Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2024 Jun 7;14(1):94.
doi: 10.1038/s41408-024-01075-x.

Additional copies of 1q negatively impact the outcome of multiple myeloma patients and induce transcriptomic deregulation in malignant plasma cells

Mattia D'Agostino  1 , Delia Rota-Scalabrini  2 , Angelo Belotti  3 , Luca Bertamini  4 , Maddalena Arigoni  5 , Giovanni De Sabbata  6 , Giuseppe Pietrantuono  7 , Anna Pascarella  8 , Patrizia Tosi  9 , Francesco Pisani  10 , Norbert Pescosta  11 , Marina Ruggeri  12 , Jennifer Rogers  13 , Martina Olivero  14 , Mariagrazia Garzia  15 , Piero Galieni  16 , Ombretta Annibali  17 , Federico Monaco  18 , Anna Marina Liberati  19 , Salvatore Palmieri  20 , Paola Stefanoni  21 , Elena Zamagni  22 , Benedetto Bruno  1 , Raffaele Adolfo Calogero  5 , Mario Boccadoro  23 , Pellegrino Musto  24   25 , Francesca Gay  26
Affiliations
Randomized Controlled Trial

Additional copies of 1q negatively impact the outcome of multiple myeloma patients and induce transcriptomic deregulation in malignant plasma cells

Mattia D'Agostino et al. Blood Cancer J. .

Abstract

Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q. We evaluated the impact of Amp1q/Gain1q on the outcome of newly diagnosed MM patients enrolled in the FORTE trial (NCT02203643). Among 400 patients with available 1q data, 52 (13%) had Amp1q and 129 (32%) Gain1q. After a median follow-up of 62 months, median progression-free survival (PFS) was 21.2 months in the Amp1q group, 54.9 months in Gain1q, and not reached (NR) in Normal 1q. PFS was significantly hampered by the presence of Amp1q (HR 3.34 vs. Normal 1q, P < 0.0001; HR 1.99 vs. Gain1q, P = 0.0008). Patients with Gain1q had also a significantly shorter PFS compared with Normal 1q (HR 1.68, P = 0.0031). Concomitant poor prognostic factors or the failure to achieve MRD negativity predicted a median PFS < 12 months in Amp1q patients. Carfilzomib-lenalidomide-dexamethasone plus autologous stem cell transplantation treatment improved the adverse effect of Gain1q but not Amp1q. Transcriptomic data showed that additional 1q copies were associated with deregulation in apoptosis signaling, p38 MAPK signaling, and Myc-related genes.

PubMed Disclaimer

Conflict of interest statement

MD has received honoraria for lectures for GlaxoSmithKline, Sanofi, and Janssen; has served on the advisory boards for GlaxoSmithKline, Sanofi, and Bristol Myers Squibb. AB has served on the advisory boards for Amgen, GlaxoSmithKline, Janssen, Pfizer. PG has served on the advisory boards for Takeda and Incyte. EZ recieved honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda. BB has received honoraria from Amgen, Janssen, Novartis, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Jazz pharmaceuticals, Astrazeneca and Incyte; has served on the advisory boards for Amgen and Jazz pharmaceuticals. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. PM has received honoraria from Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Novartis, Gilead, Jazz, Sanofi, AbbVie, and GlaxoSmithKline; has served on the advisory boards for Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Jazz, Sanofi, AbbVie, and GlaxoSmithKline. FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Consort diagram of patients enrolled in the FORTE trial.
Fig. 2
Fig. 2. Outcomes according to 1q copies.
Progression-free survival (A) and overall-survival (B) from first randomization (R1) according to 1q subgroups. HR values and the 95% CIs were estimated with a Cox proportional hazards model adjusted for the R-ISS stage (R-ISS III vs. II vs. I vs. not available), age (≥60 vs. <60 years), and randomization arm (KRd-ASCT vs. KRd12 vs. KCd-ASCT).
Fig. 3
Fig. 3. Progression-free survival in subgroups of interest.
Progression-free survival from first randomization (R1) according to 1q alterations and concomitant cytogenetic risk (A–C), LDH levels (D and E), ISS (F–H), and circulating tumor cells (CTCs) levels (I).
Fig. 4
Fig. 4. Progression-free survival from first randomization (R1) according to treatment received and 1q alterations.
A KRd-ASCT, B KRd12, and C KCd-ASCT.
Fig. 5
Fig. 5. Transcriptomic deregulation according to 1q copies.
Principal component analysis using RNAseq data was able to separate NDMM patients according to 1q copy numbers in the MMRF CoMMpass study (A). The separation was maintained when applied to a validation cohort of newly sequenced NDMM patients from the FORTE trial (B). Number of differentially expressed genes divided according to chromosome number are presented in Panel C. Ingenuity Pathway connectivity analysis of differentially expressed genes in Amp1q vs. Normal1q (D) and Gain1q vs. Normal1q (E) shows a deregulated gene network centered on Myc. Green color indicates down-regulation and red color up-regulation.
See this image and copyright information in PMC

References

    1. Perrot A, Lauwers-Cances V, Cazaubiel T, Facon T, Caillot D, Clement-Filliatre L, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;136:39. doi: 10.1182/blood-2020-134538. - DOI
    1. Caro J, Al Hadidi S, Usmani SZ, Yee AJ, Raje N, Davies FE. How to treat high-risk myeloma at diagnosis and relapse. In: American Society of Clinical Oncology, editor. Educational book. Alexandria (USA); vol. 2021. - PubMed
    1. Kumar SK, Rajkumar SV. The multiple myelomas—current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol. 2018;15:409–21. doi: 10.1038/s41571-018-0018-y. - DOI - PubMed
    1. Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2017;14:100–13. doi: 10.1038/nrclinonc.2016.122. - DOI - PubMed
    1. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol. 2015;33:2863–9. doi: 10.1200/JCO.2015.61.2267. - DOI - PMC - PubMed

Publication types

Associated data