Understanding New Treatment Options for Patients with Relapsed/Refractory Multiple Myeloma

This article was originally published Cure

There has been tremendous growth over the years in terms of treatment options for patients with multiple myeloma. That growth has extended to patients in the relapsed and refractory setting who often face an even more complex disease than patients with traditional multiple myeloma.

This is as a result of patients with relapsed or refractory multiple myeloma having double the mutations that patients with newly diagnosed multiple myeloma have, according to Dr. Paul G. Richardson. This complex disease has also led to investigators looking at a wide range of treatments to target many different patients. There are multiple treatments approved by the Food and Drug Administration with more in clinical trials that patients have potential access to. The field is also looking to grow by targeting mutations through combination treatments that can help reduce side effects with smaller doses of each drug, explained Richardson at CURE®’s Educated Patient® Multiple Myeloma Summit.

CURE® recently spoke with Richardson, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and discussed the main aspects patients with relapsed/refractory multiple myeloma should know about.

CURE®: In your panel presentation you mention that multiple myeloma is complex. What makes it complex and what’s the difference for patients when they have relapsed or refractory disease?

Richardson: Multiple myeloma is an incredibly complex illness, both in its manifestations and in the pathobiology that underlines it. Its genetics are highly complex at diagnosis, and relapse due to the mutational thrust that’s inherent to the disease, as well as in fact, in some of the therapies we might use, genomic events can multiply. And then they can also be an entity called clonal evolution. At diagnosis, there are 5,000 mutations in a given patient’s multiple myeloma, but here at relapse, after stem cell transplantation, induction therapy and maintenance, this patient’s whole genome sequencing reveals over 12,000 mutations. So, that is a reflection of some of the complexity of the pathobiology, which means that relapse refractory strategies have to be on the one hand, biologically derived, and in that sense, targeted, but you can understand that a specific, genetically targeted approach is extremely challenging in the setting of so many mutations.

And with so many of those mutations, is that why these combination treatments are so promising?

Combination strategies are absolutely essential. We have 12 approved drugs at the moment, and obviously, how do we sequence them? How do we combine them to throw a big net around this disease and shut it down? That becomes extremely important.

The options summarized in the presentation, between proteasome inhibitors, immunomodulatory drugs, and then critically, the antibody targeting approaches. Now, the targeting approaches with antibodies are very interesting because they incorporate daratumumab, but now most recently Sarclisa (isatuximab). And the data that support this are the so-called ICARIA trial with pomalidomide and dexamethasone as a backbone, with Sarclisa in one arm of the study, and pomalidomide, dexamethasone as the standard of care in in the control group. What we were able to show through this combination approach is remarkable activity. Now the important point about Sarclisa is that it obviously targets CD38, but it has a unique epitope, and that actually sets it apart from daratumumab. And it targets an actual enzyme uniformly expressed on myeloma cells through the CD38 mechanism. But importantly, there is more of an aphotic effect that it has, as well as this inhibition of CD38 enzymic activity. So, in addition to the immunological mechanisms, there are these direct effects that are qualitatively stronger with Sarclisa preclinically.

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