RNA-seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Michael A. Chapman, Jonathan Sive, John Ambrose, Claire Roddie, Nicholas Counsell, Anna Lach, Mahnaz Abbasian, Rakesh Popat, Jamie D. Cavenagh, Heather Oakervee, Matthew J. Streetly, Stephen Schey, Mickey Koh, Fenella Willis, Andres E. Virchis, Josephine Crowe, Michael F. Quinn, Gordon Cook, Charles R. Crawley, Guy Pratt, Mark Cook, Nivette Braganza, Toyin Adedayo, Paul Smith, Laura Clifton-Hadley, Roger G. Owen, Pieter Sonneveld, Jonathan J. Keats, Javier Herrero and Kwee Yong

Key Points

  • A 7-gene signature is derived that can identify myeloma patients who respond better to bortezomib- or lenalidomide-based therapy.

  • Treatment according to the signature is noninferior to treatment with combined bortezomib, lenalidomide, and dexamethasone.

Publisher's Note: There is a Blood Commentary on this article in this issue.


Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

  • Submitted May 9, 2018.
  • Accepted July 28, 2018.
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