Triplets in Newly Diagnosed Multiple Myeloma: A Q&A With 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.

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.

A paper, presented at the 57th Annual Meeting and Expedition of the American Hematology Association (ASH) looked at results of the randomized phase III SWOG S0777

trial, which studied bortezomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (without an intent for immediate autologous stem cell transplant).

The study authors concluded 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.

S. Vincent Rajkumar, MD, professor of Medicine at the Mayo Clinic, Rochester, Minnesota, and chair of the ECOG Myeloma committee, as well as the Mayo Clinic Myeloma Amyloidosis Dysproteinemia Group spoke withTargeted Oncologyduring the 2015 American Hematology Society (ASH) annual meeting to discuss this trial and other recent trials of triplet therapies in the treatment of early-stage multiple myeloma.

TARGETED ONCOLOGY: Please provide an overview of the study on bortezomib, lenalidomide, and dexamethasone versus lenalidomide plus dexamethasone in patients with previously untreated multiple myeloma.

RAJUMAR: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. Progression-free survival (PFS) was longer. But the most important finding is that overall survival (OS) was also prolonged significantly with the bortezomib, lenalidomide, dexamethasone combination.

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. And as a result, at the Mayo Clinic, we have changed our guidelines to bortezomib, len/dex as our standard for frontline therapy.

How do you think that this information will impact clinical practice?

I think 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, I think. Today, this is probably the only regimen, modern regimen, which has a clear OS benefit over the other competitors. I think maybe there'll be some more uniformity in practice in that unless there are problems with cost or lack of access or availability, I think bortezomib, len/dex would be kind of a standard frontline regimen for patients [with untreated multiple myeloma].

We do recommend nowadays 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.

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

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'd like to see. However, like I said, if we use the once-weekly subcutaneous schedule of bortezomib, which should be much lower, and may even prove to be more efficacious because we can give treatment for a longer period of time.

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

The other combination that's being used with bortezomib, the other two combinations are bortezomib, thalidomide, dex, and bortezomib, cyclophosphamide, dex; those have been used in the United States as well. We heard about another trial yesterday where bortezomib, thalidomide, and dex was compared with bortezomib, cyclophosphamide, and dex, and the bortezomib, thalidomide, and dex [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 bortezomib, len/dex will take over here.

We are doing a trial right now in ECOG [Eastern Cooperative Oncology Group] looking at bortezomib, len/dex versus carfilzomib len/dex. Carfilzomib len/dex, of course, is a little bit more cumbersome but may have more response rates, and time will tell us how that fares against this bortezomib, len/dex combination.

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

Yes. 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. Two of these are monoclonal antibodies: elotuzumab and daratumumb; the first monoclonal antibodies we've ever had in multiple myeloma. They target different antigens. Elotuzumab targets SLAM-F 7, daratumumab targets CD38. The third drug that was approved is ixazomib, which is the first, oral proteasome inhibitor to be approved.

I expect all three of them to have a major impact in the treatment of multiple myeloma. It's such an exciting time that it's almost unprecedented that the FDA is here at ASH, and there will be a joint FDA/ASH symposium tomorrow evening, where we will be discussing how these new drugs are going to be impacting clinical practice. We’re going to have the FDA present the rationale for why they approved the three drugs. Then Paul Richardson, MD, and myself will be discussing how these new drugs should be used in clinical practice.

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 think this is going to be a big problem, because I think we need to be very cautious not to 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.

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 MRD-[minimal residual disease-]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. I think the key is well-designed randomized trials. Use really intelligent, smart endpoints, and then find the answers into how best to use these drugs.

There's also some pretty important data on daratumumab that was presented. Can you comment on that?

Daratumumab is the latest drug approved that's a monoclonal antibody against CD38. So far, the results have been with monotherapy primarily. 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.