Five years ago, when Todd Druley, MD, PhD, was chief medical officer (CMO) for bulk sequencing diagnostics company ArcherDX, he began thinking about the next molecular diagnostics breakthrough.
“We had seen the limitations of bulk sequencing and a lot of the cell-free DNA stuff,” Druley, who established his career as a board-certified pediatric oncologist and tenured physician-scientist in molecular genomics at Washington University School of Medicine and St. Louis Children’s Hospital, told Inside Precision Medicine.
That’s when Druley got interested in the maturing single-cell sequencing field, which would overcome the problem of “looking at shreds of DNA floating in the blood from lysed cells.” What interested Druley about single cells was not trying to find a rare transcript of a biomarker for oncogenesis. Instead, he was interested in breaking down the acquired DNA mutations and the transcriptional changes that go with them in a sample of thousands of different clones.
The problem that Druley has gone after is the stratification of patients with smoldering multiple myeloma (SMM)—a precursor or early sign that someone may develop the cancerous plasma cell build up in bone marrow seen in multiple myeloma (MM). SMM may take years to become MM, and in most cases, people who have SMM never develop MM. The question becomes, how do you figure out who is going to progress to MM?
To address this problem, Druley, now CMO at Mission Bio, has developed the Tapestri Single-cell Multiple Myeloma Multiomics Solution, which was launched today. The new product suite is based on applying multiplexing panels for DNA, genome-wide CNVs, and antibodies on bone marrow samples to provide comprehensive clonal and subclonal insights into MM disease evolution and biology at the single-cell level.
A bunch of riff-RAF
Scientists developing new medicines for MM need to learn more about how myeloid cells and molecules change over time, why some treatments do not work, and why the disease comes back at the subclonal level.
“We’re getting to the point where there’s so many treatment options that the clinicians are telling us, ‘Don’t tell me yes or no, my patient has a problem, because I’ve got 50, 60 things to choose from. You’ve got to give me some information on what to do for this patient; otherwise, I won’t order the test because all it does is add cost and no benefit to the patient. I end up doing the same thing I would have done had I not had your test anyway.’”
One approach researchers and biopharma companies use for therapeutic selection and disease surveillance of MM is targeting RAS/RAF mutations, which occur in about 50% of MM patients. But earlier this year, Hervé Avet-Loiseau, MD, PhD, a Mission Bio collaborator and head of the Laboratory for Genomics in Myeloma in the University Cancer Center of Toulouse, published work in Blood in late April of this year showing that solely targeting the RAS/RAF pathway for MM therapeutic intervention or residual disease assessment may not be a viable approach.
Avet-Loiseau’s team found that MM gets worse through branching patterns of clonal evolution. There are new subclones already in the early stages of cancer, and they have different sets of mutations than the main MM clone, which bulk measures detected at the time of diagnosis. These low-frequency subclones can outcompete other clones due to the prescribed therapeutic agents’ selective pressure. This clonal evolution drives an ever-changing MM heterogeneity, making therapy selection challenging.
To be more specific, Avet-Loiseau’s team used Tapestri to show that variable subclonal RAS/RAF mutations happen in different ways. This suggests that just targeting and tracking RAS/RAF mutations is insufficient to expect a cure.
“The decision to use a RAS inhibitor came from the bulk sequencing data of a sample, but the clone causing disease isn’t driven by RAS mutations,” said Druley. “Our clinical colleagues are looking at this and saying they can now understand why this patient wouldn’t respond to a RAS inhibitor.”
Phenotypic prescience
Mission Bio will present findings at the 2024 European Hematology Association (EHA) Congress that build on Avet-Loiseau’s team’s work and show how the Tapestri Single-cell Multiple Myeloma Multiomics Solution can reveal the ongoing nature of subclonal evolution in MM. This is important for finding the causes of MM before symptoms show up.
“The data that we’re going to show is that patients with SMM have multiple different precursor clones, but we’re finding which ones progress,” said Druley. “We can see the reason for this progress is because [the clones] have a biallelic loss of a particular gene or a chromosome aberration that’s a bad prognostic sign, stuff that just gets averaged out when you use a bulk sequencing strategy. The Tapestri Single-cell Multiple Myeloma Multiomics Solution has better resolution than anything on the market. We can tell you exactly how many cells we measure with a particular genotype and immunophenotype.”
While the Tapestri Single-cell Multiple Myeloma Multiomics Solution is a research-use-only (RUO) product, Druley hopes to see future diagnostics designed using the same molecular multiplexing approach.
According to Druley, “We can say, ‘Your patient has BCMA expression on the cell surface, and the reason they relapsed is because they’ve lost part of chromosome one. So, maybe you should try a CAR T cell against BCMA.’ It’s early, but that’s what our goal is.”
