Expert Explains Shifting Myeloma Paradigm

Keith Stewart, MB ChB

In the shifting treatment landscape of multiple myeloma, experts are beginning to question previously established methods as new agents and techniques emerge.

Transplant

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Multiple Myeloma and Myeloproliferative Neoplasms, Keith Stewart, MB, ChB, professor of medicine, consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, discussed the role of stem cell transplant, minimal residual disease (MRD) testing, and maintenance therapy in the treatment of patients with multiple myeloma.Agents such as the immunomodulatory drug lenalidomide (Revlimid) and the proteasome inhibitor bortezomib (Velcade) have entered the myeloma space, potentially changing the progression of treatment for these patients. Specifically, the role of transplant has come under question—a therapy that Stewart says is often intolerable for patients.

"Like many of us, I was optimistic that with the use of new drugs, particularly bortezomib and lenalidomide, that we would finally be able to confine transplant to history, because it is a pretty terrible brute force therapy that we do," Stewart said.

Although novel agents have been introduced and are showing efficacy, transplant remains essential for the care of young and fit patients with myeloma, Stewart says. Data have shown a significant advantage in progression-free survival (PFS) for those who went onto transplant, even when compared with the latest drugs. Stewart said that there is probably a peak time for the usage of transplant.

“For example, the combination of bortezomib, lenalidomide, and dexamethasone continuously was compared with the same drugs followed by transplant and some consolidation [therapy]. Patients who had received a transplant had a very significant improvement in PFS, but not yet overall survival (OS) because of the short follow-up,” said Stewart.

Maintenance

In Europe, where newer agents are less available, 2 transplants have been shown to be superior to 1, said Stewart. In the United States, that has not been confirmed. The phase III StaMINA trial failed to confirm that single transplant with a tandem transplant added benefit versus single transplant with consolidation.¹ Specifically, the addition of lenalidomide, bortezomib, and dexamethasone consolidation or a second autologous hematopoietic stem cell transplant (ASCT) was not superior to a single ASCT, followed by lenalidomide maintenance, in the upfront treatment of multiple myeloma.In the posttransplant setting, maintenance therapy with lenalidomide has become a favored therapeutic approach in the United States. Maintenance therapy with lenalidomide, specifically, has shown a significant benefit in PFS, as well as OS. In a meta-analysis published in 2017, patients with multiple myeloma posttransplant assigned to lenalidomide had superior PFS (52.8 vs 23.5 months) compared with those given placebo or observation (HR, 0.48; 95% CI, 0.41-0.55).² At a median follow-up of 79.5 months, the median OS was 86.0 months for the placebo or observation group and had not been reached for the lenalidomide maintenance group (HR, 0.75; 95% CI, 0.63-0.90; P = .001).

These claims of benefit were cemented in place by the large Myeloma XI trial out of the United Kingdom, Stewart said, which looked at the role of maintenance therapy in more than 1000 patients. The study showed that patients with myeloma had deeper responses after induction and after allogeneic stem cell transplantation with outpatient-delivered quadruplet therapy than with sequential immunomodulatory triplet combinations.³ Although lenalidomide has shown benefit in patients following stem cell transplant, investigators are looking into combinations to see if the addition of more drugs may prove better.

“Based on those 2 recent updates, lenalidomide maintenance also seems to be here to stay,” Stewart said. “The question that arises is, ‘Is that enough, or should other drugs be added?’ We don't have a lot of data on that.”

MRD Testing

Additionally, ixazomib (Ninlaro) has shown potential in the maintenance setting, and the question of whether monoclonal antibodies such as daratumumab (Darzalex) might be useful in that setting is still unresolved. Stewart says that some experts suspect that that class of agents may show some benefit.A potentially paradigm-shifting advance is the use of MRD testing in patients with multiple myeloma.

"We have pretty powerful evidence at this point that MRD measurement is important. Patients who obtain MRD-negative states live longer free of disease and probably have a longer OS,” said Stewart.

MRD testing seems to be sensitive to the technique that is employed, as both flow cytometry and next-generation sequencing (NGS) can be used. Regardless, obtaining MRD negativity will become a standard of care as technology improves, Stewart explained.

“They both have their pros and cons,” he added. “If anything, NGS seems to be a little more sensitive in most people's hands, and it seems like that makes a difference.”

Stewart said that MRD could become the primary endpoint of future trials, and it may become central in the definition of cure for these patients. At the very least, MRD will be essential in stratifying patients with multiple myeloma.

The future treatment of these patients will move away from transplant, according to Stewart. He concluded that in 5 to 10 years, the treatment of patients with multiple myeloma will include a 4-drug induction regimen, which will be used until MRD negativity or a complete response, then maintenance with an oral antibody. If relapse occurs, active immunotherapy will be administered, he said.

Another path after induction could potentially include chimeric antigen receptor (CAR) T-cell therapy. There are currently multiple CAR T-cell therapies under investigation in multiple myeloma, including the BCMA-targeted CAR T-cell product bb2121, which was granted a breakthrough therapy designation by the FDA for previously treated patients with relapsed/refractory multiple myeloma in November 2017.

References

1. Stadtmauer EA, Pasquini MC, Blackwell B et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): Primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 — StaMINA Trial). In: Proceedings from the 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, California. Abstract LBA-1.
2. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis [published online]. J Clin Oncol. 2017;35(29):3279-3289. doi: 10.1200/JCO.2017.72.6679.
3. Jackson GH, Davies F, Pawlyn C, et al. Lenalidomide induction and maintenance therapy for transplant eligible myeloma patients: Results of the Myeloma XI study. J Clin Oncol. 2017;35(15):8009. doi: 10.1200/JCO.2017.35.15_suppl.8009.