Frontline Standard in Myeloma Continues to Evolve

Sergio A. Giralt, MD

The introduction of novel up-front regimens headlines the latest advancements in the multiple myeloma paradigm, said Sergio A. Giralt, MD. 

“Multiple myeloma has had enormous changes over the last decade, with many new drugs and combinations approved,” said Giralt, chief, Adult Bone Marrow Transplant Service, and Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center. “We are now using 3-drug inductions and perhaps, we will use 4-drug combinations in the future."

For example, in September 2019, the addition of daratumumab (Darzalex) to bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) was approved for transplant-eligible patients with newly diagnosed multiple myeloma, a decision that was based on the phase III CASSIOPEIA (MMY3006) trial.

Results showed a 53% reduction in risk of progression or death with the quadruplet compared with VTd alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). Additionally, the stringent complete response rate at postconsolidation therapy was 29% in patients who received the daratumumab regimen versus 20% in those who received VTd alone following consolidation therapy (odds ratio, 1.60; 95% CI, 1.21-2.12; &#8239;P &#8239;= .0010).

“In the context of myeloma, 3 drugs are better than 2,” Giralt added. “The incorporation for 4 drugs may eventually be the standard of care, but for now, 3 drugs should be considered standard while 4 drugs should be considered in clinical trials.”

In an interview during the 2019 OncLive^® &#8239;State of the Science Summit^™ on Hematologic Malignancies, Giralt discussed the changing frontline treatment setting in multiple myeloma, how to determine transplant eligibility, and the utility of testing for minimal residual disease (MRD) negativity.

OncLive:&#8239; What is the state of frontline treatment for patients with multiple myeloma?

Giralt: &#8239;The current standard in the United States is VRd [bortezomib, lenalidomide (Revlimid), and dexamethasone]. In patients with renal failure or renal dysfunction, the combination of lenalidomide, cyclophosphamide, and dexamethasone is commonly used.&#8239;

Randomized trials have shown that 3-drug regimens are better than 2-drug regimens for both transplant-eligible and -ineligible patients. VRd was shown to be superior to the combination of lenalidomide and dexamethasone in the SWOG S0777 trial, which was associated with a survival benefit.&#8239;

What factors determine transplant eligibility?

The one factor that should &#8239;not &#8239;play into that decision is age. Age is just a number.&#8239;

What should play into the decision? The patient's performance status, comorbidity score, and functional performance status. For many patients above the age of 75, we do geriatric assessments to decide whether or not transplant is a good option, as well as to determine how to transplant them.&#8239;

We also dose-adjust for older patients, so comorbidities are more important than age. &#8239;Additionally, many physicians think a patient with multiple myeloma and renal failure on dialysis should not undergo transplant. That is not the case. It has been shown that patients on dialysis can safely receive high-dose melphalan, and many patients can recover kidney function and come off dialysis.&#8239;

Could you discuss updates in maintenance &#8239;therapy and the TOURMALINE-MM3 trial results?

TOURMALINE-MM3 was a randomized trial of an oral proteasome inhibitor called ixazomib (Ninlaro) versus placebo. &#8239;It was associated with progression-free survival improvement compared with placebo.

However, my current recommendation of oral maintenance therapy is lenalidomide over ixazomib. Lenalidomide has been established as the standard of care. Ixazomib and lenalidomide have not been compared head-to-head, and you can’t [do cross-trial comparisons]. For patients who cannot take lenalidomide, ixazomib is a reasonable proteasome inhibitor to consider.

How is MRD negativity being tested for in multiple myeloma? Will this testing become more widespread?

We want to get away from the term and “MRD” and exchange it for measurable residual disease. MRD gives the idea that there is nothing left, which is not necessarily the case.

Currently, we have 2 assays to measure MRD. One is next-generation sequencing, and the second is flow cytometry.&#8239; Both [approaches] have pros and cons. Generally, the degree of sensitivity is 1 in 100,000 to 1 in 1 million myeloma cells in normal bone marrow.

There are enough data to suggest that MRD negativity is associated with better outcomes. However, we don’t know if we are changing a patient’s natural history once we convert them to MRD negativity, nor do we know the optimal testing time to measure MRD.

This is an important tool, but it is not ready for prime time clinical decision-making use yet.

Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomized, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.