May 14, 2020
Saad Usmani, MD, discusses the recent approval of daratumumab subcutaneous formulation for patients with multiple myeloma, and explains the major benefits of this treatment for this patient population.
Julie Gould: Welcome back to Pop Health Perspectives, a conversation with the population health learning network where we combine expert commentary and exclusive insight into key issues in population health management and more.
Today we are joined by Dr. Saad Usmani of the Levine Cancer Institute in Charlotte, North Carolina, Dr. Usmani discusses the recent approval of daratumumab subcutaneous formulation for patients with multiple myeloma, and he explains some major benefits of this treatment for this patient population. Dr. Usmani?
Dr. Saad Usmani: My name is Saad Usmani. I am a hematologist oncologist and a bone marrow transplant physician by trade. I'm the division chief of the Plasma Cell Disorders Program and the Director of Clinical Research for Hematologic Malignancies at the Levine Cancer Institute in Charlotte, North Carolina.
Julie: Can you briefly discuss the recent approval of daratumumab subcutaneous formulation for patients with multiple myeloma?
Dr. Usmani: Yes. This has been a long time coming. I've been involved with the daratumumab clinical development program from when daratumumab was still in phase one studies with formulation. The subcutaneous formulation studies were initiated back in 2015.
Based on the phase one data, a randomized phase three trial was designed to compare the intravenous formulation with the subcutaneous formulation. As a background, daratumumab is an anti-CD38 monoclonal antibody that is approved by the FDA for advanced myeloma patients as monotherapy for early relapse patients with combinations with the LenDex, bortezomib/dex, as well as pomalidomide/dexamethasone, and now even in the frontline setting with combinations with LenDex, VMP as well as VTD. Over the past five and a half years, we've seen several approvals come through and this drug has moved into the frontline setting.
The IV formulation that's commercially available can take several hours to infuse, and could be a matter of convenience as well as workflow for patients and oncology clinics respectively. This approval comes on the heels of a positive trial that led out.
The phase three trial called COLUMBA was a non‑inferiority trial, comparing the IV versus subcutaneous formulation of data. The primary endpoints with overall response rates as well as maximum Ctrough levels and the study was positive. It led to similar overall response rates between the two arms of the study, the maximum Ctrough was similar across the two arms.
What was striking was the fact that the subcutaneous formulation can be given in five minutes to patients compared to several hours for the IV formulation.
Julie: What existing data led research investigators to examine this drug, and can you dive a little bit deeper into those major study findings?
Dr. Usmani: Absolutely. The first trial that actually looked at the subcutaneous formulation was a phase one study. It was called the PAVO study, and it compared, initially, a mix‑and‑deliver formulation of the subcutaneous daratumumab, so utilizing the hyaluronidase recombinant formulation from Halozyme with daratumumab, showing its safety and effectiveness.
This was followed by a premixed syringe of a more concentrated formulation of daratumumab with the recombinant hyaluronidase enzyme, and then premixed syringe has about 15mls of volume which can be given as a subcutaneous injection under five minutes.
Based on those results, there was a randomized phase three trial called COLUMBA that was designed that was comparing the IV versus the subcutaneous formulation.
At the same time, there was an umbrella protocol called PLEIADES that was opened, where all the combinations that had already been examined with the IV formulation were again looked at, in combination with the subcutaneous formulation, just to make sure that the combination is safe and efficacious.
Each of these trials, in a stepwise fashion, demonstrated that the subcutaneous formulation has the same efficacy as the IV and can be combined, just like with IV formulation with other platform drugs, other regimens that we use for myeloma patients.
Based on all those results, the FDA granted an approval for the subcutaneous formulation of daratumumab, not just as monotherapy, but also in combination with almost all the existing IV formulation regimens.
Julie: Were any of the findings from the study that the approval was based on particularly surprising?
Dr. Usmani: Yes. One thing, and these were pleasant surprises, obviously, we were very happy to see that the patients felt that the subcutaneous formulation was convenient. We were also happy about the fact that the response rates were similar.
The other important thing was the infusion. The related reaction that can be seen the first-time patients are getting daratumumab with IV formulation, they were in the 30‑odd percent range for the IV formulation. But with the subcutaneous formulation, the infusion‑related reactions were about 12.5 percent or so.
It's better tolerated, it's faster, it's more convenient for patients, efficacy appears to be the same, and especially under the COVID‑19 pandemic, concerns about limiting exposure of patients to the healthcare setting, the subcutaneous formulation actually gives us that. Where we would be able to deliver this drug quickly thereby reducing the time it takes for patients to actually get it in the infusion center.
Julie: What are the real‑world applications for this approval in clinical practice?
Dr. Usmani: It's essentially that. I think it will be a big matter of convenience for patients because instead of spending several hours, they will be able to get into the infusion center, get their labs, and get this subcutaneous daratumumab and be out fairly shortly. Whereas with the IV formulation, it would take several hours. Especially with the first-time patients are getting the IV daratumumab, it can take up to seven hours.
It's a matter of convenience for patients and also for cancer centers and infusion centers where this drug would be given. Because now that you're not requiring chair time and a lot of chair time in the infusion center or nursing attention for those hours. The resource utilization will be much better in the oncology clinics.
Julie: Excellent. What are you most excited about in regards to this approval?
Dr. Usmani: I think it is all of the things that I've already shared with you. The fact that we will have a more convenient formulation for our patients. Especially, this approval comes in a very timely manner. I think that the patients will also appreciate this as well.
About Dr Usmani:
Saad Zafar Usmani received his medical education at Allama Iqbal Medical College in Lahore, Pakistan. He completed a residency in internal medicine at Sinai-Grace Hospital/Wayne State University in Detroit, Michigan and a fellowship in hematology and oncology at the University of Connecticut Health Center in Farmington, Connecticut. Dr. Usmani joined the faculty of the Levine Cancer Institute in July 2013; he also currently holds an academic appointment as Clinical Professor of Medicine at the University of North Carolina-Chapel Hill School of Medicine. Previously, Dr. Usmani served as an Assistant Professor of Medicine at the University of Arkansas for Medical Sciences in Little Rock, Arkansas and Director of Developmental Therapeutics at the Myeloma Institute for Research & Therapy.
Dr. Usmani is board certified in internal medicine, medical oncology, and hematology, and he is a Fellow of the American College of Physicians. He holds membership in several professional societies, including the International Myeloma Working Group, the SWOG Myeloma Committee, the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), and the American Society of Bone Marrow Transplantation. Dr. Usmani has served as the Track Leader on the ASCO Scientific Committee on Lymphoma and Plasma Cell Disorders, and he is a member of the ASH Committee on Plasma Cell Neoplasia and the National Cancer Institute Myeloma Steering Committee. Dr. Usmani is on the editorial review board of numerous medical journals, has authored/co-authored more than 130 peer-reviewed research manuscripts and 190 abstracts at national and international meetings. Active in clinical and translational research, Dr. Usmani has research interests focus on plasma cell disorders—in particular, high-risk multiple myeloma.