Multiagent Regimens Progress Further in Frontline Myeloma

Kenneth C. Anderson, MD

The pace of progress in multiple myeloma is such that patients are living progression-free for more than 8 years, said Kenneth C. Anderson, MD. This progress is, in large part, due to the increasing number of triplet therapies that have become available to patients, irrespective of transplant eligibility.

“We have been so blessed in myeloma with [the emergence of] several novel agents,” said Anderson, program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute and a 2014 Giant of Cancer Care^® in Multiple Myeloma. “Now the disease has become chronic for many patients. Progression-free survival (PFS) in myeloma is now 7 to 8 years, and potentially over 10 years in patients who receive standard of care with or without transplant and maintenance.”

However, each successive step forward is leading to an increasing array of questions, such as how to incorporate quadruplet therapies into the paradigm and whether minimal residual disease (MRD) can be used to inform treatment decisions in such a heterogeneous population.

In an interview with OncLive, Anderson, also the Kraft Family Professor of Medicine at Harvard Medical School, discussed available and emerging frontline treatment regimens for patients with newly diagnosed multiple myeloma and evaluated the utility of MRD in the paradigm.

OncLive: What are the current treatment options for patients with newly diagnosed multiple myeloma?

Anderson: Combinations of novel agents, usually triplets, have become the standard of care in newly diagnosed myeloma. The most commonly used regimens would be lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd), or, perhaps, cyclophosphamide, bortezomib, and dexamethasone (CyBorD). These regimens are used in all patients, irrespective of transplant eligibility, because they have a very high extent and frequency of response; that includes a high rate of MRD negativity as well. They’re also well tolerated.

In myeloma, we like to be sure that all patients can get the benefit of these 3-drug combinations. Therefore, in transplant-ineligible patients who are elderly and maybe frail, we can reduce the doses of RVd to a regimen called "RVd-lite," so they can appreciate the benefit of 3 drugs.

In the near future, 4-drug regimens will enter the field. There are many studies looking at quadruplet regimens. For example, RVd with or without daratumumab (Darzalex), elotuzumab (Empliciti), and isatuximab, which is a new CD38-targeted antibody. These studies are all already complete or ongoing. It is my expectation that we will move from triplet therapies to quadruplet therapies.

When we see new patients with myeloma—especially those who are not transplant candidates—we evaluate their frailty status. They're either fit, intermediate, or frail. I mention that because in a newly diagnosed, frail, transplant-ineligible patient, we might use lenalidomide and dexamethasone alone, or bortezomib and dexamethasone alone, rather than a 3-drug regimen.

Additionally, in June 2019, the FDA approved another triplet for use in newly diagnosed patients—specifically, daratumumab, lenalidomide, and dexamethasone (DRd). We will have to see how this is integrated into frontline therapy.

Could you discuss the data that led to the FDA approval of DRd?

Patients who received DRd achieved a higher extent and frequency of response compared with those who received lenalidomide and dexamethasone alone. There was also a higher rate of MRD negativity in the triplet arm. This correlated with—especially in the transplant-ineligible patients—a longer PFS and a trend towards overall survival (OS). Additionally, the tolerability was very good. The expectation is that, in the not-too-distant future, daratumumab will be given subcutaneously. DRd might eventually be a subcutaneous injection of daratumumab together with oral lenalidomide and dexamethasone, which will make it user friendly for patients and caregivers.

With so many different options, how do you select what's best for your patient?

The fact that we have so many options and even more coming is a wonderful opportunity for patients and caregivers alike. When it comes to deciding on a therapy, we evaluate the status of the patient. For a newly diagnosed patient, we consider their frailty status and whether they are fit, intermediate, or frail. That will help inform us in terms of whether we use a 2-drug or a 3-drug regimen. We also consider clinical characteristics of the patient. If, for example, a patient presents with neuropathy, we would avoid bortezomib and perhaps go with carfilzomib (Kyprolis). If they present with renal dysfunction, we would include a proteasome inhibitor (PI).

In the setting of renal dysfunction or hypercalcemia where we need to have a rapid response, we might utilize intravenous RVd for a cycle or 2 to get a response and then switch over to subcutaneous bortezomib weekly instead of twice weekly. With weekly subcutaneous bortezomib, the neuropathy levels are quite low. We have to consider a patient’s risk status as well. Although that doesn’t influence initial therapy, it does influence what we utilize for maintenance. Plainly, we use lenalidomide continuously in standard-risk patients. In those who have high-risk disease, we incorporate a PI with lenalidomide as continuous maintenance.

Could you highlight the data supporting 4-drug regimens?

The only data that exist at the present time for 4-drug regimens is really early. In the GRIFFIN trial, investigators are testing the quadruplet regimen of daratumumab, lenalidomide, bortezomib, and dexamethasone compared with lenalidomide, bortezomib, and dexamethasone alone. In a short run-in trial of daratumumab with RVd, the response rates were very high, the tolerability was good, and there was a high MRD-negative rate. The randomized phase III GRIFFIN trial is now complete, and I suspect we will hear about that at subsequent national meetings.

In terms of other quadruplet therapies, there are early data regarding the other CD38-targeted antibody, isatuximab. Isatuximab was tested in combination with RVd in transplant-ineligible patients. Those data were presented at the 2018 ASH Annual Meeting by Enrique Ocio, MD, PhD, from the Marqués de Valdecilla University Hospital. The regimen induced a 100% response rate; a very high fraction of patients had a very good partial response or better—I believe it was 92%. Then, half of the patients achieved MRD negativity. I do believe we’ll incorporate an antibody in this setting. However, we don't have the results of the phase III randomized trials yet.

What role does MRD testing currently have?

MRD testing is exciting in the sense that we can now reach MRD levels with triplet therapies with or without high-dose treatment and stem cell transplant. The first point is that MRD is achievable; it was previously only achievable with allogeneic transplant. There, we knew that if a patient was MRD-negative after allogeneic transplant, it portended for a long-term PFS and OS benefit. We know from meta-analyses of retrospective data that PFS and OS is better in patients who achieve MRD negativity.

The main prospective data set that we have comes from the IFM/DFCI 2009 trial. In the trial, RVd was tested with or without transplant and investigators showed that in both arms, there were high rates of MRD negativity. However, these rates were slightly higher in the transplant arm. In both arms, if patients achieved MRD negativity, PFS and OS rates were improved.

In 2019, MRD is only being evaluated in clinical trials; it's being used to test its value after transplant. For example, should patients who have MRD-positive disease after transplant receive consolidation—or in the maintenance setting? A very important question that's now being evaluated in clinical trials is whether or not we can discontinue maintenance in patients who have persistent MRD negativity.

The question is, “How we are going to develop novel agents without waiting for PFS as a regulatory endpoint?” It's clearly too late to wait for patients, caregivers, and companies to try to carry out trials that are a decade or longer; it’s simply not practical. We're trying to validate the utility of MRD negativity early—say at 18 months—in terms of its ability to predict for OS benefit. That's being done in cooperative group studies. Individuals, companies, and centers all around the world are doing single-patient meta-analysis of the available data to determine whether we have data robust enough to justify utilizing MRD as a regulatory endpoint.

How do you see the role of MRD testing developing in the future?

MRD negativity will become a clinical and a regulatory endpoint. A greater proportion of patients are going to be able to achieve and maintain it in the future. My sincerest hope is that we can use MRD negativity to inform therapy. If we combine novel targeted therapies with [immunomodulatory (IMiD) agents], my expectation is that there will be patients who will have persistent MRD negativity in whom we can discontinue maintenance. From a patient perspective, to have MRD negativity and be off therapy is a goal they would cherish, as would we.

What are the challenges that need to be overcome in our understanding of MRD in myeloma?

There are many challenges that we need to address when it comes to MRD. The clinical utility simply isn't determined yet. There are many clinical trials looking at its value in induction, consolidation, and maintenance. We don't know whether MRD negativity will have the same value in different genetic contexts, including 14 translocations and 17p deletion, nor are we sure that we have data to suggest that MRD will mean the same thing in different clinical settings.

For example, [we still don’t know] whether MRD after induction in a transplant-ineligible patient is the same as MRD negativity after high-dose therapy and transplant. In relapsed myeloma, is the value the same regardless of what a patient is initially treated with? Furthermore, if a patient achieves MRD negativity in the relapsed setting, does a certain regimen portend the same benefit or not? Those data are coming from meta-analyses of already available clinical trial data. Most importantly, it will come from prospective trials that are now evaluating MRD in many different settings.

What advice can you give to community oncologists treating patients with newly diagnosed myeloma?

Right now, initial therapy is typically a triplet, such as an IMiD drug like lenalidomide, a PI like bortezomib or carfilzomib (Kyprolis), and dexamethasone. The 4-drug regimens are coming with the incorporation of an antibody, but they're not here yet. The practicing oncologist needs to evaluate the frailty status of the patient and may need to adjust the regimen so that patients can enjoy the benefit of the triplet.

In terms of the clinical utility of MRD negativity, I don't believe it's really known; it does not change clinical practice. You would use the same initial therapy, do the same transplant, and use maintenance therapy. As of now, you would not discontinue maintenance therapy with persistent MRD negativity; that is potentially going to change. We certainly hope so, but I don't believe MRD negativity adds very much value in routine clinical practice right now.

The novel therapies that we have and that are coming are exciting; we can achieve long-term PFS. Equally exciting is the fact that we have triplets of second-generation agents available for patients who have relapsed myeloma. We also have very exciting targeted and immunotherapy agents to address that problem. If you add the benefit from initial treatment to the benefit that is achieved with therapies in the relapsed setting, you can start to see how we’re changing the natural history of the disease and making myeloma a chronic illness for many patients. I believe we have had 24 FDA approvals in the past 10 to 15 years. The future is brighter still.