Next Article in Journal
The Impact of Protein Glycosylation on the Identification of Patients with Pediatric Appendicitis
Previous Article in Journal
The Effect of Body Mass Index on Melanoma Biology, Immunotherapy Efficacy, and Clinical Outcomes: A Narrative Review
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma—Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries

by
Anja Seckinger
1,2,†,
Hans Salwender
3,†,
Hans Martin
4,
Christof Scheid
5,
Thomas Hielscher
6,
Uta Bertsch
7,
Manuela Hummel
6,
Anna Jauch
8,
Wolfgang Knauf
9,
Martina Emde-Rajaratnam
1,
Susanne Beck
1,
Kai Neben
10,
Jan Dührig
11,
Walter Lindemann
12,
Ingo G. H. Schmidt-Wolf
13,
Mathias Hänel
14,
Igor W. Blau
15,
Katja Weisel
16,
Niels Weinhold
7,
Marc S. Raab
7,
Hartmut Goldschmidt
7,17,
Mimi Choon-Quinones
2 and
Dirk Hose
1,2,*
add Show full author list remove Hide full author list
1
Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), 1090 Jette, Belgium
2
Independent Myeloma Alliance, 8808 Pfäffikon, SZ, Switzerland
3
Department of Internal Medicine II, Asklepios Klinik Altona, 22763 Hamburg, Germany
4
Department of Medicine, Hematology/Oncology, Goethe-University of Frankfurt, 60590 Frankfurt, Germany
5
Department I of Internal Medicine, University of Cologne, 50923 Köln, Germany
6
Abteilung für Biostatistik, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany
7
Medizinische Klinik V, Universitätsklinikum Heidelberg, 69120 Heidelberg, Germany
8
Institut für Humangenetik, Universität Heidelberg, 69120 Heidelberg, Germany
9
Onkologische Gemeinschaftspraxis, Agaplesion Bethanien Krankenhaus, 60389 Frankfurt, Germany
10
Klinikum Mittelbaden, Medizinische Klinik 2, 76530 Baden-Baden, Germany
11
Katholisches Krankenhaus Hagen, 58099 Hagen, Germany
12
Department of Hematology, University Hospital Essen, 45147 Essen, Germany
13
Department of Integrated Oncology, CIO Bonn, University of Bonn, 53127 Bonn, Germany
14
Department of Internal Medicine III, Klinikum Chemnitz GmbH, 09113 Chemnitz, Germany
15
Medical Clinic III Hematology and Oncology, Charité University Medicine Berlin, 13353 Berlin, Germany
16
Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
17
Nationales Centrum für Tumorerkrankungen, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(12), 6431; https://doi.org/10.3390/ijms25126431
Submission received: 17 May 2024 / Revised: 5 June 2024 / Accepted: 7 June 2024 / Published: 11 June 2024
(This article belongs to the Section Molecular Oncology)

Abstract

Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront “novel agents” in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with “conventional” (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to “outdated” treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront “novel agents”.
Keywords: multiple myeloma; response; survival; proliferation; molecular profiling; LMIC multiple myeloma; response; survival; proliferation; molecular profiling; LMIC

Share and Cite

MDPI and ACS Style

Seckinger, A.; Salwender, H.; Martin, H.; Scheid, C.; Hielscher, T.; Bertsch, U.; Hummel, M.; Jauch, A.; Knauf, W.; Emde-Rajaratnam, M.; et al. Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma—Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries. Int. J. Mol. Sci. 2024, 25, 6431. https://doi.org/10.3390/ijms25126431

AMA Style

Seckinger A, Salwender H, Martin H, Scheid C, Hielscher T, Bertsch U, Hummel M, Jauch A, Knauf W, Emde-Rajaratnam M, et al. Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma—Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries. International Journal of Molecular Sciences. 2024; 25(12):6431. https://doi.org/10.3390/ijms25126431

Chicago/Turabian Style

Seckinger, Anja, Hans Salwender, Hans Martin, Christof Scheid, Thomas Hielscher, Uta Bertsch, Manuela Hummel, Anna Jauch, Wolfgang Knauf, Martina Emde-Rajaratnam, and et al. 2024. "Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma—Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries" International Journal of Molecular Sciences 25, no. 12: 6431. https://doi.org/10.3390/ijms25126431

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop