Expert Discusses the Changing Treatment Landscape of Multiple Myeloma

Keith Stewart, MB ChB

Keith Stewart, MB ChB

Experts are now questioning the previously established methods and strategies for the treatment of patients with multiple myeloma as new agents and treatment techniques continue to emerge in the field.

Keith Stewart, MB, ChB, a professor of medicine and consultant for the Division of Hematology/Oncology, Department of Internal Medicine at the Mayo Clinic, recently discussed how stem cell transplant is changing the treatment landscape for multiple myeloma, as well as minimal residual disease (MRD) testing and maintenance therapy.

Transplant

Lenalidomide (Revlimid), an immunomodulatory drug, and bortezomib (Velcade), a proteasome inhibitor, are of these new agents entering the treatment landscape of multiple myeloma. The role of transplant is under questoin, which Stewart says is often found intolerable.

"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 explained.

Transplant remains essential for the care of young and fit patients with myeloma, despite newer novel agents that have shown efficacy, Stewart says. A significant advantage has been found in progression-free survival (PFS) for patients who went onto transplant, even after being compared to 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]," Stewart added. "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."

Two transplants have been shown to be superior to 1 in Europe where newer agents are not as available, said Stewart. That has not been confirmed in the United States. The StaMINA trial, a phase III study, did not confirm single transplant with tandem transplant would add benefit compared to single transplant with consolidation.¹Specifically, addition of lenalidomide, bortezomib, and dexamethasone consolidation or a second autologous hematopoietic stem cell transplant (ASCT) was not found to be superior to a single ASCT that is followed by lenalidomide maintenance, in the upfront treatment of patients with multiple myeloma.

Maintenance

Maintenance therapy with lenalidomide in the posttransplant setting has become a favored therapeutic approach in the United States. Specifically, maintenance therapy with lenalidomide 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).²The median OS at a median follow-up of 79.5 months was 86.0 months for the placebo group and was not reached in the lenalidomide maintenance group (HR, 0.75; 95% CI, 0.63-0.90; P= .001).

Stewart explained that these claims of benefit were put in place by the large Myeloma XI trial out of the United Kingdom, which looked specifically at the role of maintenance therapy in over 1000 patients. Patients with myeloma had deeper responses after induction, according to the results from this study, and after allogeneic stem cell transplantation with outpatient-delivered quadruplet therapy than with sequential immunomodulatory triplet combinations.³Although benefit was shown with lenalidomide in patients following a stem cell transplant, investigators are looking at combinations to see if addition of more drugs can cause an improvement.

“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.”

Ixazomib (Ninlaro) has also shown potential as a treamtnet in the maintenance setting. The question of whether monoclonal antibodies such as daratumumab (Darzalex) can be be useful in that setting is still unresolved, but Stewart says some experts believe that that class of agents will show some benefit.

MRD Testing

There is potential for a paradigm-shifting advance is the use of MRD testing in the treatment landscape of 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,” Stewart said.

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

“They both have their pros and cons,” he continued. “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. It may become central in the definition of cure for these patients. MRD, at the very least, will be essential in stratifying patients with multiple myeloma.

Future treatment will move away from transplant, Stewart said, adding that in 5 to 10 years, the treatment for this patient population will include a 4-drug induction regimen, which will be used until MRD negativity or a complete response, then maintenance with an oral antibody. He said that if relapse occurs, active immunotherapy will be administered to those patients.

Another potential path after induction includes chimeric antigen receptor (CAR) T-cell therapy. Multiple CAR T-cell therapies are currrently under investigation in multiple myeloma, including the BCMA-targeted CAR T-cell product bb2121, granted a breakthrough therapy designation in Novemeber 2017 by the FDA for previously treated patients with relapsed/refractory multiple myeloma.

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.