Expert Discusses Daratumumab Developments in Myeloma

Ajai Chari, MD

Daratumumab (Darzalex) was shown to be safe and effective when added to the backbone of carfilzomib (Kyprolis) and dexamethasone in an analysis of patients with relapsed/refractory multiple myeloma enrolled on the phase Ib MMY1001 trial. Findings presented during the 2018 ASCO Annual Meeting signaled promising efficacy in patients who are refractory to lenalidomide (Revlimid), according to lead study author Ajai Chari, MD.

In this subgroup from MMY1001, 51 lenalidomide-refractory patients were treated with daratumumab plus carfilzomib and dexamethasone. At a median follow-up of 12.0 months, the median progression-free survival (PFS) in the lenalidomide-refractory population was 14.1 months (95% CI, 12.0-NE) and the 12-month PFS rate was 62%. Additionally, the overall response rate was 79%, including a complete remission (CR) rate of 10% and a stringent CR rate of 8%.

Chari also presented early findings from the PAVO study at the 2018 ASCO Annual Meeting, which is a phase I study evaluating subcutaneous daratumumab in patients with relapsed/refractory myeloma. This trial is aiming to cut down on infusion-related reactions for patients undergoing treatment with daratumumab.

OncLive: Can you begin by giving some background information on MMY1001?

In an interview with OncLive^®, Chari, associate professor, Mount Sinai Hospital, discussed the addition of daratumumab to carfilzomib and dexamethasone, as well as the potential impact of subcutaneous daratumumab in the treatment of patients with myeloma.Chari: The purpose of MMY1001 was to show the safety of adding daratumumab to various myeloma backbone regimens. In this particular subgroup, there was an addition of daratumumab to carfilzomib and dexamethasone.

What was the rationale for the analysis?

The study showed that the addition of daratumumab did not add much to the safety profile of these other regimens. There was no synergistic or increased toxicity, with the only possible caveats being infusion-related toxicities from the monoclonal antibody administration. In some studies, there is a slightly higher rate of neutropenia, but typically without any associated increase in infections. The rationale for the subgroup analysis—to look at the lenalidomide-refractory population—is basically coming from the fact that there is an increase in the use of lenalidomide maintenance after induction therapy and transplant due to the overall survival benefits reported. This means that the multiple large phase III studies that were published in high-impact journals, comparing triplet novel regimens with doublet control arms of lenalidomide/dexamethasone, would not apply to most patients who are refractory to these 2 agents. [In our study], we looked at patients who were refractory to lenalidomide see what the efficacy might be.

The overall population in this subgroup was 85, of whom approximately 50 were refractory to lenalidomide. What we saw was that the response rate did not seem to differ in the 2 groups, at around 80%. Most interestingly, the PFS was 14 months for the lenalidomide-refractory population. Admittedly, it has not been reached in the overall population but, even for lenalidomide-refractory groups, that is very impressive.

What is the design of that phase III study?

With so many regimens emerging in this treatment landscape, how would this combination fit into sequencing?

Is there anything else from MMY1001 that you would like to highlight?

While we should not compare directly across studies—to put this number into context—the PFS for pomalidomide (Pomalyst) plus dexamethasone was only approximately 4 months. Other regimens in this space with lenalidomide-refractory patients [showed a PFS of] up to 9 months. This 14-month signal is interesting, and hopefully we will see it validated when carfilzomib and dexamethasone is compared with or without daratumumab. The phase III study is ongoing.The phase III study that is open is carfilzomib at 56 mg/m² twice weekly with dexamethasone, with the experimental arm having the additional treatment with daratumumab at the standard dosing schedule. If this particular combination gets approved, it gives us yet another option to pair with carfilzomib. The benefit of that is that there is no right prescriptive treatment for every patient. At the end of the day, when you pick a regimen, it is going to depend on host factors, such as age, compliance, and ability to do oral therapy versus interest in doing parenteral therapy, and molecular risk, such as 17p deletion, renal function, cardiac function, and neuropathy. When you put all of those variables together, there is not going to be one regimen for everyone. That is what our job is as physicians—to tailor therapies to an individual. It is exciting for patients and physicians to have a lot of choices. An important part of this particular analysis is that daratumumab was given as a split dose for about 75 patients. We know that one of the biggest hassles in the community setting is the length of the first infusion. That is true for both patients and physicians. At academic centers, we can usually do this without any difficulty; the median duration is 7 hours. But in this study, 75 patients received split-dose daratumumab over 2 days, and the median infusion time was approximately 2 hours. The infusion-related reactions are typically around 40% to 50% in the first dose. Here, it was about 37% percent with the split dose, but on day 2, it was 3% to 4%.

You also presented phase I data on subcutaneous daratumumab in patients with relapsed/refractory myeloma. Can you give some background on the PAVO trial?

This is yet another advancement for patients and doctors to be able to give daratumumab more conveniently in the community setting until subcutaneous daratumumab becomes available.The main side effect of daratumumab is the infusion-related reactions and the long first infusion. PAVO is looking at subcutaneous daratumumab, which has already been done for other drugs, such as trastuzumab (Herceptin) and rituximab (Rituxan). The idea is that you can't just take a drug intravenously and inject that same huge volume under the skin. You can concentrate it, then you have to break down the hyaluronidase barrier. These drugs are basically administered with a coformulation combining the monoclonal antibody with hyaluronidase.

This particular update is the coformulation. Previously, pharmacists had to mix and deliver each part of the drug—both the hyaluronidase and the daratumumab. Here, the drugs are premixed, which makes it much easier for pharmacists.

What are the next steps?

What we found is that the infusion time is only 3 to 5 minutes; the infusion-related reactions were lower than what you would expect with intravenous (IV) daratumumab at about 16%, and the efficacy seems to be as good—if not better. The pharmacokinetics were actually superior, but the response rate was approximately 56%, with a median follow-up of 6.5 months. It is hard to compare across populations. However, as a single agent, that is an impressive response rate. It is one of those rare advancements in medicine where it is not only more effective and safer, but also more convenient. It will be a game changer for patients.The next steps will be the randomized study. The FDA did want a direct comparison of IV to subcutaneous infusion—it is a head-to-head study that is already open to accrual. The readout will be pretty quick, as I am sure it will accrue fast due to the interest in this agent. I am looking forward to seeing this drug get FDA approved [in this indication].

Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (Len)-refractory patients (Pts) with relapsed multiple myeloma (MM): Subgroup analysis of MMY1001. J Clin Oncol. 2018;36 (suppl; abstr 8002).