Assistant Professor TGen - City of Hope Phoenix, Arizona, United States
Introduction: Myeloma patients have many therapeutic options available but multiple relapses remains a common scenario. Genomic profiling may help us better understand resistance mechanisms and ultimately select optimal therapies. We present a t(4;14) patient treated with radiation therapy and CyBorD followed by VRd induction, HDT+ASCT, and 27 months of proteasome inhibitor based maintenance therapy (CR). At relapse they received daratumumab based salvage in combination with lenalidomide and then pomalidomide. Subsequent progression was treated with a BCMA directed bispecific with initial sCR but progression occurred seven months later. Subsequent therapy with Isa-Kd resulted in a short PR before progressing two months later and being unresponsive to SVd. The first profiled bone marrow was collected during leukapheresis for cilta-cel but due to progressive disease the patient received an FCRL5 directed bispecific, and a second sample was collected at progression after a brief sCR to this agent. Unfortunately, the patient did not respond to subsequent therapy including a GPRC5D directed bispecific and the stored cilta-cel product.
Methods: Plasma cells were enriched from bone marrow and peripheral blood using the human CD138+ Positive Selection Kit on an Applied Cells MARS CS Flex Cell Separator. PCR-free short read WGS and mRNA sequencing libraries were sequenced on a NovaSeq 6000. Long-read WGS libraries were sequenced on PromethION R10.4.1 flow cells.
Results: WGS confirmed the presence of t(4;14), gain(1q21) and del(13q14). Additional events detected included: t(8;22)-IgL::MYC, chromothripsis within and between chromosomes 4 and 17, plus bi-allelic deletions of BCL2L11/BIM, RB1, and CDKN2A/CDKN2B suggesting an apoptosis resistant and proliferative tumor. Therapeutic resistance to anti-CD38 agents and IMiDs started with one copy deletions of CD38 and IKZF3 created by the chromothripsis event. Convergent evolution occurred to inactivate the second CD38 allele with three clones having different interstitial deletions. The second IKZF3 allele was inactivated by a frameshift mutation. This sample also had bi-allelic loss of TNFRSF17/BCMA with eleven different deletions overlapping TNFRSF17/BCMA and a 3 bp deletion in the extracellular domain (Ser30), indicating the presence of multi-clonal resistance. A significant clonal selection was evident in the second timepoint with single inactivation events detected in BIM, CD38, and BCMA. Interestingly, the three copies of FCRL5 detected initially were fully intact even after evaluation with long read sequencing but the expression of FCRL5 was almost undetectable by RNAseq (0.6 TPM) compared to the median seen in the MMRF CoMMpass cohort (243 TPM).
Conclusions: This case represents the first known bi-allelic loss of CD38 and acquired loss of FCRL5 expression. These events, along with the loss of BCMA highlight the need for more advanced clinical testing to assess the actionability of the diverse therapeutic targets available to treat patients today.
