Zonder Addresses Unanswered Questions in Newly Diagnosed Myeloma

Jeffrey Zonder, MD

Nontransplant regimens and discrepancies between real-world patient populations and those on clinical trials are areas currently being explored in the newly diagnosed multiple myeloma space, explained Jeffrey A. Zonder, MD.

In this setting, the triplet regimen evaluated in the SWOG S0777 trial of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd), continues to be the most widely used 3-drug induction regimen in the current treatment paradigm. However, researchers are investigating whether carfilzomib (Kyprolis), another proteasome inhibitor, would have better efficacy than bortezomib in this combination.

Secondly, researchers are looking more at minimal residual disease (MRD) negativity along with complete remission in ongoing clinical studies. However, Zonder said there is a disconnect in real-world outcomes between patients who are eligible for clinical trials and those who are not.

Results of a multicenter study revealed that there was great diversity in the treatment regimens used to manage multiple myeloma in real-life practice. The diversity, researchers found, was linked to factors such as novel agent accessibility and evolving treatment standards.

OncLive: Please provide an overview of your presentation.

What are some nontransplant regimens to note, and what are the expectations from those patients?

What is the role of carfilzomib in this setting?

What are the discrepancies between real-world patients and clinical-trial patients?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Zonder, an associate professor of clinical hematology-oncology at Karmanos Cancer Institute, Wayne State University School of Medicine, discussed triplet regimens in multiple myeloma and patient eligibility for clinical trials.Zonder: I spoke about the evolution of current therapy, including some of the data in favor of early transplant and supporting the use of high-dose chemotherapy as induction therapy for eligible patients. Additionally, I focused on the role of maintenance therapy and nontransplant therapy, as well as expectations from that group. I concluded with the role of antibody therapy and some of the latest data in that area. There is also the issue of real-world patients versus clinical-trial patients.Lenalidomide, bortezomib, and dexamethasone is probably the most commonly used triplet regimen in the United States. The data on that, from a number of studies, show the efficacy and the synergy between those 3 agents. In my presentation, I also spoke about the [bortezomib, melphalan, and prednisone] plus daratumumab (Darzalex) combination.Carfilzomib is being explored as a substitution for bortezomib in this triplet. There's an ongoing study looking at this and is asking 2 questions: the maintenance question and the induction question. We are looking at depth of response. The phase II data have been very provocative and we're seeing good-quality responses. We're just wondering whether this will translate to a phase III study. Presumably, the response rates will be the same as the triplet with bortezomib, but we believe the depths of response might be better in the carfilzomib arm.A group of European investigators looked at the inclusion and exclusion criteria in 8 upfront studies; 4 were done in older patients and 4 were in younger patients. They looked for commonalities in the inclusion and exclusion criteria. Then, they used the Danish Multiple Myeloma Registry to look at what percentage out of 2400 patients would have been eligible to be on those studies when they needed induction treatment. It turns out, in the younger patients, it was about 50%. In the older patients, only about 35% to 40% were eligible.

What does this mean for the frailer patient population?

When you look at the outcomes and PFS curves in patients who weren't eligible for the studies, there is a disconnect. What it has to do with is the ability to continue delivering therapy. We know that even in studies, it's common make dose reductions.It's important to consider that this study compared patients who would have been eligible for a clinical trial versus those who wouldn't have been eligible. What it tells us is we need to figure out how to deliver therapy more effectively to these frailer patients. It also reminds us that we don't need to feel wedded to the specific doses, and it doesn't have to be a triplet versus a doublet.

Recently, there were 2 next-generation sequencing assays approved by the FDA in myeloma. Can you shed some light on these?

Are there any remaining challenges in terms of diagnosing myeloma?

In one of the studies included in this analysis, the triplet arm actually did worse than the doublet arm. The therapy has to be tolerable for a patient to stay on it. Starting with a dose reduction for a patient who is expected to struggle probably makes sense.This deals with the question of MRD testing. Right now, we don't know what to do with it. We are able to, but we don't know what role it plays. There are commercial assays now to permit this. We know that when patients reach MRD negativity, they do better as a group. Depth of response predicts better and better PFS. Therefore, what do we do with this now? At this point, I don't know that we're ready to make treatment decisions based on MRD status. There are a few studies looking at this. We need to start asking the question of what exactly to do when patients are MRD negative.The diagnostic criteria are clear, and people are increasingly using better skeletal imaging to determine if a patient is symptomatic. Some of the newer criteria for diagnosis have a little bit of debate attached to them. Different people feel differently about it.

Mohty M, Terpos E, Mateos M, et al. Multiple myeloma treatment in real-world clinical practice: results of a prospective, multinational, noninterventional study. Clin Lymphoma Myeloma Leuk. 2018;18(10):e401-e419. doi: 10.1016/j.clml.2018.06.018.