Expert Discusses Transplant and Emerging Strategies in Myeloma

Thomas G. Martin, MD, discusses the clinical utility of autologous stem cell transplantation and the rapidly evolving treatment paradigm of myeloma.

Thomas G. Martin, MD

Autologous stem cell transplantation (ASCT) continues to have an imperative role in the multiple myeloma paradigm, as most patients with the disease are able to tolerate it and it is a go-to strategy for physicians, explained Thomas G. Martin, MD.

The best sequence of treatment for newly diagnosed patients, he added, is induction therapy, between 3 and 6 cycles of triplet-based therapy, followed by ASCT. However, with all of the available therapies in the myeloma landscape, the challenge lies in figuring out which patients derive the most benefit from which agents, Martin said.

Other therapeutic developments continue to show encouraging activity as monotherapy and combination regimens in the landscape, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory agents, and potentially, chimeric antigen receptor (CAR) T-cell therapy.

“The future of myeloma is very bright,” said Martin. “It's really fun to be a myeloma doctor with all of these therapies we have. It is only going to get better, especially with CAR T-cell therapy. Off-the-shelf products will also have an impact.”

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In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Martin, associate director of the Myeloma Program at the University of California, San Francisco, discussed the clinical utility of ASCT and the rapidly evolving treatment paradigm of myeloma.Martin: There are some limitations to ASCT. Patients older than age 75 are rarely transplant candidates. I would say almost all patients younger than 70 are eligible candidates. Most of the patients, if they're ineligible, it's because they have ongoing pulmonary comorbidities or cardiac issues.

In general, most patients can tolerate transplant. We have done a number of randomized trials in the frontline setting—at least 4—where patients are randomized to either upfront single ASCT versus standard triplet therapy. Essentially, in every one of the trials, we see that the PFS in the depth of remission is better if you undergo ASCT. Many of those trials have looked at delayed transplant or salvage transplant. This is when disease recurs.

Unfortunately, when people have relapsed disease, most of the time they don't receive ASCT. We don't have a lot of data in the novel era suggesting that's a better strategy. For me, I stick with frontline transplant.

I also spoke about maintenance-based therapy. The data these days really support this following transplant. We have had a number of randomized trials looking at single-agent lenalidomide (Revlimid) as maintenance. In a meta-analysis, patients who received lenalidomide had a 2.5-year advantage in terms of overall survival compared with patients who received placebo. Lenalidomide is now the standard of care for posttransplant patients.

The one thing that comes into question is what to do with patients who have high-risk disease, in terms of transplant and maintenance. In the United States, we did a trial looking at a single ASCT versus tandem ASCT. There was no difference in terms of benefit. That was the StaMINA trial. There was also a European trial called the EMN02 trial, which looked at bortezomib-based induction with cyclophosphamide and dexamethasone. Those patients who received induction followed by tandem ASCT did better than those who received induction followed by single transplant. The best results were seen in patients with high-risk disease.

The difference between these studies is that in the European study, they didn't use an immunomodulatory agent as initial induction therapy. In the United States, almost every patient gets immunotherapy and a proteasome inhibitor. That is why, in the United States, if you still give that regimen, a single transplant is probably best. In terms of maintenance, there was a trial done in the United Kingdom that showed benefit with lenalidomide maintenance, even if you had high-risk disease.

In terms of induction, is lenalidomide, bortezomib, and dexamethasone (RVd) still the standard or can physicians use carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd)?

The future is bright in terms of all the agents we have. In the future, because we're seeing such great activity in patients who are receiving CAR T-cell therapy, it's very possible this type of treatment early on will limit the use of transplant. We will need a randomized trial looking at this.We have had several trials that have combined a proteasome inhibitor plus an immunomodulatory agent versus a proteasome inhibitor plus an alkylating agent. We have done that with bortezomib and carfilzomib. In all these randomized trials, the arms that had a proteasome inhibitor plus an immunotherapy did better. Frontline therapy should be a proteasome inhibitor, immunotherapy, and dexamethasone. This is in a transplant-ineligible population.

Could you speak to the minimal residual disease (MRD)-negative population?

Even in the frail patients, we have what we call an “RVd-light” regimen, so it's given every 35 days. Patients can tolerate this regimen no matter their age; you just have to dose accordingly. However, if I have a young patient with myeloma, I have a bias. It's my preference; I like KRd for those patients.I say, “You should put the cart before the horse” in terms of MRD testing in myeloma. Yes, we're doing it very frequently at the university, and we've been doing it for the last 2 to 5 years. We have a good track record with doing next-generation sequencing for MRD testing.

What happens when a patient progresses on lenalidomide maintenance?

We know triplets are better than doublets, so are quadruplets better than triplets? Is it too early to decide this?

What is the impact of selinexor in penta-refractory patients?

For us, it's only assessing prognosis. We are making no treatment decisions based on MRD status. Patients who achieve an MRD-negative state certainly have a longer PFS. It's a prognostic marker. We don't know what to do with this information as far as treatment. Should we not give maintenance, or should we shorten maintenance? We need to figure this out soon with clinical trials. Many clinical trials are using this as an endpoint.When someone relapses on the drugs they are taking at that point in time, I consider them refractory to those drugs. We have so many other treatment options. If someone is on lenalidomide maintenance and they relapse, then yes, we can do something else. We have pomalidomide (Pomalyst), carfilzomib, and so much more. Daratumumab (Darzalex) with pomalidomide or dexamethasone has shown promise. There are so many potent regimens, so we can make those switches as we need to.For newly diagnosed patients, we have tested some 4-drug regimens. In fact, they haven't made much of an improvement. They did not use monoclonal antibodies, and now we're testing a lot of quadruplets with these agents. An example would be daratumumab, dexamethasone, bortezomib, and lenalidomide. You could switch carfilzomib in there. We don't have significant follow-up on these studies, though.We're learning now that this patient population does very poorly. Those patients have aggressive disease, and we have very limited therapeutics. If I had to predict how many of those patients would respond, I would guess 10% or less. The duration of response is even poorer. Selinexor has shown promise. It inhibits tumor suppressor proteins; it tries to make the cancer cells act normally. Over 100 patients were treated this way, and the overall response rate was 66%. That's an amazing response rate, and I think we will all use this drug eventually.