Relapsed/Refractory Multiple Myeloma Landscape

Kenneth Shain, MD, PhD: The treatment landscape in relapsed myeloma is a dynamic place. It’s changing significantly over time. We have a lot of new therapeutics and combinations approved and available for our patients, both in the early relapse setting as well as late relapse setting. We’re incorporating approved agents, new monoclonal antibodies targeting CD38, and isatuximab. We know we’re incorporating new formulations of drugs. We’ve been using another monoclonal antibody, daratumumab Faspro, which is under-the-skin or subcutaneous utilization of this monoclonal antibody. These are things that have been approved in phase 3 studies. We’re thinking more about late relapse disease with a number of exciting approvals, including melphalan flufenamide and belantamab mafodotin. These things are all helping us add therapies to our armamentarium. Obviously there will be a new frontier of cellular and noncellular direct immunotherapeutics like CAR [chimeric antigen receptor] T cells and BiTEs, which are bispecific T-cell engagers. Our landscape is changing as we go, and it’s important that we all continue to update and make sure we’re all on the same page about what’s available for our patients to best support their care and help them with algorithms to manage these patients as they walk through this chronic disease, moving from 1 therapy to the next.

In the early relapse setting, we have some strong phase 3 data that will help us drive new ways of taking care of patients. When you think about it, 2 of them revolve around isatuximab, a monoclonal antibody targeting CD38 as an IV [intravenous] formulation. ICARIA-MM has led to the approval of isatuximab in myeloma paired with pomalidomide and dexamethasone. The phase 3 study comparing isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone demonstrated superior progression-free survival and overall response rates.

These are exciting data, which allow us a second monoclonal antibody–targeting CD38 in the early relapse space. Isatuximab-based therapy is in IKEMA, which is a phase 3 study comparing isatuximab, Kyprolis [carfilzomib], and dexamethasone vs Kyprolis [carfilzomib] and dexamethasone. As suspected when we add an exciting and powerful monoclonal antibody targeting CD38 to these combinations, we have a triplet that is more effective with improved progression-free survival. All these things demonstrate the success and the importance of incorporating not just a monoclonal antibody, maybe during earlier lines of therapy in early relapse disease, but also the concept of 3 drugs is probably superior for most if not all patients than double therapy.

Another really important study is called the APOLLO study. This is another phase 3 study comparing subcutaneous formulation of daratumumab. We know that daratumab has been approved with pomalidomide and dexamethasone in the relapse setting, but this is focusing on that early phase of relapse. The study compared subcutaneous daratumumab—not IV—pomalidomide, and dexamethasone with pomalidomide and dexamethasone. It has been similar to what we would expect. There was a significant advantage within the context of adding a monoclonal antibody to the pomalidomide-dexamethasone backbone. In the subcutaneous formulation—meaning therapy is given in a faster and safer way to the same patient—there’s an improvement in overall response rates and a significant improvement in progression-free survival. Those are 3 highly successful treatment-altering phase 3 clinical trials to help dictate how we should be able to take care of our patients in the early relapse setting.

Adding to our stable therapies and finding the right patient for the right set of drugs is going to be critical for us. We learn more and more as we go along. That’s how I’d look at the 3 big, new phase 3 studies, which are important for us to think about how we use isatuximab as we continue to use Darzalex or daratumumab as an earlier line of therapy, a second monoclonal antibody to utilize in patients with strong, positive data from phase 3 randomized studies. We now know significant benefits of subcutaneous daratumumab in the phase 3 randomized study, in addition to pomalidomide-dexamethasone when it comes to Darzalex or daratumumab utilization.

Over the last decade, we’ve continued to identify new drugs with new targets or new mechanisms of action. In the world of myeloma and other cancers, as we get initial approvals late in disease state—with multiple relapses as monotherapy or doublet therapy with dexamethasone—and as we learn how to use these therapies, they become incorporated into early lines of therapy and in multidrug combinations. Triplet combinations are the most commonly utilized today. We realize that we need to treat patients earlier with the best drugs we have because we want to give them the best chance of long-term outcomes. Myeloma is a disease that’s heterogeneous, meaning that it’s different within patients. But even within the same patient, different clones that are growing. We need to target those by using as many mechanisms as we can. By using multiple targets and mechanisms of action, we’re able to do that in a given patient.

Another important reason why we need to incorporate therapies that are the best early on is because there’s way more attrition than we think about when it comes to treatment, meaning that as you walk from each subsequent line of therapy, we’re losing 30% to 50% of the patients for each therapy. That means that if we don’t use the best drugs we have early in the right accommodations, we may not be benefiting those patients because we’ll never get to use them later on. Overall, these things are all a culminating way for us to think about how we take care of patients. Right now, we think about newly diagnosed patients. Can we go from 3-drug therapy to 4-drug therapy? Can we give them all those drugs up front to make sure the maximum depth of response, which generally translates into longer-term outcomes? With novel therapies, monoclonal antibodies, and novel proteasome inhibitors, we’re able to drive disease down even in early relapse and, in the future, with CAR T and bispecifics, even in late relapse. These are all ways in which we should be affecting our patients.

Utilizing the best drugs in the right combination needs to start happening as early as possible so we can make sure our patients are seeing these drugs and getting maximal benefit from them. Identifying the right drugs and drug combinations is going to be critical. Thankfully, over the last several decades, we have a lot of new therapies available and new management strategies of multiple novel mechanisms of action. These are all things that we need to continue to incorporate into our therapy. We want to think about earlier therapy, getting these drugs in there as quickly as we can, with multiple mechanisms of action, and then try to balance those as we go across the landscape of treatment.

Transcript edited for clarity.