Rajkumar on Triplet Regimens in Multiple Myeloma

S. Vincent Rajkumar, MD

With numerous newly approved drugs for patients with early-stage multiple myeloma reaching the clinics, understanding what drugs, combinations, and sequences to use has become an important area of research. Several recent studies have demonstrated increased efficacy with nominally increased adverse events in these triplet arms.

The phase III randomized SWOG S0777 study that was presented at the 2015 ASH Annual Meeting looked at bortezomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with previously untreated multiple myeloma, without an intent for immediate autologous stem cell transplant.

Results of the study showed that the addition of bortezomib to lenalidomide and dexamethasone for induction therapy in previously untreated myeloma resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and also an increased overall survival (OS). The triplet combination showed an acceptable safety and tolerability profile, despite increased neurotoxicity. The authors believe that this could represent a potential new standard of care.

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: Can you discuss the study of bortezomib, lenalidomide, and dexamethasone versus lenalidomide plus dexamethasone in patients with previously untreated multiple myeloma?

S. Vincent Rajkumar, MD, professor of Medicine at the Mayo Clinic, Rochester, Minnesota, spoke with to discuss this trial and other recent studies of triplet therapies in the treatment of early-stage multiple myeloma.Rajkumar: Brian Durie, MD, presented the SWOG study, which compared lenalidomide, bortezomib, and dexamethasone versus lenalidomide and dexamethasone. This is a classic triplet versus doublet study. It was conducted in patients with newly-diagnosed multiple myeloma. Patients were treated until progression, and the key findings of the study were that the response rates were much higher with the triplet combination compared with lenalidomide and dexamethasone. PFS was longer. However, the the most important finding is that OS was also prolonged significantly with the bortezomib, lenalidomide, dexamethasone combination.

How do you think this information will impact clinical practice?

This, of course, is a major finding. It is one of the first trials in which a modern triplet has come out on top in OS. As a result, at the Mayo Clinic, we have changed our guidelines to bortezomib, lenalidomide, and dexamethasone as our standard for frontline therapy.In clinical practice, there have been a number of regimens used in multiple myeloma for frontline therapy in the United States. The NCCN, for example, on their website recommends approximately 20 different regimens for newly-diagnosed myeloma. This actually gives physicians more clarity. Today, this is probably the only regimen—modern regimen—which has a clear OS benefit over the other competitors. There will be some more uniformity in practice in that, unless there are problems with cost or lack of access or availability, Bortezomib, lenalidomide, and dexamethasone would be kind of a standard frontline regimen for patients with untreated multiple myeloma.

The tolerability between the two different arms was similar. Were there any additional toxicities found?

Do you foresee any other combinations with bortezomib that you think might be tested for this population?

Nowadays, we do recommend a different dosing schedule for bortezomib than was used in the trial. The once-weekly subcutaneous schedule is what we are using, and that's what we would continue to use.Mostly the same. There's always going to be extra side effects when you use a triplet combination, and those were seen, but they were, by and large, as expected and not something that we cannot manage. Neuropathy was much higher than what we would like to see. However, like I said, if we use the once-weekly subcutaneous schedule of bortezomib, which should be much lower, it may even prove to be more efficacious because we can give treatment for a longer period of time.The other two combinations are bortezomib, thalidomide, and dexamethasone, and bortezomib, cyclophosphamide, and dexamethasone. Those have been used in the United States, as well. We heard about another trial yesterday where bortezomib, thalidomide, and dexamethasone was compared with bortezomib, cyclophosphamide, and dexamethasone, and the bortezomib, thalidomide, and dexamethasone arm had higher response rates.

In the United States, we do have the option of using lenalidomide, which is a more modern immunomodulatory drug than thalidomide, and that's why the bortezomib, lenalidomide, and dexamethasone triplet will take over here.

Can you talk about some of the recent FDA approvals that have occurred and what this means for the field?

Currently, we are doing a trial in ECOG [Eastern Cooperative Oncology Group] looking at bortezomib, lenalidomide, and dexamethasone versus carfilzomib, lenalidomide, and dexamethasone. Carfilzomib, lenalidomide, and dexamethasone, of course, is a little bit more cumbersome but may have more response rates. Time will tell us how that fares against this bortezomib, lenalidomide, and dexamethasone combination.We have had two new drug approvals in 2013: carfilzomib and pomalidomide. Earlier this year, panobinostat was approved. More exciting right now is that, in 3 weeks, the FDA approved three drugs: ixazomib, daratumumab, and elotuzumab. Elotuzumab and daratumumb are the first monoclonal antibodies we've ever had in multiple myeloma. They target different antigens. Elotuzumab targets SLAM-F 7, while daratumumab targets CD38. The third drug that was approved is ixazomib, which is the first, oral proteasome inhibitor to be approved.

What do you think, with all these new agents now available, will be the optimal sequencing? When is the best time to use them all and how?

I expect all three of them to have a major impact in the treatment of multiple myeloma. It's such an exciting time.This is going to be a big problem, because I think we need to be very cautious to not jump in with the latest phase II study and change practice, because sometimes that may end up giving us the wrong outcome. It's important to wait for well-designed phase III trials, except perhaps in the high-risk population, where you might need things to move a little bit quicker. It's going to be challenging to incorporate new antibodies into frontline therapy because frontline therapy is already associated with such an excellent outcome.

There's also some pretty important data on daratumumab that was recently presented at the 2015 ASH Annual Meeting. Can you comment on that?

You are talking about 80% 3-year, 4-year survival rates, and it's going to be hard to improve on them in a short period of time. We have to look at new surrogate endpoints, and one of them that is very prominent now is minimal residual disease (MRD)-negative state. If we can get to MRD-negative state and use it as a surrogate endpoint for better long-term outcomes, then I think we'll be able to answer these questions in a more rapid fashion. The key is well-designed randomized trials. Use really intelligent, smart endpoints, and then find the answers into how best to use these drugs.Daratumumab, a monoclonal antibody against CD38, is the latest drug approved. Thus far, the results have primarily been with monotherapy. In monotherapy, in the relapsed/refractory setting, it works in about 30% of patients who have failed everything else. In this meeting, we have data on daratumumab combined with lenalidomide and dexamethasone into a nice triplet combination, and in the same relapsed/refractory population, you are seeing a high level of response, 88% is being reported, and that is very exciting for the field.