• John P Campbell, Jennifer L J Heaney, Sankalp Pandya, Zaheer Afzal, Martin Kaiser, Roger Owen, J Anthony Child, David A Cairns, Walter Gregory, Gareth J Morgan, Graham H Jackson, Chris M Bunce, and Mark T Drayson.
• Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Department for Health, University of Bath, Bath, UK.
• Lancet Haematol. 2017 Dec 1; 4 (12): e584-e594.

BackgroundMultiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), which is usually only treated by a form of anti-multiple myeloma therapy if it is causing substantial disease through deposition of secreted M proteins. However, studies comparing how MGUS and multiple myeloma plasma cell clones respond to these therapies are scarce. Biclonal gammopathy multiple myeloma is characterised by the coexistence of an active multiple myeloma clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-multiple myeloma therapy, in the same patient, at the same time. We aimed to identify how MGUS and multiple myeloma plasma cell clones responded to anti-multiple myeloma therapy in patients newly diagnosed with biclonal gammopathy multiple myeloma.MethodsIn this retrospective cohort study, we identified patients with biclonal gammopathy multiple myeloma by central laboratory analysis of 6399 newly diagnosed patients with multiple myeloma enrolled in three UK clinical trials (Myeloma IX, Myeloma XI, and TEAMM) between July 7, 2004, and June 2, 2015. In addition to the inclusion criteria of these trials, our study necessitated at trial entry the presence of two distinct M proteins in immunofixation electrophoresis. The primary endpoint was difference in response achieved with anti-multiple myeloma therapy on MGUS (which we defined as M2) and multiple myeloma (M1) clones-overall, within patients, and between therapy types-with international therapy response criteria assessed with χ2 analyses. We analysed by intention to treat.Findings44 patients with biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones were subsequently identified from the three trials and then longitudinally monitored. 41 (93%) of M1 clones had a response to therapy (either complete response, very good partial response, partial response, or minor response) compared with only 28 (64%) of M2 clones (p=0·0010). For the 20 patients who received intensive therapy, there was no difference between the proportion of responding clones in M1 (19 [95%]) and M2 (15 [75%], p=0·13). However, for the 17 patients who received non-intensive therapy, 16 (94%) of M1 clones had a response compared with ten [59%] of M2 clones (p=0·031). When examining clones within the same patient, 30 (68%) of 44 individual patients had different levels of responses within the M1 and M2 clones. One patient exhibited M2 progression to myeloma and subsequently died.InterpretationThese results show that, in patients with biclonal gammopathy multiple myeloma, anti-multiple myeloma therapies exert a greater depth of response against multiple myeloma plasma cell clones than MGUS plasma cell clones. Although some MGUS clones exhibited a complete response, many did not respond, which suggests that the underlying features that render multiple myeloma plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies might seek to identify, with biclonal gammopathy multiple myeloma as an investigative model, the genetic and epigenetic alterations that affect whether MGUS plasma cell clones are responsive to anti-multiple myeloma therapy.FundingNational Institute of Health Research, Medical Research Council, and Cancer Research UK.Copyright © 2017 Elsevier Ltd. All rights reserved.

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