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191 Evaluation of Minimal Residual Disease (MRD) By Next Generation Sequencing (NGS) Is Highly Predictive of Progression Free Survival in the IFM/DFCI 2009 Trial

Myeloma: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Amyloidosis and Related Plasma Cell Disorders
Sunday, December 6, 2015: 8:30 AM
Tangerine 2 (WF2), Level 2 (Orange County Convention Center)

Herve Avet-Loiseau, MD, PhD1*, Jill Corre2*, Valerie Lauwers-Cances, MD3*, Marie-Lorraine Chretien4*, Nelly Robillard, Engineer5*, Xavier Leleu, MD, PhD6, Cyrille Hulin, MD7*, Catherine Gentil, Engineer8*, Bertrand Arnulf9*, Karim Belhadj, MD10*, Sabine Brechignac, MD11*, Laurent Garderet, MD12, Lionel Karlin13*, Gerald Marit14*, Lotfi Benboubker15*, Frederique Orsini-Piocelle, MD16*, Bruno Royer, MD17,18*, Bernard Drenou, MD19*, Mourad Tiab, MD20*, Thierry Lamy, MD, PhD21, Margaret MACRO, MD22*, Paul G. Richardson, MD23, Kenneth C Anderson, MD24, Malek Faham, MD, PhD25, Thierry Facon26, Philippe Moreau27,28,29*, Michel Attal30 and Nikhil C. Munshi, MD31

1Unit for Genomics in Myeloma, Institut Universitaire du Cancer, Toulouse, France
2Institut Universitaire du Cancer, Toulouse, France
3CHU Toulouse, Toulouse, France
4Service Hematologie, CHU Dijon, Dijon, France
5CHU, Nantes, France
6Service des Maladies du Sang, Hopital Huriez, CHRU, Lille, France
7CHRU Hopitaux de Brabois, NANCY CEDEX, France
8CHU, Toulouse, France
9Hôpital Saint Louis, Paris, France
10CHU Henri Mondor, Creteil, France
11Hopital Avicenne, bobigny, France
12Hôpital Saint Antoine, Paris, France
13Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France
14CHU, Bordeaux, France
15CHU, Tours, France
16CHD, Annecy, France
17CHU, Amiens, France
18Hematology, Centre Hospitalier Universitaire, Amiens, France
19CH MULHOUSE, MULHOUSE, France
20Hopital la Roche Sur Yon, La Roche Sur Yon Cedex 9, France
21Haematology, CHU Pontchaillou, Rennes, France
22Hopital Cote De Nacre, Caen Cedex 9, France
23Division of Hematologic Malignancy, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
24The Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
25Adaptive Biotechnologies, South San Francisco, CA
26Maladies du Sang, Hôpital Claude Huriez, CHRU Lille, Lille, France
27Hopital Hotel Dieu Et Hme, Nantes Cedex 1, France
28Nantes University Hospital, Hôtel‐Dieu, Nantes, France
29chu, NANTES, France
30Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
31Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA

Evaluation of MRD in multiple myeloma (MM) is becoming an important trial endpoint, especially in young patients. With current intensive approaches, the complete remission (CR) rates are up to 70%, making conventional evaluations of response quite useless. More sensitive tools are mandatory. Two techniques may help investigators to reach this goal, flow cytometry (FCM) and NGS. We applied both techniques to the IFM part of the IFM/DFCI 2009 trial. Briefly, this trial enrolled 700 patients under 66 years of age who were randomized to receive either 8 cycles of VRD (Velcade®-Revlimid®-Dexamethasone) (arm A), or 3 VRD cycles, high-dose melphalan, followed by two consolidation VRD cycles (arm B). All patients received a lenalidomide maintenance for 12 months. A bone marrow MRD evaluation was planned before and after maintenance for all patients achieving at least very good partial response (VGPR). A one-mL bone marrow aspirate was sent overnight to one of the central labs. The primary purpose was to assess MRD by FCM. When extra cells were available, they were frozen as a dry pellet for NGS analyses, using the LymphoSight® platform (Sequenta/Adaptive Inc.). A total of 246 patients have been evaluated by NGS before maintenance and 178 after maintenance. Patients were classified in 3 categories: negative (< 10-6), low-positive (between 10-4 and 10-6), and positive (> 10-4). At pre-maintenance, 87 patients were negative, 80 were low-positive, and 79 were positive. At post-maintenance, these numbers were respectively 86, 52, and 40. Using a cutoff at 10-6, patients below 10-6 at pre-maintenance presented a 3-year PFS at 83%, vs 53% for patients > 10-6. At post-maintenance, these % were 90% and 59% respectively. When restricted to patients in CR, the 3-year PFS was 87% and 63% at pre-maintenance, and 92% and 64% at post-maintenance (Figure). Finally, we compared the two MRD techniques. Using a 7-color FCM strategy, the sensitivity level was 10-4. Amongst the 163 patients negative with the FCM approach, 84 ( 51 %) patients were positive using NGS and among 72 patients positive with FCM, 67 (93%)  were also positive using NGS. In the subgroup of patients with negative MRD using FCM, the 3 year PFS was 86% for NGS negative patients vs 66 % for NGS positive at pre-maintenance and 91% vs 65% at post maintenance. Looking at high-risk patients, 26 patients with t(4;14), and 16 with del(17p) were evaluated. Half of the t(4;14) patients achieved MRD negativity, versus only 1/16 patients with del(17p). Interestingly, 9/13 patients with t(4;14) who achieved MRD negativity, and 0/1 patients with del(17p) did not relapse, showing the importance of achieving deep response in these high-risk patients. In conclusion, this study clearly demonstrates that a sensitive technique like NGS is able to predict PFS in patients treated with modern approaches.

Disclosures: Avet-Loiseau: Takeda: Research Funding ; Celgene: Research Funding ; Janssen: Research Funding . Hulin: celgene: Membership on an entity’s Board of Directors or advisory committees ; jansen: Membership on an entity’s Board of Directors or advisory committees . Arnulf: Janssen: Membership on an entity’s Board of Directors or advisory committees ; Celgene: Membership on an entity’s Board of Directors or advisory committees . Garderet: Bristol-Myers Squibb: Consultancy . Karlin: Sandoz: Honoraria , Membership on an entity’s Board of Directors or advisory committees ; Amgen: Honoraria ; BMS: Honoraria ; Janssen: Honoraria ; Celgene: Honoraria . MACRO: millenium: Membership on an entity’s Board of Directors or advisory committees ; jansen: Membership on an entity’s Board of Directors or advisory committees ; celgene: Membership on an entity’s Board of Directors or advisory committees . Richardson: Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees ; Millennium Takeda: Membership on an entity’s Board of Directors or advisory committees ; Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Novartis: Membership on an entity’s Board of Directors or advisory committees . Faham: Adaptive Biotechnologies: Employment , Equity Ownership . Facon: Onyx: Membership on an entity’s Board of Directors or advisory committees ; BMS: Membership on an entity’s Board of Directors or advisory committees ; Celgene: Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Janssen: Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Millenium: Membership on an entity’s Board of Directors or advisory committees ; Novartis: Membership on an entity’s Board of Directors or advisory committees ; Amgen: Membership on an entity’s Board of Directors or advisory committees ; Pierre Fabre: Membership on an entity’s Board of Directors or advisory committees . Moreau: Novartis: Honoraria , Other: Adboard ; Takeda: Other: Adboard ; Celgene: Honoraria , Other: Adboard ; Janssen: Honoraria , Other: Adboard ; Takeda: Honoraria , Other: Adboard ; Amgen: Other: Adboard ; Amgen: Other: Adboard ; Novartis: Other: Adboard . Attal: celgene: Membership on an entity’s Board of Directors or advisory committees ; jansen: Honoraria .

*signifies non-member of ASH