Clinical Challenges: Options for Triple-Class Refractory Myeloma

Patients with so-called triple-class refractory multiple myeloma have poor survival, substantial hospitalizations, and a clinically meaningful decline in health-related quality of life, according to recent data.

Triple-class refractory disease — more a research term than a clinical term, according to Alfred Garfall, MD, of the Hospital of the University of Pennsylvania in Philadelphia — describes a patient with multiple myeloma who has disease refractory to all three of the major classes of myeloma treatments: immunomodulatory drugs lenalidomide (Revlimid) or pomalidomide (Pomalyst); proteasome inhibitors bortezomib (Velcade) or carfilzomib (Kyprolis); and an anti-CD38 monoclonal antibody such as daratumumab (Darzalex).

“Recognizing that myeloma is incurable in most patients, with time we anticipate that all of our patients will become triple-class refractory,” Garfall said.

Garfall noted that some patients with triple-class refractory disease may even have what some are referring to now as penta-refractory disease.

“This means a patient is refractory to both bortezomib and carfilzomib, to both lenalidomide and pomalidomide plus daratumumab,” Garfall said. “Patients in this category are a much higher-risk group. They still have some treatment options available, but not a ton.”

Individualized Treatment

Clinicians treating patients with triple-class refractory disease are challenged both by deciding how aggressively to treat and what to treat with.

“When some patients get to that penta-refractory category you have to temper expectations about how long we are going to be able to keep the disease under control,” Garfall said. “This likely includes a conversation about how much time the person wants to spend being a ‘patient’ as opposed to backing off therapy and prioritizing time at home.”

That said, if a patient decides to pursue further treatment, there are three main options available, according to Brandon Blue, MD, of Moffitt Cancer Center in Tampa, Florida. The first is use of conventional cytotoxic chemotherapy.

“Typically to pursue this route patients have to be in the hospital,” Blue said. “Unlike a lot of the earlier myeloma treatment options, these chemotherapy treatments come with a lot of harsh side effects as well.”

Garfall said that conventional chemotherapy is indeed a much riskier option for patients, but as a one-time maneuver can help to “reset” the clock. He added though that patients have to be healthy enough to tolerate this type of approach.

Novel Agents

Another approach that clinicians might pursue is the use of available novel agents, Blue said.

One novel agent for patients whose disease is refractory to more standard treatments is belantamab mafodotin (Blenrep). The FDA granted accelerated approval to the B-cell maturation antigen (BCMA)-directed antibody and microtubule conjugate for patients with relapsed or refractory multiple myeloma who have had at least four prior therapies. Results from DREAMM-2 showed an overall response rate of 31% among eligible patients. However, belantamab was approved with a boxed warning about changes in corneal epithelium resulting in alterations to vision.

An option in recent years for relapsed disease, the HDAC inhibitor panobinostat (Farydak), was recently withdrawn from the market by the drugmaker following discussions with the FDA.

Selinexor (Xpovio) was approved in 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma with resistance to at least two immunomodulatory agents, two proteasome inhibitors, and an anti-CD38 agent. This approval was based on a subgroup analysis from the STORM trial that showed a 25.3% response rate among these penta-refractory patients. Median duration of response was 3.8 months.

“These novel agents each have a novel mechanism of action than that of the triple-class group of medications,” Blue said. “Because each mechanism of action is novel, that mechanism could potentially work for the patient, but in general the response rates with these agents are not as high.”

Garfall said that because response rates with individual novel agents remain low, more research is being done looking into combining these therapies with other standard myeloma treatments.

“Even if a patient is penta-refractory, maybe the last time they had lenalidomide or pomalidomide was more than 2 years ago, so you could combine one of these novel agents with a standard myeloma drug that the patient hasn’t had recently,” Garfall said. “Early reports of some combinations are showing response rates over 50%, which is a much better proposition to present to patients.”

CAR T-Cell Therapy

The final option for patients with triple-class refractory disease is CAR T-cell therapy with the BCMA-directed idecabtagene vicleucel (ide-cel; Abecma). The FDA approved ide-cel in March for patients with multiple myeloma that has not responded to or has returned after treatment with at least four different prior therapies.

Data from the trial that led to the approval showed a 72% response rate to ide-cel, with a 28% complete response rate. An estimated 65% of patients who achieved a complete response remained in response for at least 12 months.

“The problem with CAR T-cell therapy remains duration of response,” Blue said. “In the patients this treatment works for, it may only work for 16-18 months. It is short-lived.”

However, CAR T-cell therapy is an option for older or frailer patients who might not be able to handle cytotoxic chemotherapy, and with the rapid progression of treatment options, a response of 16 to 18 months may be enough time for data about new treatment options or combinations, Blue said.

For example, Blue said, there is a lot of excitement around the use of bispecific T-cell engagers (BiTE), with new data presented recently at the American Society of Hematology Annual Meeting.

Garfall noted that another issue with ide-cel is availability of the product.

“[Penn] is a pretty big cancer center for myeloma but we haven’t been able to treat many people with ide-cel,” Garfall said. “We have maybe one slot per month.”

These availability issues are in addition to all the other barriers to getting CAR T-cell therapy such as proximity to a treatment center, the ability to wait 4 to 6 weeks for treatment, and associated costs.

Clinical Trials

Finally, both Blue and Garfall emphasized the importance of clinical trials for this triple-class refractory patient population.

“I would even put clinical trials in the mix with FDA-approved therapies in this patient population,” Garfall said. “In some ways, some of the drugs in clinical trials have shown results that are better than the preliminary results of some of the FDA-approved drugs.”

Anybody who is triple-class refractory should be considered for clinical trials. In fact, Garfall said, as patients become refractory to more lines of treatment, clinicians should refer them early to centers offering clinical trials.

“There are so many variables with study availability and eligibility criteria,” Garfall said. “When we see people referred at the time of disease progression they seldom can go right onto a clinical trial. With earlier referral, we can plan ahead for clinical trial availability.”