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MULTIPLE MYELOMA, GAMMOPATHIES

Cell-free DNA for the detection of emerging treatment failure in relapsed/ refractory multiple myeloma

Leukemia volume 36, pages 1078–1087 (2022)Cite this article

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Abstract

Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass whole genome sequencing (LPWGS) of cfDNA for its predictive value in relapsed/ refractory MM (RRMM). We observed that cfDNA positivity, defined as ≥10% tumor fraction by LPWGS, was associated with significantly shorter progression-free survival (PFS) in an exploratory test cohort of 16 patients who were actively treated on diverse regimens. We prospectively determined the predictive value of cfDNA in 86 samples from 45 RRMM patients treated with elotuzumab, pomalidomide, bortezomib, and dexamethasone in a phase II clinical trial (NCT02718833). PFS in patients with tumor-positive and -negative cfDNA after two cycles of treatment was 1.6 and 17.6 months, respectively (HR 7.6, P < 0.0001). Multivariate hazard modelling confirmed cfDNA as independent risk factor (HR 96.6, P = 6.92e-05). While correlating with serum-free light chains and bone marrow, cfDNA additionally discriminated patients with poor PFS among those with the same response by IMWG criteria. In summary, detectability of MM-derived cfDNA, as a measure of substantial tumor burden with therapy, independently predicts poor PFS and may provide refinement for standard-of-care response parameters to identify patients with poor response to treatment earlier than is currently feasible.

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Fig. 1: Tumor fraction in cfDNA as proxy for tumor burden and as prognostic marker.
Fig. 2: Tumor fraction in cfDNA is predictive of progression-free survival.
Fig. 3: Comparing MM-derived cfDNA with serological parameters and bone marrow infiltration.
Fig. 4: Refining IMWG response criteria with cfDNA as an orthogonal marker of response.
Fig. 5: Cox proportional hazard model for PFS and cfDNA tumor fraction after two cycles of elo-PVD.

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Acknowledgements

JMW is supported by a postdoctoral fellowship of Deutsche Forschungsgemeinschaft (German Research Foundation, 391926441) and the International Myeloma Society Young Investigator Award (IMW, Boston, 2019). JGL is supported by the NCI (K08CA191026), the V Foundation for Cancer Research, and the Anna Fuller Fund. BK is supported by the NCI (K08CA191091).

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Author notes

  1. These authors contributed equally: Johannes M. Waldschmidt, Andrew J. Yee, Tushara Vijaykumar.

  2. These authors jointly supervised this work: Noopur S. Raje, Birgit Knoechel, Jens G. Lohr.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Johannes M. Waldschmidt, Tushara Vijaykumar, Julia Frede, Praveen Anand, Giada Bianchi, Guangwu Guo, Charles Seifer, Monica S. Nair, Antonis Kokkalis, Jake A. Kloeber, Jacob P. Laubach, Nikhil C. Munshi, Paul G. Richardson, Kenneth C. Anderson & Jens G. Lohr

  2. Harvard Medical School, Boston, MA, USA

    Johannes M. Waldschmidt, Andrew J. Yee, Julia Frede, Praveen Anand, Giada Bianchi, Antonis Kokkalis, Elizabeth K. O’Donnell, Jacob P. Laubach, Nikhil C. Munshi, Paul G. Richardson, Kenneth C. Anderson, Noopur S. Raje, Birgit Knoechel & Jens G. Lohr

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Johannes M. Waldschmidt, Ricardo A. Pinto, Julia Frede, Praveen Anand, Antonis Kokkalis, Cheng-Zhong Zhang, Birgit Knoechel & Jens G. Lohr

  4. Massachusetts General Hospital, Boston, MA, USA

    Andrew J. Yee, Samantha Shapiro, Lillian Budano, Mason Mann, Elizabeth K. O’Donnell & Noopur S. Raje

  5. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA

    Ricardo A. Pinto & Cheng-Zhong Zhang

  6. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    Ricardo A. Pinto & Cheng-Zhong Zhang

  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Sayalee Potdar & Birgit Knoechel

  8. Newton Wellesley Hospital, Newton, MA, USA

    Robb Friedman

  9. University of Rochester, Rochester, NY, USA

    Brea Lipe

  10. University of Michigan, Ann Arbor, MI, USA

    Erica Campagnaro

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Contributions

JMW, TV, SP, BK, and JGL designed and performed experiments and analyzed the data. AJY, NSR, JGL, MM, LB, GB, SS, RF, BL, EC, ED, JPL, NCM, PGR, and KCA designed the study and provided clinical data analysis. JMW, TV, RPR, PA, CZZ, BK and JGL conceived and implemented computational methods for data analysis. JF, SP, MSN, AK, GG, and JK provided analytical support. JMW, AJY, TV, NSR, BK, and JGL wrote the paper. JGL, BK, and NSR designed the experimental strategy and supervised the analysis. All authors discussed the results and implications and reviewed the paper.

Corresponding author

Correspondence to Jens G. Lohr.

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Competing interests

No disclosures are related to this publication. JMW: Advisory boards of Janssen and Sanofi. AJY: Advisory boards of Adaptive, Amgen, Bristol-Myers Squibb, GSK, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi and Takeda. Clinical trial support from Adaptive, Amgen, BMS, Bristol-Myers Squibb, Janssen and Takeda. BL: Research funding from Amgen and Cellectar. Advisory boards of Bristol-Myers Squibb, Janssen, and GlaxoSmithKline. C-ZZ: Co-founder, advisor, and equity holder of Pillar BioSciences. PGR: Advisory boards of AbbVie, AstraZeneca, GSK, Bristol-Myers Squibb, Oncopeptides, Celgene, Takeda, and Karyopharm. Advisory boards of Oncopeptides, Janssen, Sanofi, and Secura Bio. KCA: Advisory boards of Janssen, Amgen, Pfizer, AstraZeneca, Precision Biosciences, Bristol-Myers Squibb, Mana, Starton, Window during the conduct of the study; other support from C4 Therapeutics, Oncopep, Raqia; and other support from NextRNA outside the submitted work. NSR: Advisory boards of Amgen, Bristol-Myers Squibb, Janssen, Sanofi, Takeda, AstraZeneca, GSK, Pfizer, Caribou, Immuneel and C4 Therapeutics. Research funding from BluebirdBio. JGL: Consultant for T2 Biosystems outside the submitted work. Research funding from Bristol-Myers Squibb, Celgene. All other authors declare no conflicts of interest.

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Waldschmidt, J.M., Yee, A.J., Vijaykumar, T. et al. Cell-free DNA for the detection of emerging treatment failure in relapsed/ refractory multiple myeloma. Leukemia 36, 1078–1087 (2022). https://doi.org/10.1038/s41375-021-01492-y

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