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<p>Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (&gt;1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.</p>

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Temporal genomic dynamics shape clinical trajectory in multiple myeloma

  • 期刊论文

  • 发表日期：

    2025年8月20日

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  • Francesco Maura,
  • Marcella Kaddoura,
  • Alexandra M. Poos,
  • Linda B. Baughn,
  • Bachisio Ziccheddu,
  • Marc-Andrea Bärtsch,
  • Anthony Cirrincione,
  • Kylee Maclachlan,
  • Monika Chojnacka,
  • Benjamin Diamond,
  • Marios Papadimitriou,
  • Patrick Blaney,
  • Lukas John,
  • Philipp Reichert,
  • Stefanie Huhn,
  • Dylan Gagler,
  • Yanming Zhang,
  • Ahmet Dogan,
  • Alexander M. Lesokhin,
  • Faith Davies,
  • Hartmut Goldschmidt,
  • Roland Fenk,
  • Katja C. Weisel,
  • Elias K. Mai,
  • Neha Korde,
  • Gareth J. Morgan,
  • S. Vincent Rajkumar,
  • Shaji Kumar,
  • Saad Usmani,
  • Ola Landgren,
  • Marc S. Raab,
  • Niels Weinhold

摘要

Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.