-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3283 Prognostic Impact of Molecular Response Assessed By Next-Generation Sequencing in a Large Cohort of Multiple Myeloma Patients

Myeloma: Biology and Pathophysiology, excluding Therapy
Program: Oral and Poster Abstracts
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II
Sunday, December 4, 2016, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Beatriz Sanchez-Vega, PhD1*, Rafael Alonso, MD2*, Isabel Cuenca2*, Santiago Barrio, PhD3*, Yanira Ruiz-Heredia1*, Carlos Marin2*, Inmaculada Rapado, PhD2*, Cristina Jimenez, BSc4*, Xabier Aguirre5*, Rosa M. Ayala, MD, PhD6, Teresa Cedena2*, Bruno Paiva, PhD5*, Maria-Victoria Mateos, MD, PhD4, Laura Rosiñol7*, Joan Bladé8, Jesus San Miguel, MD, PhD5, Ramon Garcia-Sanz, MD, PhD9*, Juan José Lahuerta, MD PhD2* and Joaquín Martínez-López, MD, PhD6*

1Hospital Universitario 12 de Octubre-H12CNIO, Madrid, Spain
2Hospital Universitario 12 de Octubre, Madrid, Spain
3Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
4Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
5Centro de Investigación Médica Aplicada (CIMA), IDISNA, Pamplona, Spain
6Hematology Department, 12 de Octubre Hospital, Madrid, Spain
7Department of Hematology, Amyloidosis and Myeloma Unit. Hospital Clínic, IDIBAPS, Barcelona, Spain
8Hospital Clinic, IDIBAPS, Barcelona, Spain
9Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), Salamanca, Spain

INTRODUCTION

Minimal residual disease (MRD) assessment is an essential prognosis factor in multiple myeloma (MM). In this way different high-sensitivity quantification methods are being developed and improved using molecular or flow-cytometry approaches. Currently, the only method available to study molecular response by NGS in MM is clonoSEQ; this is offered as external service by Adaptative Technologies. We have optimized a simplified method to quantify molecular response using NGS. In this work, we compare results when quantifying molecular response by our simplified NGS method or by clonoSEQ. Also we study the prognostic impact of molecular response assessed by NGS techniques in a large series of 181 cases.

METHODS

We evaluated the molecular response in 71 patients included in GEM2010MAS65 clinical trial by our simplified method, and in 110 patients included in GEM2005 clinical trial by clonoSEQ. Immunoglobulin clonotype quantification by our simplified method: DNA was amplified in accordance with the terms of BIOMED-2 Concerted Action BMH4-CT98-3936. Standard kits were used to prepare libraries (Life Technologies or New England Biolabs), and sequencing was performed with Ion Torrent™ PGM, Ion S5, or MiSeq systems. The resulting FASTQ were analyzed with specific bioinformatic applications in order to identify and quantify clonal specific sequences (clonotype) present in every proband.

RESULTS

MRD negativity showed significant longer Progression Free Survival (PFS), regardless of the method employed (median 34 months for local method and 32 months for clonoSEQ method in MRD+ patients (MRD>10-5) vs median not reached and 81 months in MRD- patients, respectively, p=0.0001). Likewise, significant differences were observed in terms of Overall Survival (OS) between patients with MRD+ (median 81 months for local method vs 50 months for clonoSEQ method) and  MRD- patients (median not reached for both methods), p=0.014. No significant differences were observed in OS and PFS between both local and clonoSEQ NGS techniques (Figure 1).

Then, we performed a global analysis with all patients to assess the potential of molecular response evaluated by any NGS method to predict survival regardless of treatment,  Molecular response by SEQ was achieved in 43 cases out of 181 (23.7%). Median PFS were 34 vs 80 months for MRD+ and MRD- patients, respectively (p<0.0001, HR=2.8). Median OS were not reached in MRD- patients vs 81 months in MRD+ patients (p=0.004, HR=2.78) (Figure 2).

Regression analysis did not show association between any biological variable and MRD- achievement by NGS. When analyzing MRD- patients, no significant differences in PFS or OS were detected between high or standard-risk cytogenetics cases, comparing to differences observed in overall series or in the MRD+ patients group.

CONCLUSION

Molecular response assessed by NGS is able to identify patients with higher risk, independently of the treatment administered and the method employed. MRD negativity achievement by NGS is an independent risk factor to other clinical and biological variables. Our simplified NGS method offers molecular response information with prognostic value similar to standardized molecular techniques.

 

Disclosures: Paiva: Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding. Garcia-Sanz: Takeda: Research Funding. Martínez-López: Novartis: Honoraria, Speakers Bureau.

*signifies non-member of ASH