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723 Targeted Sequencing of Relapsed/Refractory Myeloma Patients Identifies an Enrichment of Mutations in Cereblon and MAPK Pathways

Myeloma: Biology and Pathophysiology, excluding Therapy
Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Clinical Insights from the Next Generation Characterization of Multiple Myeloma
Monday, December 7, 2015: 3:15 PM
W224ABEF, Level 2 (Orange County Convention Center)

Elias Karl Mai, MD1*, K. Martin Kortuem, MD2*, Nur Hanafiah1*, Santiago Barrio3*, Laura Ann Bruins3*, Maximilian Merz, MD4*, Jing Xu5*, Koenuel Pashayeva, MD1*, Yuan-Xiao Zhu2*, Chang-Xin Shi, PhD2*, R. Alexander Stewart2*, Patrick Jedlowski2*, Mindaugas Andrulis, MD5*, Anna Jauch, Prof.6*, Jens Hillengass, MD7, Hartmut Goldschmidt, MD1,8, P. Leif Bergsagel, MD, PhD2, Esteban Braggio, PhD2, A. Keith Stewart, MD3,9 and Marc Steffen Raab, MD, PhD1,10

1Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany
2Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
3Mayo Clinic, Scottsdale, AZ
4Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
5Institute of Pathology, University Clinic Heidelberg, Heidelberg, Germany
6Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
7Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
8National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
9Oncospire Inc., Rochester, MN
10Max Eder Group for Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany

Introduction: We employed a customized Multiple Myeloma (MM) specific Mutation-Panel (M3P) to screen a homogenous cohort of refractory MM (rMM) patients in a timely and cost-effective manner. rMM was defined as progressive disease (PD) during therapy or within 60 days after discontinuation of therapy. The M3P provides a practical alternative to whole genome/exome sequencing approaches and includes 88 genes selected for being either actionable targets, potentially related to drug response or part of known key pathways in MM biology.

Patients and Methods: Tumor and germline samples of 50 rMM patients were screened using M3P. Patients received a median of five lines of treatment at the time of tumor sampling (range 2-15 lines). All patients received at least one immunomodulatory agent (IMiD) and proteasome inhibitor (PI), and 88%, 76% and 66% were refractory to either an IMiD, PI or both. All patients had received lenalidomide and bortezomib, 48% and 34% were additionally exposed to pomalidomide and thalidomide and 18% to carfilzomib at any time prior to sampling. The majority of patients had a progressive and refractory disease immediately prior to sampling (82% and 78%), with 43% of them being IMiD-refractory and 46% being PI-refractory in the most recent line of therapy. Cytogenetic data at time of sampling were available from 78% of patients. Adverse cytogenetics were detectable in 82% of patients with gain 1q21 > 2 copies (62%), deletion 17p (33%), t(4;14) (13%) and t(14;16) (8%) being the most common.

Results: An average sequencing depth of 750x was obtained across the samples. Our screening revealed an increased prevalence of mutations in the MAPK pathway (72%), including 34% of KRAS, 26% of NRAS, 18% of BRAF (with one patient carrying two BRAF mutations and 8% in actionable p.V600E). Additionally, two mutations (4%) were found in RASA2, a RAS inhibitor. Other potentially actionable mutations were seen in p.R132H IDH1 and p.R248C FGFR3 (2% each).

Most prominently, the CRBN pathway was found mutated in 22% of cases, including CRBN (12%, one case with concomitant CUL4B mutations), CUL4B (4%), IRF4 (4%) and IKZF1 (2%). In CRBN we found four cases with mutations leading to a truncated protein (frameshift, nonsense and splicing) and two cases with missense mutations located within the thalidomide-binding domain, suggesting a causal effect on IMiD resistance. All CRBN mutated patients and 91% of the CRBN pathway mutated patients were at least once unresponsive to IMiD based treatment. In one patient with IRF4mutation sensitivity to IMiDs remained unknown.

A majority of patients were also resistant to PI treatment (76%), however mutations in proteasome subunits (PSMD1 and PSMB8) and XBP1 were rare (4%), but only a limited number of this gene family were represented in our panel.

Other recurrently mutated genes were TP53 (26%), FAM46C (12%), ATM (10%) and TRAF3 (8%). Notably, DIS3 mutations were identified in only 6% of cases. As previously reported, TP53 mutations were associated with deletion 17p (8/13 cases, 62%). A correlation between the absolute number of mutations and previous lines of treatment was not observed (r=0.05, p=0.73).

Conclusion: Targeted sequencing on a homogenous cohort of heavy pretreated rMM patients gives key insights in the landscape of the rMM genome, uncovering an increasing frequency of MAPK, TP53 and CRBN mutations. Importantly, this is the first study showing recurrent mutations in CRBN in patients unresponsive to IMiD treatment, supporting a potential association with resistance to IMiD based therapies.

Disclosures: Mai: Onyx: Other: Travel Grant ; Janssen-Cilag: Other: Travel Grant ; Celgene: Other: Travel Grant ; Mundipharma: Other: Travel Grant . Merz: Janssen: Other: Travel grants ; Celgene: Other: Travel grants . Hillengass: Takeda: Honoraria , Other: Travel support ; Novartis: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Sanofi: Research Funding ; Janssen-Cilag: Honoraria , Other: Travel support ; Celgene: Honoraria , Other: Travel support . Goldschmidt: Celgene: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Janssen-Cilag: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Millennium: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Onyx: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Novartis: Consultancy , Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Chugai: Research Funding , Speakers Bureau . Stewart: Oncospire Genomics: Research Funding .

*signifies non-member of ASH