Proteasome inhibitors and IMiDs can overcome some high‐risk cytogenetics in multiple myeloma but not gain 1q21

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population‐based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow‐up of patients still alive at analysis was 40 months for the high‐dose (HDT)‐treated ones and 29 months for the whole population. Three hundred forty‐seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14;16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3‐yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P < 0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3‐yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3‐yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P < 0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted.

[1]  S. Jagannath,et al.  Patients with newly diagnosed multiple myeloma and chromosome 1 amplification have poor outcomes despite the use of novel triplet regimens , 2014, American journal of hematology.

[2]  H. Goldschmidt,et al.  IMWG consensus on risk stratification in multiple myeloma , 2014, Leukemia.

[3]  M. Beksac,et al.  Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. , 2013, Blood.

[4]  S. Ševčíková,et al.  Gain(1)(q21) is an unfavorable genetic prognostic factor for patients with relapsed multiple myeloma treated with thalidomide but not for those treated with bortezomib. , 2013, Clinical lymphoma, myeloma & leukemia.

[5]  R. Hájek,et al.  Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients , 2013, Hematological oncology.

[6]  P. Sonneveld,et al.  Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders , 2012, Haematologica.

[7]  B. Pégourié,et al.  Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  D. Hose,et al.  Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. , 2012, Blood.

[9]  D. Hose,et al.  Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone , 2011, Cancer.

[10]  M. Beksac,et al.  Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. , 2011, The oncologist.

[11]  M. Mohty,et al.  Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  P. Moreau,et al.  Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  P. Fayers,et al.  Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. , 2010, Blood.

[14]  P. Sonneveld,et al.  Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  B. Pégourié,et al.  Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  G. Gahrton,et al.  Impact of chromosome 13 deletion and plasma cell load on long-term survival of patients with multiple myeloma undergoing autologous transplantation. , 2009, Oncology reports.

[17]  L. Zech,et al.  2 translocations, t(11;14) and t(1;6), in a patient with plasma cell leukaemia and 2 populations of plasma cells. , 2009, Scandinavian journal of haematology.

[18]  G. Gahrton,et al.  The prognostic significance of 8p21 deletion in multiple myeloma , 2008, British journal of haematology.

[19]  M. Boccadoro,et al.  Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. , 2008, Blood.

[20]  Bin Jiang,et al.  Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. , 2008, The New England journal of medicine.

[21]  S. Rajkumar,et al.  Multiple myeloma: new staging systems for diagnosis, prognosis and response evaluation. , 2007, Best practice & research. Clinical haematology.

[22]  B. Pégourié,et al.  Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial , 2007, The Lancet.

[23]  B. Barlogie,et al.  Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3 , 2007, British journal of haematology.

[24]  T. Plesner,et al.  Interphase fluorescence in situ hybridization in multiple myeloma and monoclonal gammopathy of undetermined significance without and with positive plasma cell identification: analysis of 192 cases from the Region of Southern Denmark. , 2007, Cancer genetics and cytogenetics.

[25]  R. Bataille,et al.  Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. , 2007, Blood.

[26]  G. Ahmann,et al.  Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma , 2006, Leukemia.

[27]  Vincenzo Callea,et al.  Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial , 2006, The Lancet.

[28]  G. Ahmann,et al.  Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. , 2005, Blood.

[29]  J. Shaughnessy.  Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27 Kip1 and an aggressive clinical course in multiple myeloma , 2005, Hematology.

[30]  D. Reece,et al.  p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. , 2004, Blood.

[31]  D. Reece,et al.  The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant , 2004, British journal of haematology.

[32]  S. Jagannath,et al.  CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION , 1998, British journal of haematology.

[33]  R S Chaganti,et al.  Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. , 1998, Blood.

[34]  B. Barlogie,et al.  Cytogenetic findings in 200 patients with multiple myeloma. , 1995, Cancer genetics and cytogenetics.

[35]  B. Barlogie,et al.  Plasma cell myeloma--new biological insights and advances in therapy. , 1989, Blood.

[36]  R. Kyle,et al.  The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. , 1985, Blood.

[37]  J. Rowley,et al.  Karyotypic abnormalities and clinical aspects of patients with multiple myeloma and related paraproteinemic disorders , 1979, Cancer.

[38]  P. Sonneveld,et al.  Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials , 2007, Leukemia.

[39]  R. Wieser,et al.  Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion , 2007, Leukemia.

[40]  L. Escoda,et al.  Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis , 2007, Leukemia.