Danielle C. Croucher1,2, Anup Joseph Devasia1, Dor D. Abelman1,2, Ali Mahdipour-Shirayeh1, Zhihua Li1, Natalie Erdmann1, Rodger Tiedemann1,2, Trevor J. Pugh1,2,3 and Suzanne Trudel1,2 1Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada; 2Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; 3Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada Corresponding authors: trevor.pughutoronto.ca; Suzanne.Trudeluhn.ca Abstract

Genomic characterization of cancer has enabled identification of numerous molecular targets, which has led to significant advances in personalized medicine. However, with few exceptions, precision medicine approaches in the plasma cell malignancy multiple myeloma (MM) have had limited success, likely owing to the subclonal nature of molecular targets in this disease. Targeted therapies against FGFR3 have been under development for the past decade in the hopes of targeting aberrant FGFR3 activity in MM. FGFR3 activation results from the recurrent transforming event of t(4;14) found in ∼15% of MM patients, as well as secondary FGFR3 mutations in this subgroup. To evaluate the effectiveness of targeting FGFR3 in MM, we undertook a phase 2 clinical trial evaluating the small-molecule FGFR1–4 inhibitor, erdafitinib, in relapsed/refractory myeloma patients with or without FGFR3 mutations (NCT02952573). Herein, we report on a single t(4;14) patient enrolled on this study who was identified to have a subclonal FGFR3 stop-loss deletion. Although this individual eventually progressed on study and succumbed to their disease, the intended molecular response was revealed through an extensive molecular characterization of the patient's tumor at baseline and on treatment using single-cell genomics. We identified elimination of the FGFR3-mutant subclone after treatment and expansion of a preexisting clone with loss of Chromosome 17p. Altogether, our study highlights the utility of single-cell genomics in targeted trials as they can reveal molecular mechanisms that underlie sensitivity and resistance. This in turn can guide more personalized and targeted therapeutic approaches, including those that involve FGFR3-targeting therapies.

Received September 30, 2022. Accepted November 29, 2022.