Dr Paul Discusses Magrolimab Combinations in Patients With R/R MM

Barry Paul, MD, Division of Plasma Cell Disorders, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute II, Carolinas HealthCare System, Charlotte, North Carolina, discusses a phase 2 multi-arm study of magrolimab combinations in patients with relapsed or refractory (R/R) multiple myeloma (MM). These data were presented at the 2021 Lymphoma, Leukemia & Myeloma (LL&M) Congress.

Transcript

Hi. My name is Barry Paul. I'm a physician and also an assistant professor of medicine and a division of plasma cell disorders. The department of hematologic oncology and blood disorders at the Levine Cancer Institute in Charlotte, North Carolina.

We know that the development of cancer requires normal cells to acquire methods to dysregulate proliferation and to avoid cell death. One of the ways that cancer cells do this is to overexpress the molecule CD47, which is the "don't eat me signal." CD47 causes cells to evade macrophage-initiated phagocytosis. Cells that overexpress this are not phagocytosis that they normally would be. 

Interestingly, all solid cancer cells, all hematologic cancer cells that have been studied to date overexpress CD47. It's particularly highly overexpressed in multiple myeloma (MM) cells. It also seems to have higher levels in MGUS, which is a precursor condition of myeloma, but even higher, still in MM. When patients progress from a precursor condition to active myeloma, levels of CD47 go up. 

It's also more highly expressed in patients who have higher risk cytogenetics, such as deletion 17p. It's been associated with shorter, medium progression-free survival (PFS) and overall survival (OS). Certainly, this seems to be an appropriate target.

Some preclinical data that's recently been generated has shown that using a CD47 targeting antibody has reversed the antiphagocytic effect of molecule in both cell lines and xenograph models. This does seem to be an appropriate target.

Additionally, I should say that there was a phase 1 trial that was conducted in high-risk myelodysplastic syndrome (MDS) that did show an overall response rate (ORR) on the order of 90 percent in combination of a CD47 targeting antibody called magrolimab and azacitidine. 

Based on all these data, we have justification to move forward with a combination study of magrolimab in MM patients.

This is an open-label, phase 2, multi-arm, multicenter trial that aims to evaluate the safety and tolerability of magrolimab, an anti CD47 antibody, in combination with standard care backbones such as daratumumab, pomalidomide and dexamethasone, and bortezomib dexamethasone in patients with relapsed refractory (R/R) MM.

The study will enroll up to 153 patients with R/R MM who have previously been treated with 3 or more lines of therapy, including an immunomodulatory agent and a proteasome inhibitor.

The specific objectives of this study are to evaluate the safety tolerability and recommended phase 2 doses of magrolimab combinations and to evaluate the efficacy of magrolimab combinations.

Also, we'll be looking at pharmacokinetics, pharmacodynamics, and immunogenicity of magrolimab in combination of other therapies in patients with R/R MM. 

The vast majority of myeloma patients today are being treated with multiple classes of agents, including IMiDs or immunomodulatory agents, proteasome inhibitors, CD38 antibodies. Most patients now or in the near future will also get a BCMA targeting therapy as these agents become more ubiquitous. Unfortunately, myeloma remains incurable, and all these patients eventually will progress even if they've had all of these lines of therapy.

We do need to continue to push the envelope and to have novel targets that are appropriate for patients who, unfortunately, have relapsed and have refractory disease to all the conventional targets at this point.

I would also say that I think it's important to recognize that a lot of our myeloma therapy does target the adaptive immune system. The more chemotherapy-exposed these patients are, the less robust their adaptive immune system becomes. 

I think that having an agent that targets the innate immune system rather than the adaptive immune system makes a lot of sense and has the potential to have significant efficacy in this relapse population.

The pandemic has, unfortunately, exacerbated this issue. We're seeing patients who are, unfortunately, diagnosed late in their disease course. They are coming into our clinic when they already have pretty significant burden of disease that could have been caught earlier ideally.

It's coming upon us sub-specialists to reach out to our primary care and community oncology colleagues to remind them to consider myeloma if a constellation of symptoms is present that oftentimes is quite, unfortunately, nonspecific. I can understand why it would be chalked up to something else. It's never wrong to send a workup, and it always helps to catch it early. It's certainly worthwhile to send the workup if patients have a nebulous constellation of symptoms that could be consistent with MM. 

With regard to enrolling patients on clinical trials, that oftentimes is a challenge. I always try to remind my patients that every drug they've been treated with, up until this point, goes through FDA approval without going through clinical trials. 

We stand on the shoulders of those that came before us. A lot of my patients, thankfully, want to be involved in this process and want to drive the field forward.

I always try to encourage them. I'm looking out for their best interests and that these agents do have that potential to be impactful in their treatment. Using those kinds of languages is helpful to help patients understand the law of clinical trials and how they don't just help drive the forward but also help the patients themselves.