of 43% extra-medullary disease progression was observed in the current study which was not reported in the only similar study. Based on these data, Dara treatment for relapsing patients after allo-HCT creates no safety concerns and provides acceptable efficacy

Disclosures
Vincent: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Minnema:Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Teipel:janssen: Honoraria. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Sanofi: Other: Travel grant for congress; Novartis: Other: Travel grant for congress. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Beksac:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.