Usmani Elucidates Management of Early Relapse in Multiple Myeloma

Saad Z. Usmani, MD

Although physicians cannot predict exactly when a patient with multiple myeloma will go into relapse, certain high-risk features can alert providers to those at the highest risk for early relapse. Once a patient relapses, physicians can use a patient’s prior exposure to therapy and type of relapse to guide the next line of treatment, said Saad Z. Usmani, MD.

Some of the main indicators of early relapse include t(4;14), t(14;16), t(14;20), del(17p), and amplification of chromosomal q21. Additional signals are those who present with extramedullary disease or have highly proliferative myeloma, said Usmani.

In addition to identifying these cytogenetic abnormalities upon diagnosis, Usmani explained that physicians have to isolate the type of progression—–be it clinical or biochemical––to understand what the next line of therapy should be.

Additionally, knowing whether the patient progressed on, or is refractory or naïve to a proteasome inhibitor (PI) or immunomodulatory drug (IMiD) can signify the best salvage regimen, he added.

“One size does not fit all; you have to look at each of these potential triplet regimens to see which one fits best for your patient,” said Usmani. “You also have to look at patient preferences, as well. If there are 2 regimens that would give you a similar benefit, convenience may sway you toward one versus the other.”

OncLive: How has first-line newly diagnosed multiple myeloma treatment evolved?

In an interview with OncLive, Usmani, chief of Plasma Cell Disorder, director of Clinical Research in Hematologic Malignancies, Levine Cancer Institute, Atrium Health, shared insight on approaches to early relapse in myeloma given the evolution of frontline treatment advances.Usmani: The landscape of myeloma has evolved over the last 10 years. We've gone from treating patients with one drug and one mechanism of action, to doublets with 2 or 3 different mechanisms of action, to 3-drug regimens. This is based on data from the SWOG S0777 trial, FIRST trial, and most recently, the MAIA and ALCYONE studies for transplant-ineligible patients.

Is it possible to anticipate early relapse among most patients with myeloma?

We still put patients in 2 broad buckets: transplant eligible or ineligible. We tend to make that assessment as they're going through their induction treatment. Most physicians tend to use lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) when they use a triplet. For older transplant-ineligible patients, we use dose-modified versions of that particular regimen. If patients have renal insufficiency, we start them off with a regimen such as cyclophosphamide, bortezomib, and dexamethasone and then transition them to something like RVd. Doublets still have utility for elderly, frail patients who have a lot of comorbidities and cannot tolerate coming into the clinic frequently for bortezomib shots.Myeloma has a “remission and relapse” kind of a course. For the most part, we don't have a long-term solution or cure for this disease. Patients go through different lines of therapy. There are certain high-risk features that help prognosticate at the time of diagnosis. We're a little more vigilant with those patients who are at the highest-risk for relapse. Patients who have revised International Staging System stage III disease, patients with specific cytogenetic abnormalities, such as t(4;14), 4(14;16), t(14;20), del(17p), and amplification of chromosomal q21. Additionally, patients who present with extramedullary disease, or have highly proliferative myeloma [are signals]. Those are some of the things we look for along with gene expression profiling.

How do you typically manage these patients when they relapse?

There are other subcategories where patients may not have these features, but the disease evolves, and patients relapse early. We look at those predictors, but we're also following the patient’s clinical course.About 4 or 5 years ago, we only had PIs and IMiDs. Then, we would think about the kind of relapse patients had, the kinds of regimens they had received, and whether they were off therapy or on a particular [agent] when they relapsed. Moreover, [we looked at] whether the relapse was florid and clinical or a slow biochemical relapse. We would factor in a lot of these things and then decide if a PI-based regimen or an IMiD-based regimen was better for the patient.

We have many different options for these patients. The treatment patterns in the United States have also changed where you have more uptake of maintenance treatment after induction and/or transplant. You have to keep all of those things in mind now, along with some of these newer nuances. You also have look at what depth of response the various 3-drug regimens afford you. You also have to think about the patient populations in the phase III trials that informed our knowledge of that particular triplet regimen.

What are the key points for community oncologists in managing early relapse in their patients?

In picking the best option for your patient, you have to know whether they had exposure to a PI or IMiD and whether they’re refractory or naïve to that therapy. If they were transplant eligible, did they defer stem cell transplant as part of their first-line treatment? Could that be an option now? Do they have stem cells left over? All of these things go into play as we think about which salvage regimen we pick and whether a second or even a salvage transplant would be an option.We have to think about what [therapies] patients have been exposed to or are refractory to and start thinking about regimens in that fashion. For example, if the standard-of-care arm in a phase III trial was an IMiD doublet, you wouldn’t enroll patients who are refractory to IMiDs on the trial; that would not be ethical.

That's a little different from some of the solid tumor trials that we do, but for myeloma, that is the thought process. There are also some things that are coming down the line, such as newer triplet regimens with the anti-CD38 monoclonal antibody isatuximab. New triplet data with pomalidomide (Pomalyst) were presented at the 2018 ASCO Annual Meeting.

A year from now we'll be talking about the same topic with several other options. That makes our job more interesting and complicated. As good clinicians, we’ll have to tease out which populations fit best for those newer regimens.