Possible Treatment for Multiple Myeloma Using Designed Oligonucleotide Created

A collaborative research team from the University of California San Diego School of Medicine and Ionis Pharmaceuticals are taking a new, targeted approach to myeloma treatment by silencing IRF4, a gene that allows myeloma stem cells and tumor cells to proliferate and survive. In the study published in Cell Stem Cell, the team details their successes inhibiting IRF4 with an antisense oligonucleotide, an engineered piece of DNA specifically designed to bind the genetic material coding for IRF4, causing it to degrade. 

One challenge myeloma researchers face is that myeloma cells don't grow well in laboratory dishes. To study the disease and test new treatments, the best method, the team says, is to transplant human myeloma cells into mice that lack an immune system and thus won't reject the human cells—making avatars of each unique patient, in a way.

The team tested ION251 on these myeloma mouse avatars. Compared to untreated mice, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice died. There were 10 mice in each treatment or control group and they received daily doses of ION251 or a control for one week, followed by three doses per week.

In separate experiments using human cells isolated from myeloma or healthy donor samples, doses of ION251 used were enough to eradicate the myeloma stem cells while sparing healthy blood cells. "The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank—in the treated mice, we couldn't find any myeloma cells left for us to study," said lead author Leslie Crews. "It makes the science more difficult, but it gives me hope for patients."

In addition to working on its own, the treatment improved myeloma tumor cell sensitivity to standard cancer therapeutics. The researchers also identified the mechanisms at play and described the molecular effects of IRF4 inhibition—information that both clarifies how myeloma forms in the first place, and how the treatment works.