Page 229 - 2021_10-Haematologica-web

Letters to the Editor
ses from the start of maintenance (Online Supplementary Figure S1). There was no significant difference between gain and amp(1q) for arm A (thalidomide) or arm B (bortezomib) of HD4, both being associated with adverse outcome. The same held true for MM5 and MyXI, in which patients received lenalidomide maintenance for 2 years or until progression in the respective treatment arms. Together, gain and amp(1q21) had a similar prog- nostic impact and neither ongoing bortezomib nor immunomodulatory drug therapy could mitigate it. This is in keeping with reports on the significance of gain(1q) in the context of different induction therapies.4,5 Since in summary these results did not demonstrate a significant difference in outcome between gain and amp(1q), we subsequently analyzed 1q copy number aberrations under the overarching label ‘gain(1q)’.
To examine if gain(1q) is independent of the R-ISS, we performed multivariate Cox-regression analyses, includ- ing R-ISS risk markers individually. By meta-analysis, gain(1q) was associated with both progression-free and overall survival (progression-free survival: HR=1.42 [95% CI: 1.11-1.81], P=0.005; overall survival HR=1.68 [95% CI: 1.21-2.32], P=0.002) (Online Supplementary Table S1). The same held true for all R-ISS markers. Having estab- lished its independent impact, we investigated the addi- tional value gain(1q) could bring to the R-ISS. Considering gain(1q) as an equivalent risk marker in the R-ISS, termed R-ISS-1q, 68/219 GMMG and 29/125 MyXI patients were upstaged from stage I to stage II and 35/480 GMMG and 46/600 MyXI patients from stage II to stage III, with nearly identical outcome discrimination between groups compared to that based on the R-ISS. The median progression-free survival for R-ISS-1q was 55.4 (GMMG) and 45.3 (MyXI) months for stage I, 35.7 and 28.5 months for stage II, and 21.5 and 18.4 months for stage III. The respective overall survival values were not reached (stage I), 89.7/67.2 months (stage II) and 41.9/36.3 months (stage III) (Figure 2, Online Supplementary Figure S2).
In the current R-ISS, all patients with ISS II are assigned to stage II, irrespective of the presence or number of risk markers. However, consistently across trials and in line with other data,15 we found an increasingly adverse out- come, the more risk markers, including gain(1q), t(4;14), t(14;16), del(17p) and lactate dehydrogenase, a patient’s tumor showed (Online Supplementary Figure S2). Specifically, patients with two or more co-occurring tumor risk markers (also called hits) had significantly worse outcome than those with a single marker in isola- tion. Combining this information with the R-ISS-1q, co- occurrence of two or more markers identified ~18% of stage II patients with significantly poorer outcome than the general stage II group (GMMG: median progression- free survival 26.4 [95% CI: 22.9-34.5] months; MyIX: 19.6 [95% CI: 17.0-29.4] months) (Figure 2, Online Supplementary Figure S2). R-ISS-1q stage III patients with multi-hits had very poor outcome (GMMG: median pro- gression-free survival 18.5 [95% CI: 14.9-25.9] months; MyXI: 15.9 [95% CI: 11.8-20.0] months). Although multi-hit tumors have been recognized as a predictor of ultra high-risk disease,15 they have not been investigated in the context of R-ISS and are not assessed or reported in the majority of clinical trials to date. Our validation of multi-hits in multiple trial cohorts supports wider report- ing, with all markers being accessible through standard fluorescence in situ hybridization diagnostics.
In conclusion, gain(1q) is associated with inferior sur- vival in NDMM, irrespective of current standard thera- pies, and should be considered as an independent risk
factor. Whether additional risk factors may also refine risk prediction will be the subject of future studies and their useful integration subject to international consen- sus, taking accessibility to testing into account, which is well established for gain(1q). While the interaction of novel immunotherapies such as bispecific antibodies or chimeric antigen receptor T cells with tumor biology may differ, inclusion of gain(1q) testing should be considered in their clinical development. Our data support integra- tion of gain(1q) and the concept of multi-hits in future consensus risk prediction frameworks for individualizing care and improving tailored management of NDMM patients.
Niels Weinhold,1 Hans J. Salwender,2 David A. Cairns,3 Marc S. Raab,1 George Waldron,4 Igor W. Blau,5 Uta Bertsch,1 Thomas Hielscher,6 Gareth J. Morgan,7 Anna Jauch,8
Faith E. Davies,7 Mathias Hänel,9 Gordon Cook,10
Christoph Scheid,11 Richard Houlston,4 Hartmut Goldschmidt,1,12 Graham Jackson13 and Martin F. Kaiser4,14
1Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany; 2Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany; 3Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, UK; 4Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; 5Medical Clinic, Charité University Medicine Berlin, Berlin, Germany; 6Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany; 7Perlmutter Cancer Center, NYU Langone Health, NY, USA; 8Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; 9Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany; 10Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; 11Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany; 12National Center for Tumor Diseases (NCT), University Clinic Heidelberg, Heidelberg, Germany; 13Department of Haematology, University of Newcastle, Newcastle Upon Tyne, UK and 14Department of Haematology, The Royal Marsden Hospital, London, UK
Correspondence:
NIELS WEINHOLD - niels.weinhold@med.uni-heidelberg.de MARTIN F. KAISER - martin.kaiser@icr.ac.uk doi:10.3324/haematol.2021.278888
Received: March 30, 2021.
Accepted: May 21, 2021.
Pre-published: June 3, 2021.
Disclosures: HJS reports honoraria from AbbVie and Takeda; and travel support from: Amgen, Bristol-Myers Squibb (BMS), Janssen, Sanofi, and Celgene. DAC reports research funding from Celgene Corporation, Amgen, and Merck Sharp and Dohme. MSR reports honoraria from Celgene, BMS, Novartis, Janssen, Takeda; consulting or advisory role for Celgene, BMS, Novartis, Janssen, and Takeda; research funding from Celgene, Novartis, and Amgen; and travel, accommodation, and expenses from Janssen, BMS, and Takeda. IWB reports research funding from Celgene, BMS, and Janssen. MHä reports honoraria from Novartis, Amgen, Roche, and Takeda; and con- sulting or advisory role for Celgene. GJM has received research funding from Janssen; consultancy fees and honoraria from BMS, Roche, Amgen, GSK, Karyopharm and Takeda; and consultancy fees, hono- raria, and research funding from Celgene Corporation. FED has received consultancy fees and honoraria from Amgen, AbbVie, Takeda, Janssen, Celgene and Roche. GC has received consultancy fees, hono- raria, research funding, and speakers’ bureau fees from Takeda, Celgene Corporation, Janssen, and Amgen; consultancy fees and hono- raria from BMS and Roche; and consultancy fees, honoraria, and speakers’ bureau fees from Sanofi. CS reports honoraria from BMS,
haematologica | 2021; 106(10)
2757