Navigating Triplet Therapies in Relapsed/Refractory Multiple Myeloma

Saad Z. Usmani, MD

To determine the best way to navigate treatment decisions for patients with relapsed/refractory multiple myeloma, especially with regard to triplet regimens, several factors must be considered, according to Saad Z. Usmani, MD.

“We group factors into 3 buckets: patient-related factors, disease-related factors, and prior therapy—related factors,” said Usmani. “Each factor has its own significance and importance.”

In an interview during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma, Usmani, chief of the Plasma Cell Disorders Program and director of Clinical Research in Hematologic Malignancies at Levine Cancer Institute, Atrium Health, expanded on some of the key principles to inform the treatment of patients with relapsed/refractory multiple myeloma.

OncLive: What factors do you consider when selecting therapy in the relapsed setting?

Usmani: We look at patient-related factors, which include age, comorbidities, socioeconomic support, and the setting the patients reside in—be it urban or suburban. These factors play a role in routes of administration and the kind of schedule you set up. Then, you have disease-related factors, which include the aggressiveness of the relapse. Is it a slow biochemical relapse? Is the patient clinically symptomatic? Are they presenting with circulating plasma cells or extramedullary disease? [Do they have] renal failure? Additionally, does the patient have other high-risk genomic features on their karyotypic analysis?

The third factor to take into account is prior therapies; specifically, we consider a history of stem cell transplant, proteasome inhibitors (PIs), immunomodulatory drugs, and monoclonal antibodies. Additionally, what adverse events (AEs) did patients experience [on those treatments] and what was their tolerability to those approaches? How long did their response last? Over time, patients pick up other comorbidities. They may have not had diabetes or heart disease before, but at the time of relapse they might.

How do you know whether a patient requires immediate treatment?

Clinical symptoms [could indicate the need for immediate treatment]. For example, if patients develop significant fatigue due to drops in hemoglobin, they experience new bone pain, or they present with renal failure, we want to reverse that organ damage and address the disease fairly quickly. Other situations [where we would want to intervene] include [when there’s] a very quick doubling time of a patient’s monoclonal protein or serum free light chains. If the doubling time is measured in days to weeks, there's trouble. [If] the doubling time is measured in months, it's a slow-growing kind of [relapse]. You have to pay attention to all of these things.

What does the landscape look like for relapsed/refractory myeloma right now?

Many different options are out there. One thing that we have learned over the past 8 years is that 3-drug combinations, or a multidrug chemotherapy regimens, works better than 2-drug combinations; that is consistent with what we know about the disease biology of myeloma. Many triplet options exist. You have to pay attention to the previous drugs that patients received and the kind of responses they had to them. [You want to know whether] patients had any drug-free intervals from specific drug classes [so you can] pair them with the right 3-drug combination. There are situations where we start off with 2-drug combinations, especially in older, frail patients, and then consider the addition of a third drug. [This kind of treatment scenario] is more art than science.

You discussed the Levine Cancer Institute pathway approach during the State of the Science Summit™. What does that methodology entail?

We approach treatment for patients in first relapse based on their exposure to lenalidomide (Revlimid) and bortezomib (Velcade), and whether they’re refractory to one or both of those drugs. We try to create the right 3-drug combination based on that information.

For example, if patients are progressing on lenalidomide-based maintenance therapy, putting them on a lenalidomide-based triplet does not make sense. In that case, we would choose a triplet that contains a PI along with another drug, which is generally a monoclonal antibody like daratumumab (Darzalex). If someone was exposed to lenalidomide but isn’t refractory to the drug, it's okay to consider a lenalidomide-based triplet therapy. If someone is progressing on PI-based maintenance given every other week, putting them on a bortezomib-based salvage regimen does not make sense. In that case, you would choose a triplet that does not contain bortezomib.

Patients who are sensitive to bortezomib and lenalidomide have many options. You can essentially repeat the same regimen they received in the frontline setting to get them into remission. You have to sit down with your patient, go through all the options, and help them choose the right regimen. The most difficult-to-treat patients are those who are refractory to both lenalidomide and bortezomib. In that case, we have to consider choosing a 3-drug regimen that does not contain lenalidomide or bortezomib. As such, you would probably want to choose a carfilzomib (Kyprolis)-based or pomalidomide (Pomalyst)-based triplet regimen.

Could you speak to some of the data that were presented in the relapsed/refractory setting at the 2019 ASH Annual Meeting?

In the early relapse setting, we saw many updates with 3-drug combinations, including several daratumumab-based triplets. The most recent [regimen that is being examined] is daratumumab, carfilzomib, and dexamethasone (DKd). I presented [data from] the CANDOR trial as a late-breaking abstract at the 2019 ASH Annual Meeting, and I spoke about how we can use that triplet in our schema of therapies. We also have longer-term follow-up from the POLLUX and the CASTOR trials, as well as data from the ELOQUENT-2 and ELOQUENT-3 trials. How we use each of these regimens depends on prior therapies patients have received.

Could you expand on the data from the CANDOR trial?

The CANDOR study was a randomized phase III trial that compared DKd with carfilzomib and dexamethasone (Kd) alone. It was a 2:1 randomization, so for every patient who received Kd, 2 were randomized to receive DKd. The primary end point of the trial was progression-free survival (PFS). After a median follow-up of 17 months, the median PFS was 15.8 months in the Kd arm but was not yet reached in the DKd arm; that [difference] was determined to be statistically significant. The overall responses were also higher in the DKd arm. The 12-month rate of minimal residual disease negativity was a key secondary end point, and this too, was higher in the DKd arm.

However, the AEs were numerically higher in the DKd arm, particularly with regard to infections. Interestingly, the rate of cardiotoxicity appeared to be lower in the DKd arm. However, 5 fatal serious AEs (SAEs) were reported in the DKd arm compared with none in the Kd arm; 4 of the SAEs were infection-related. A higher incidence of infections [appears to be associated] with the daratumumab-based regimens. Many of us discussed whether we should give these patients prophylactic treatments or identify those who already have recurrent infections and give them prophylactic intravenous immunoglobulins with potential antibiotic prophylaxis. That’s an area of ongoing debate.

Ultimately, CANDOR was a positive trial, which showed that DKd is superior to Kd alone. One-third of the patients were refractory to, or had been exposed to, lenalidomide. Many patients who undergo stem cell transplant stay on lenalidomide maintenance [in the United States]. When they relapse, many of the triplets that contain lenalidomide are not suitable options for them. Having a lenalidomide-free regimen for those patients is important.

Could you highlight the long-term follow-up data from the POLLUX trial?

The POLLUX trial was a randomized phase III study that compared daratumumab, lenalidomide, and dexamethasone (DRd) with Rd alone in patients who received 1 to 3 prior lines of therapy. The study read out more than 3 years ago. It was a positive trial that led to the FDA approval of this regimen.

In the initial analysis, we [didn’t see a difference] in high-risk patients. With subsequent follow-up, there does appear to be a benefit. The PFS was approximately 27 months in high-risk patients. That is an important piece of information. Now we know that the addition of daratumumab to Rd improves median PFS, even in high-risk patients. Does it overcome high risk? Probably not. If you look at the whole patient population, which includes standard-risk patients, the median PFS was about 44 months. There is certainly an improvement [in PFS] when compared with Rd, but it doesn't bring the median PFS up to the same mark as that of the standard-risk patients. We saw similar data for daratumumab, bortezomib, and dexamethasone.