No Transplant, No Problem: Redefining First-Line Myeloma Care With Anti-CD38 Therapies | Written Recap

Ajai Chari, M.D., is the director of the multiple myeloma program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. In this Managed Healthcare Executive K-Cast video series, Chari reviewed the evolution of first-line therapy for patients with transplant-ineligible myeloma, clinical trials comparing triplet (three-drug) therapy to quadruplet (four-drug) therapy and the role of anti-CD38 therapies, two of which have been approved by the FDA: daratumumab (sold under the brand name Darzalex) and isatuximab (sold under the brand name Sarclisa).

From doublet to triplet

Many patients with myeloma receive stem cell transplants. Still, patients who are older or have other health problems may not be eligible for transplants, and the treatment choices and strategies for these patients who are transplant ineligible differ from those who receive transplants. Chari said patients who are transplant ineligible used to be treated with melphalan-based regimens before the lenalidomide (sold under the brand name Revlimid) and dexamethasone combination became established. The next shift in first-line treatment was to the triplet therapy with bortezomib (sold under the brand name Velcade), lenalidomide and dexamethasone, a combination that became known as VRd because of the brand names, and a modified, less intense version dubbed VRd lite. In Chari’s view, though, the results from the MAIA study of combination daratumumab, lenalidomide and dexamethasone “threw the gauntlet down” as a first-line treatment for patients who are transplant ineligible. “[I]n patients with a median age in the early 70s, it gave a PFS [progression-free survival] of five years, which is, I think, incredible, and that’s without the use of a transplant,” Chari said.

CEPHEUS and IMROZ trials

After VRd became established as a common treatment regimen, researchers, with pharmaceutical company backing, launched clinical trials assessing quadruplet regimens. The CEPHEUS trial assessed VRd with the addition of daratumumab, and the IMROZ trial assessed VRd with the addition of isatuximab. Chari said results of a subgroup analysis of the CEPHEUS trial presented at the annual meeting of the American Society of Clinical Oncology this year showed all groups seemed to benefit from the addition of daratumumab, with the largest benefit for patients in a standard risk group. Similarly, in the IMROZ trial, patients benefited from the isatuximab, he said. But Chari has questions about both trials. Was CEPHEUS really a study of patients who were transplant ineligible? “To me, if you can get twice-weekly bortezomib, you’re transplant eligible. And that’s the struggle with this CEPHEUS study. It was criticized that it’s really a blend of [patients who are] transplant ineligible and transplant deferred,” Chari said. “It’s not really asking what we really want to know, which is does weekly bortezomib add value, and if so, how much do you need to give?” He noted, though, that a subgroup analysis showed that the favorable results of the trial were not different for a subgroup that was “truly ineligible” for transplants.

Chari noted that because the IMROZ trial did not include patients older than 80, it left out a group of frail patients. Still, Chari noted that the IMROZ results showed that the quadruplet therapy benefited patients deemed frail according to their International Myeloma Working Group frailty score.

The CEPHEUS and IMROZ trials are commonly framed as comparing triplet therapy, namely VRd, to quadruplet therapy. Chari said that is a mistake. “It’s not the number of drugs that we should be focused on,” he said. “It should be the dosing and schedule. I would bet money that a full-dose triplet will be much more toxic than a dose-attenuated quadruplet.” Chari expressed concern that if patients didn’t fare well on quadruplet therapy, oncologists in the community would be inclined to blame the fourth drug, daratumumab or isatuximab. “The trouble wasn’t the fourth drug; it was probably the twice-weekly bortezomib, the full-dose len [lenalidomide], the full-dose dex [dexamethasone],” he said.

A different backbone

Chari said he also disagreed with the thinking that has identified VRd as the “backbone” of the treatment of patients with myeloma who are transplant ineligible. He said the question researchers should instead be focused on is how to improve upon the daratumumab-lenalidomide-
dexamethasone combination assessed in the MAIA trial, and he mentioned the BENEFIT study as helping to answer that question. The backbone regimen in that study is isatuximab as the anti-CD38 agent, instead of daratumumab, in combination with lenalidomide and dexamethasone with bortezomib added as the fourth drug. Bortezomib was given weekly for approximately 12 months and then every other week for an additional six months, according to Chari. The results on the minimal residual disease (MRD) end point suggest the addition of bortezomib benefits patients, but Chari said longer-term follow-up is needed to know whether the MRD results translate into PFS.

Chari said bortezomib, a proteasome inhibitor (PI), should be used sparingly. He said he might prescribe a PI weekly — “not twice weekly, that’s for the birds” — and that he might decide whether to prescribe a PI based on whether a patient has high-risk disease and other factors. He added that in clinical practice, oncologists can see how a patient is doing after a few treatment cycles. Chari noted, though, that all of these studies show significant rates of peripheral neuropathy. “We talk about grade 1, grade 2,
grade 3 peripheral neuropathy, but why should we even accept any grade 1
neuropathy? If your PFS is five years, why do we need to give this patient any additional chronic adverse event? And that’s where I think this thought about the dosing intensity of bortezomib is so important,” Chari said.

Daratumumab vs. isatuximab

Chari said he did not see major differences in efficacy and safety of the two anti-CD38 therapies. Cost issues, he said, are “above my pay grade,” but he said cost issues are one of the main reasons one drug is used over another in a particular health system. He said both drugs are on the formulary at his health system. One notable difference between the two drugs is that daratumumab is administered by subcutaneous injection and isatuximab by intravenous infusion. “Is that the end-all and be-all? No. But if you can compare a five-minute injection versus a 90-minute or two-hour infusion, I think that’s a big difference,” Chari said, noting that the convenience of the injection may stand out if isatuximab
is the only drug that the patient is receiving intravenously. Chari said another difference is the dosing schedule, which is monthly for daratumumab long-term and every two weeks for isatuximab. He said “treatment fatigue” affects real-world use of cancer drugs, so the dosing schedule of daratumumab is an advantage.

Chari noted that a new subcutaneous formulation of isatuximab is coming out that will be delivered through an “on-body device” that releases the drug, in contrast to the daratumumab injections that are administered by a healthcare professional, often a nurse. Chari said patients, pharmacists and nurses are the stakeholders who will drive the choice between on-body device delivery of isatuximab and the subcutaneous injection of daratumumab.

Chari discussed the possibility of home administration of isatuximab with the one-body device. He also noted the regulatory barriers and the possible negative consequences on revenues for oncology practices.

Barriers to first-line anti-CD38 therapies

The evidence, based on results of the MAIA study, for anti-CD38 therapy is stronger for the treatment of patients with myeloma who are transplant ineligible than the evidence for VRd lite, which comes from a single-arm,
phase 2 study that included 50 patients, Chari said. The anti-CD38 regimens also have more favorable delivery schedules: every week for two months, every other week for four months and then once a month, in contrast with the twice-weekly injections of bortezomib. “So, why is it that in the U.S. only 40% to 60% of patients get frontline CD38?” Chari asked. He said the answer is inertia and that community-based oncologists treat relatively few patients with myeloma. In contrast, oncologists who practice at academic medical centers are using frontline anti-CD38 therapy overwhelmingly, and so are the community doctors who work with them.

“There’s a whole swath of patients and doctors who are not coming into contact with academia, and we know the vast majority of patients in the U.S. are being treated in the community. So, how do we get to those patients?” Chari asked. He answered his question with a suggestion to increase outreach to patient advocates. He also said efforts to educate community oncologists could be ramped up. Community oncologists might be more likely to attend educational sessions that provide concise updates on a number of cancers than an all-day session on myeloma, said Chari.