Feasibility and Benefit of Molecularly-Informed Enrollment into Personalized Therapies or Early Phase Trials for Patients with Relapsed or Refractory Multiple Myeloma
Authors: Assi Tarek , Michot Jean-Marie , Ibrahim Toni , Le Bras Fabien , Belhadj Karim , Lazarovici Julien , Ghez David , Rossignol Julien , Vergé Veronique , Arfi-Rouche Julia , Cotteret Sophie , Massard Christophe , Soria Jean-Charles , Danu Alina , Ribrag Vincent 
Published: October 2019

Abstract
Background: Treatments of patients with relapsed or refractory multiple myeloma (r/r MM) remains a challenge and there is no molecular-informed personalized therapies available in this context. Cytogenetics and next-generation sequencing (NGS) panels can rapidly identify recurrent molecular abnormalities, thus helping to orient patients (pts) in appropriate targeted therapies or clinical trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with a better outcome.
Methods: From 2013 to 2018, all pts with r/r MM screened for molecular and/or cytogenetics before enrollment in early clinical trials (eaCTs) were included. Molecular screening methods included bone marrow cytogenetics, sanger assays for BRAF screening or next-generation sequencing on sorted CD138 positive bone-marrow cells. The actionable targets and therapies related were BRAF V600E mutation with BRAF inhibitor and t(11;14) with BCL2 inhibitor. The objective were to evaluate the feasibility and potential benefit of using tumor genotyping to orient patients with molecularly-informed multiple myeloma in personalized therapies or eaCTs. The tumor responses rates, median duration of treatments and overall survival (OS) were assessed in molecularly oriented (MO) and non-molecularly oriented (non-MO) pts. Efficacy was evaluated using International Myeloma Working Group Uniform Response Criteria.
Results: Forty-six pts with r/r MM were enrolled, mean age was 66 y (range 52-81), median of previous lines of therapies was 3 (range 1-8). Prior systemic therapies included immunomodulatory agents (n=46, 100%), alkylating agents (n=43, 94%) or proteasome inhibitors (n=44, 95%), and 28 (62%) pts had previously received auto stem-cell transplant. Identification of potentially actionable targets was found in 13 (28%) pts, including 8 (17%) pts with t(11;14) and 5 (11%) pts with BRAF V600E mutations. Eight (17%) out of the 46 pts were treated in molecularly oriented (MO) personalized therapies or eaCTs, and 38 (83%) pts were treated in non-MO therapies or eaCTs. The MO pts received BRAF inhibitor alone or in combination with MEK inhibitor (n=5), or BCL2 inhibitor given in combination with bortezomib and dexamethasone (n=3). The overall response rate was 75% (4 VGPR, 1 PR and 1 CR) in MO pts versus 11% (4 PR) in non-MO pts (p<0.0001). The median decrease of serum monoclonal component was -94% (range: -99; -55) in MO pts versus -4% (range: -72; +967) in the non-MO pts (p<0.0001). The median durations of treatment were 7.3 [CI95: 0.5-29.0] months and 2.3 [CI95: 1.7-8.0] months in MO and non-MO pts, respectively (p=0.009). The median OS were not reached in MO pts and 43 months in non-MO pts (p=0.76; HR=0.8 [CI95: 0.2-3.4]).
Conclusions: Molecular-oriented treatments of relapse or recurrent multiple myeloma can be associated with higher responses rates and prolonged durations on therapy. Accelerating the use of prospective genomics tumor molecular portraits may increase the chances of precision medicine for patients with relapse or recurrent multiple myeloma.

Disclosures
Le Bras: Amgen: Consultancy. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Soria:Medimmune: Employment. Ribrag:Amgen: Research Funding; Gilead: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Incyte Corporation: Consultancy; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; argenX: Research Funding; MSD: Honoraria; pharmamar: Other: travel; Servier: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel.