Response comparison of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) to the same anti-MM therapy, in the same patient, at the same time: a retrospective cohort study

Research output: Contribution to journalArticle

Authors

  • Sankalp Pandya
  • Zaheer Afzal
  • Martin F Kaiser
  • Roger G Owen
  • J Anthony Child
  • David A Cairns
  • Walter M Gregory
  • Gareth J Morgan
  • Graham H Jackson

Colleges, School and Institutes

External organisations

  • University of Bath
  • Institute of Immunology & Immunotherapy; College of Medical and Dental Sciences; University of Birmingham; Birmingham UK

Abstract

Background: Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is usually only treated if it is causing significant disease through deposition of secreted M-proteins, when a form of anti-MM therapy is then employed. However, there are few studies comparing how MGUS and MM plasma cell clones respond to these therapies. In this novel study, we aimed to identify how MGUS and MM plasma cell clones responded to anti-MM therapy in patients newly diagnosed with biclonal gammopathy MM (BGMM). BGMM is characterised by the co-existence of an active MM clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-MM therapy, in the same patient, at the same time. Methods: We identified BGMM patients by central laboratory analysis of 6,399 newly diagnosed MM patients enrolled in three UK clinical trials (Myeloma IX, Myeloma XI and TEAMM) between 7 July 2004 and 2 June 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. To exclude confusion with lymphoplasmacytic cell clones, all BGMM patients with an IgM M-protein were excluded (14/6,399). Thus, 44 BGMM patients with IgG or IgA MGUS clones were subsequently identified and then longitudinally monitored. The primary endpoint was difference in response between MGUS and MM clones. Employing international therapy response criteria, we examined differences in the frequencies of different response codes (complete / very good partial / partial / minor responses, or stable / progressive disease) achieved by anti-MM therapy on MGUS and MM clones – overall, within patients, and between therapy types – using chi-squared analyses. Analyses were by intention to treat. Findings: Longitudinal assessment of BGMM revealed disparate MM and MGUS responses in 30/44 (68%) individual patients. 16/44 (36%) MGUS clones did not respond to anti-MM therapy compared to only 3/44 (7%) non-responsive MM clones (p<0.01). In 27/44 (61%) dual responders, the MM response was greater in 5/44 (11%) patients, the MGUS response greater in 9/44 (20%) patients, and the MM and MGUS responses the same in 13/44 (30%) patients - of which 10/44 (23%) were complete responses; 1/44 (2%) were very good partial responses, and 2/44 (5%) were partial responses. Duration of response was better for MGUS with progression in only 1/31 (3%) clones versus 17/31 (55%) MM plasma cell clones. Interpretation: These results show that, in BGMM, anti-MM therapies exert a greater depth of response against MM plasma cell clones than MGUS plasma cell clones. Whilst some MGUS clones exhibited a complete response, many did not respond, suggesting that the underlying features that render MM plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies may seek to identify, using BGMM as an investigative model, the genetic and epigenetic alterations that dictate whether MGUS plasma cell clones are responsive to anti-MM therapy.

Details

Original languageEnglish
JournalThe Lancet Haematology
Volume4
Issue number12
Early online date13 Nov 2017
Publication statusPublished - Dec 2017