Outcome of BCMA Bite (AMG420) Therapy in Relapse and Refractory Multiple Myeloma (RRMM) Patients
Authors: Topp Max S. , Duell Johannes , Mauser Mareike , Einsele Hermann 
Published: February 2021

Introduction
The B-Cell Maturation Antigen (BCMA) serves as a target for T cell directed therapy either by CAR-T or bispecific antibodies (BiAb's) in relapsed or refractory multiple myeloma patients. ITo this end we recently reported on the outcome of the BiAb's short half life BITE® molecule (AMG420//BI 836909) targeting BCMA in RRMM patients (NCT02514239), which resulted in ORR rate of 70% at a recommend dose level of 400 mg/d (Topp et al, Vol.38. JCO 2020). Here we report on the long term outcome of our patients with medium follow up of close to 3 years.
Methods
In the first in human dose escalation trial with the anti-BCMA BITE® molecule AMG420/42 patients were recruited and treated with 4 weeks on and two weeks off by continuous infusion. The primary end points were DLT and MTD. Secondary end points included response per International Myeloma Working Group 2006 including the objective response rate (ORR; partial response [PR], very good PR [VGPR], complete response [CR], minimal residual disease [MRD]-negative CR) and duration of response.
At our center, 23 out of 42 drug exposed study subjects were recruited and this is the reported outcome of this subgroup with respect to overall survial by ad hoc analysis (OS), progression free survival (PFS), the ORR rate, medium cycles given for non resonders versus responders, time of B-cell recovery in patients with long term control of their RRMM as well as additional safety events.
Results
We enrolled 23 patients out of 42 treated study patients of the Anti-BCMA BITE trial with AMG 420 in RRMM. Patients received treatment from May 2015 until June 2019 with a data cut off 3. August 2020. Among the 23 patients, who had on average 3,5 prior lines of therapy (range 2-9); 10 patients showed a response (7 CR including 5 stringent CR and 3 PR) starting from 6,5 mg/d to 400 mg/d.
The OS for the entire 23 patients is 34,9 months (range from 4 to 59), the median OS for the responders was 32 months (range from 26 to 42 months) and for the 13 non responders 39 month (4- 59) with a medium follow up of 35 months. Of note, the vast majority of patients in the early dose escalation proportion of the study did not responded whereas the patients in the last cohort at 400 mg/d showed a response of 70%.
The PFS was for the 10 responders 23,5 months, who received on average 7 cycles of AMG 420 with 4 patients completing 10 cycles. 2 patients are still in CR and one patient remains in continuous PR. Relapses were documented either medullary and/or extramedullary of patterns. For 5 responding patients a B cell recovery was observed on an average at 17 months after achieving a response. Post treatment recovery of B cells was seen at 6.3 months.
The initial safety event of increased rate of infectious diseases led to adaption of management guidelines by including mandatory herpes virus and PcP prophylaxis. For patients with respiratory infections IgG substitution every four weeks was applied until endogenous IgG recovery was documented. No long-term severe safety events were observed.
Discussion
Our report of the subgroup of patients treated at our institution demonstrates that these heavily pretreated cohort of RRMM patients had a durable response of 23,5 months after AMG420 BITE® therapy. Despite this small numbers and reporting of single institutional experience these results are encouraging in light of recent long term data of BCMA CAR-T therapy reporting on a PFS of less than 12 months. The data warrante further investigation of -BCMA targeted BiAB's as a treatment modality in RRMM patients.

Disclosures
Topp: Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Duell:Morphosys: Research Funding. Einsele:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau.