More Research Required to Determine Best Practices in High-Risk Myeloma

Andrew Branagan, MD

Autologous stem cell transplantation continues to have a significant role for patients with high-risk myeloma; however, research efforts continue to focus on novel induction, consolidation, and maintenance regimens, as well as the use of tandem transplant, explained Andrew Branagan, MD.

“High-risk patients have the greatest need,” said Branagan, adding that future research efforts must focus on closing that gap.

In the maintenance setting, for example, an ongoing challenge is determining the optimal maintenance therapy for high-risk patients.

The phase III TOURMALINE-MM3 trial examined the efficacy of ixazomib (Ninlaro) compared with placebo as a maintenance therapy for newly diagnosed patients with multiple myeloma, 18% of whom had high-risk cytogenetics. At a median follow-up of 30.9 months, a 28% reduction in the risk of progression or death was observed with ixazomib compared with placebo; the median PFS was 26.5 months versus 21.3 months, respectively (HR 0.72, 95% CI 0.58-0.89; P = .0023). The PFS benefit with ixazomib extended to those with high-risk cytogenetics (HR, 0.62; 95% CI, 0.38-1.02).

While the data are encouraging, Branagan also expressed the need to compare lenalidomide (Revlimid) with ixazomib in the maintenance setting, and also discussed interest in combining both classes of agents.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma, Branagan, a medical oncologist in the Center for Multiple Myeloma at Mass General Cancer Center in Massachusetts General Hospital, discussed the evolving role of transplant and ongoing research in high-risk multiple myeloma.

OncLive: How has the role of transplant in multiple myeloma evolved over recent years?

Branagan: It's very exciting that [transplant] has held up [in multiple myeloma treatment] because there is a benefit to transplant. The recommendation in 2020 is still to do an upfront transplant consolidation in transplant-eligible patients [with multiple myeloma]. [Transplant] seems to improve PFS as well as OS, and it seems beneficial for patients who have high-risk disease.

How do you determine whether or not a patient is eligible for transplant?

Part of [eligibility for transplant] is age. [Eligible patients] used to be [under] 65 years of age. Now, pretty commonly in the United States, patients can get [transplant] into their early 70s. Overall, a patient should have no major comorbidities and no detriments on a frailty score. Someone who is young without comorbidities would be an ideal candidate.

What are the latest updates with transplant in myeloma?

One of the latest updates was whether to use a tandem transplant, meaning 2 back-to-back transplants. This isn't entirely a new idea. People have done tandem transplants for quite some time. There was some interesting data that using 2 back-to-back transplants was beneficial for these high-risk patients.

The European Society for Blood and Marrow Transplantation had a very promising study showing that doing tandem transplant was beneficial in high-risk patients. The problem is that [these results] were not validated in the United States. I don't think [tandem transplants] are going to change practice yet, but it's certainly a consideration for a high-risk patient to do 2 transplants back-to-back.

What are the challenges to performing an autologous transplant?

There are a lot of risks to an autologous transplant. That's why we have studies like the DETERMINATION trial where we're still trying to figure out if we need a transplant in this day of novel agents where, every 1 to 2 years, we get even better drugs. The latest answer to that question is, “Yes, we do.” There is still is an advantage to transplant, but there is a morbidity cost of infections and severe fatigue. Doing tandem transplants certainly heighten all of those adverse events.

How are novel induction therapies being used with transplant to improve outcomes?

We have come a long way with induction therapies, where previously very good partial remission (VGPR) rates used to be less than 50%, and are now observed in two-thirds of patients. We have even seen some data showing that up to 100% of patients achieved VGPR. We have a standard regimen of lenalidomide, bortezomib (Velcade), and daratumumab (Darzalex; RVd). There are some great growing data suggesting that current standards should probably change in the near future.

We had data from the GRIFFIN trial recently, which added the monoclonal antibody daratumumab to RVd. It showed an increased PFS, which was very remarkable, was very tolerable. The next change in the future is probably going to be moving toward a 4-drug regimen. The only caveat is that the highest-risk patients still could benefit more from something else, which might be carfilzomib (Kyprolis) instead of bortezomib.

There are some promising data from the FORTE trial that [carfilzomib, lenalidomide, and dexamethasone [KRd] followed by transplant and KRD consolidation] may benefit high-risk patients. We might get in a situation where, if you have a high-risk patient, you would use [the FORTE regimen] but not in those with standard-risk cytogenetics.

What safety concerns exist with the use of quadruplet regimens?

There is always a tradeoff; not every 4-drug regimen is better than a 3-drug regimen. For example, adding cyclophosphamide to RVd was actually detrimental; we did not see better response rates. Daratumumab [likely has] some increased risk of infection. Time will tell if there is any increased signals beyond the study we have now, but 5 drugs may be a little too far [to start working towards].

Could you provide an overview of the TOURMALINE-MM3 trial and the implications of those data?

This was a very exciting trial; we have a great maintenance drug in lenalidomide that works for most patients. Patients with high-risk cytogenetics or who are otherwise high-risk don't fare as well on lenalidomide alone. Another option is an oral proteasome inhibitor, making it ideally suited as a maintenance drug. If you look at all groups, patients with high-risk cytogenetics did just as well [on ixazomib]. If a patient has high-risk cytogenetics, we prefer a proteasome inhibitor as maintenance therapy.

This is a good first step, but I would like to see [how ixazomib] fares against lenalidomide. Furthermore, how would ixazomib combined with lenalidomide perform compared with lenalidomide alone? This is a big first step into a lot of exciting questions about maintenance therapy.

For high-risk patients, we don't know what to do with these confusing data. Do we use a proteasome inhibitor? Do we combine it with lenalidomide? Do we want to use a monoclonal antibody like daratumumab or isatuximab? These questions are being actively explored. In the near future, we're going to have some really interesting data to help manage the unmet need of maintenance therapy in patients with high-risk myeloma.

For high-risk patients, my practice is to, at this time, combine dual maintenance therapy with lenalidomide and a proteasome inhibitor. Most commonly, I would give bortezomib every other week. For someone who couldn't tolerate [bortezomib], I would give ixazomib. In the near future, as we get more trial data, ixazomib might actually pan out to be better than bortezomib. The default should be to err on the side of caution when using a proteasome inhibitor in someone with high-risk disease.

Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253-264. doi: 10.1016/S0140-6736(18)33003-4