Expert Discusses Rapid Advances, Next Steps in Multiple Myeloma

Peter Voorhees, MD

Novel agents and treatment combinations have rapidly expanded the armamentarium in multiple myeloma. However, additional progress is needed to extend these successes to a greater population of patients, according to Peter Voorhees, MD.

“The future is definitely brighter for patients with multiple myeloma,” said Voorhees. “The high-risk group of patients perhaps have not had the same magnitude of benefit as the standard-risk patients, and we need to continue to work harder to benefit those patients in particular. But across the board, whether you have standard-risk or high-risk [disease], the treatment paradigms are getting better. There are a lot of exciting agents in the pipeline and they will only get better as we move forward.”

OncLive: What treatments are available for newly diagnosed patients with multiple myeloma?

Voorhees, who specializes in hematology and medical oncology at Levine Cancer Institute, Carolinas HealthCare System and UNC Chapel Hill, discussed treatments for both newly diagnosed and relapsed patients with multiple myeloma during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies.Voorhees: I had the opportunity to talk about the treatment of newly diagnosed patients who are not necessarily eligible for autologous stem cell transplantation. There are 3 things in particular that are worth commenting on. First off, there has been a larger body of literature that has come forth supporting the paradigm of continuous treatment until disease progression. The FIRST trial is a good example of that. This was a randomized phase III study that has been published for a few years now, which compared continuous lenalidomide (Revlimid)/dexamethasone therapy versus 18 months of treatment. There was a clear improvement in PFS with [the continuous] approach.

I also talked about an important retrospective analysis of 3 phase III trials, which looked at different treatment strategies looking at continuous versus fixed-duration therapy and, in that particular analysis, they found that not only the first progression-free survival (PFS) improved with continuous treatment paradigms, but time to second progression, or PFS2 as we call it, was also prolonged. There was a survival advantage seen in that particular analysis, as well. Until treatment paradigms change and the therapy gets better, continuous treatment is the most advantageous, as long as patients are tolerating it.

Secondly, the SWOG S0777 trial is an incredibly important study. This was a phase III study done in a cooperative group setting comparing lenalidomide/dexamethasone to lenalidomide/dexamethasone with bortezomib (Velcade) for newly diagnosed patients with myeloma. There was a mix of both transplant-eligible and transplant-ineligible patients, but transplant was not part of the treatment strategy. Patients were given 24 weeks of therapy, followed by lenalidomide/dexamethasone until disease progression. Importantly, what they found is not only was there an improvement in PFS, but there as an improvement in overall survival (OS), as well.

The reason that this study is important is that it strongly suggests that this particular triplet is a new standard of care for transplant-ineligible patients who would otherwise tolerate that type of approach. All of the patients on the lenalidomide/dexamethasone arm had access to bortezomib in subsequent lines of therapy, so it leads to this important issue of sequencing. Can you get away with a doublet followed by a bortezomib-based regimen? Lenalidomide/dexamethasone followed by a bortezomib-based regimen? Or, should you use all 3 [drugs] together? This study suggests that you should use all 3 together in those situations where you think that the patient can tolerate it.

Lastly, a lot of the breakthroughs that have occurred in patients with relapsed myeloma with 1 to 3 prior lines of therapy is that a lot of those lenalidomide/dexamethasone-based backbones that have recently received regulatory authority approvals are all being tested in the frontline setting—now also in the transplant-ineligible situation, so we have lenalidomide/dexamethasone with or without daratumumab (Darzalex).

Which of these trials do you believe would have the greatest impact on the field?

There is also lenalidomide/dexamethasone with or without elotuzumab (Empliciti), or with or without ixazomib (Ninlaro). We have a number of different studies that are out there now. Most, if not all of those, are going to be positive trials, so there are going to be even more treatment options for these patients moving forward. It is likely that the addition of daratumumab to the lenalidomide/dexamethasone backbone will likely lead to a very significant magnitude of benefit with regards to PFS, and hopefully OS, as well. We will see a pretty respectable overall response rate (ORR) in that group of patients; the proportion of patients who will achieve a very good partial response (VGPR) or better is going to be incredibly high.

In the relapsed setting, lenalidomide/dexamethasone plus daratumumab produced ORRs of over 90%; approximately three-quarters of the patients achieved at least a VGPR, and a little over 40% of patients achieved a complete response or better. We can only assume that that is going to be even better in a newly diagnosed situation. I do like the concepts of lenalidomide/dexamethasone with elotuzumab and lenalidomide/dexamethasone with ixazomib in this patient population, as well.

Can you give advice to clinicians on how to best manage treatment-related toxicities? What should they look for?

While the magnitude benefit may not be quite as dramatic with those agents when combined with lenalidomide/dexamethasone in a relapsed setting, they were positive studies. Secondly, the side effect profile of lenalidomide/dexamethasone with elotuzumab or lenalidomide/dexamethasone with ixazomib is very similar to the side effect profile of the lenalidomide/dexamethasone doublet. The addition of elotuzumab or ixazomib adds some toxicity but, in general, they are very well tolerated agents that will fit very nicely for patients who are frailer and may not be able to handle a conventional triplet. One of the concerns raised by the SWOG study that I mentioned earlier is the fact that the addition of bortezomib to the lenalidomide/dexamethasone doublet significantly increases toxicity; peripheral neuropathy is a significant concern in that group of patients. First off, bortezomib was given intravenously in the SWOG study because of patients enrolled prior to the regulatory approval of subcutaneous bortezomib.

The use of subcutaneous bortezomib will help ameliorate the risk of neuropathy. A lot of us have started moving toward a modified RVd [lenalidomide, bortezomib, and dexamethasone]—type platform for older patients who may be more prone to side effects, including peripheral neuropathy.

I’ll sometimes use a 28-day cycle as opposed to the 21-day classic cycle, in which I’m giving lenalidomide at a 10- to 15-mg dose initially instead of a 25-mg dose for 3 weeks, give bortezomib subcutaneously on a once-weekly basis, and give dexamethasone on a once-weekly basis, as well.

For those patients 75 years of age or older, or for patients who have brittle diabetes or congestive heart failure, I would lean toward a 20-mg dose of dexamethasone as opposed to a 40-mg dose of dexamethasone. This way, you can adjust the schedule of administration, and the mode of administration, with regard to bortezomib. The actual dose and all of those things are important.

What therapies have become available for patients with relapsed/refractory disease?

Toxicity is important because, again, this continuous treatment method appears to be advantageous, at least with what we have available to treat patients now. We need to minimize side effects if we are going to actually treat patients continuously. There have been a large number of regulatory approvals of therapies for patients who have had 1 to 3 prior lines of therapy. There are 4 different lenalidomide/dexamethasone-based triplets that are now FDA approved: with ixazomib, elotuzumab, carfilzomib (Kyprolis), and daratumumab.

There was carfilzomib/dexamethasone which outperformed bortezomib/dexamethasone in the ENDEAVOR trial. Then, we had the PANORAMA-1 results of bortezomib, dexamethasone, and panobinostat (Farydak).

There are a large number of patients in the United States who are going to be treated with lenalidomide-based therapies in the frontline setting until disease progression. If a patient has disease that is progressing in the face of lenalidomide therapy, giving them a lenalidomide/dexamethasone-based platform on their first relapse may not be as relevant. In this case, a proteasome inhibitor—based approach would make more sense, such as carfilzomib/dexamethasone and bortezomib/dexamethasone with daratumumab.

Bortezomib/dexamethasone with panobinostat has shown improvement with regard to PFS, but has fairly significant side effect issues, such as severe fatigue, gastrointestinal issues, weight loss, loss of appetite, nausea, diarrhea, and significant cytopenias, that make it challenging. That particular regimen has not been used very much in this space.

What take-home message can you provide for community oncologists?

For those patients who do receive a limited duration of therapy, go off treatment, and then, subsequently, relapse, those are the perfect patients for a lenalidomide/dexamethasone-based platform. Then again, as we eluded to before, the lenalidomide/dexamethasone with daratumumab regimen looks quite good in that setting.The main take-home message is to help walk them through the decision-making process as far as how you choose among these different options. There are a number of different things that people have to consider. What are the comorbidities? What other medical problems is the patient bringing to the table that may impact the safety of 1 regimen versus another? If you have a patient with congestive heart failure, you may want to avoid a carfilzomib-based strategy, whether it is carfilzomib/dexamethasone or lenalidomide/dexamethasone with carfilzomib, so that is important.

Secondly, what have they been treated with previously? How did they tolerate those agents and what are they resistant to at that point? A patient who is progressing on lenalidomide/dexamethasone may not be a good candidate for a lenalidomide/dexamethasone-based platform.

The other thing we look at is, is the patient in a clinical relapse or a biochemical relapse? That means the free light chain level is going up, but the patient is not experiencing morbidity or symptoms related to it, whereas a clinical relapse has symptoms related to their progression. They are becoming more anemic, their calcium levels are now high, their kidney function has gotten worse, and the bone pain is worse than before. When you have a clinical progression, you need a user regimen that has a high likelihood of working and a high likelihood of producing a greater depth of response, something such as lenalidomide/dexamethasone with daratumumab or lenalidomide/dexamethasone with carfilzomib may be the most appropriate strategy. There are a number of different things you need to look for when you’re making these decisions, and it is incredibly complicated. It is hard for us.