A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis

Elisabet E. Manasanch, Guangchun Han, Rohit Mathur, Yun Qing, Zheng Zhang, Hans Lee, Donna M. Weber, Behrang Amini, Zuzana Berkova, Karina Eterovic, Shaojun Zhang, Jianhua Zhang, Xingzhi Song, Xizeng Mao, Margaret Morgan, Lei Feng, Veera Baladandayuthapani, Andrew Futreal, Linghua Wang, Sattva S. Neelapu and Robert Z. Orlowski

Key Points

  • Pembrolizumab induced a complete remission in a patient with high-risk smoldering multiple myeloma who also had high-risk myeloma features.

  • Immune and transcriptomic analyses identified a distinct profile that indicated a preexisting immune response in the responder.


Multiple myeloma is, in most patients, an incurable cancer. Its precursors can be identified with routine tests setting the stage for early intervention to prevent active myeloma. We investigated the efficacy and safety of pembrolizumab, an antiprogrammed cell death 1 antibody, in smoldering myeloma patients with intermediate/high risk of progression to symptomatic myeloma. Thirteen patients were treated with a median number of 8 cycles. One patient achieved a stringent complete response with bone marrow next-generation sequencing negativity at 10−4 that is ongoing at 27 months (8%); 11 had stable disease (85%), and 1 progressed (8%). Three patients discontinued therapy due to immune-related adverse events: 2 with transaminitis and 1 due to tubulointerstitial nephritis. Immune profiling of bone marrow samples at baseline showed markers associated with a preexisting immune response in the responder compared with nonresponders and features of increased T-cell exhaustion in nonresponders. Consistent with this, transcriptome sequencing of bone marrow samples at baseline revealed an increased interferon-γ signature in the responder compared with the nonresponders. In summary, our results suggest that smoldering myeloma may be immunogenic in a subset of patients, and therapies that enhance antitumor T-cell responses may be effective in preventing its progression. This trial was registered at as #NCT02603887.

  • Submitted April 15, 2019.
  • Accepted July 1, 2019.
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