Expert Highlights Encouraging PFS Data With Maintenance Ixazomib in Multiple Myeloma

Gareth Morgan, MD, discusses the TOURMALINE-MM3 findings in multiple myeloma and other clinical trials that are impacting the landscape for this patient population.

Gareth Morgan, MD

Two-year maintenance therapy with the oral proteasome inhibitor (PI) ixazomib (Ninlaro) following autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) in patients with multiple myeloma, according to a final PFS analysis presented at the 2019 Transplantation and Cellular Therapy (TCT) Meetings.

In the phase III TOURMALINE-MM3 trial, investigators aimed to determine whether maintenance treatment with the oral PI could improve outcomes in this patient population following ASCT. More than 600 patients were randomized to receive ixazomib or placebo for 2 years.

In the final PFS analysis of the TOURMALINE-MM3 study, at a median follow-up of 31 months, maintenance ixazomib led to a 28% reduction in the risk of progression and death in patients with newly diagnosed multiple myeloma. The median PFS was 26.5 months with ixazomib compared with 21.3 months with placebo (HR, 0.72; 95% CI, 0.582-0.890; P = .002).

Many patients remained on treatment throughout the duration of this study, with only few discontinuing ixazomib due to toxicities. These data support the idea that 2-year maintenance can influence disease progression after ASCT.

OncLive: Could you provide some background to the phase III TOURMALINE-MM3 trial?

What unmet need did the trial aim to address?

Could you discuss the findings?

In an interview with OncLive at the 2019 TCT meeting, Gareth Morgan, MD, director of Myeloma Research at NYU Langone's Perlmutter Cancer Center, discussed the TOURMALINE-MM3 findings in multiple myeloma. In addition, he highlights other trials that are impacting the landscape for this patient population.Morgan: Maintenance is an interesting concept for the treatment of [patients with] cancer. At one stage, people thought that it wouldn’t work, but data with immunomodulatory drugs suggested that you could influence PFS and overall survival (OS), so the outstanding question was, “If you used a PI and stayed on it for 2 years in the form of maintenance, would that make a difference in patient outcomes?”People have transplants as an induction treatment and, traditionally, you stopped therapy. We designed a double-blind, placebo-controlled trial, and the answer was that there was a significant improvement in PFS, and that improvement in survival was achieved at very negligible toxicity.Basically, more than 600 patients were randomized 3:2 to maintenance ixazomib or no maintenance. Most people stayed on the treatment. There was some minimal decrease in the platelet count, some nausea, and some diarrhea, but mostly, patients remained on treatment for the duration of 2 years. The hazard ratio showed a significant reduction with a very clinically significant improvement in PFS. That was achieved for all groups of patients: those with extreme age, high-risk cytogenetics, and those with high-risk clinical disease. Everyone seemed to benefit from it.

What should oncologists take away from these findings?

What is the potential of the anti-BCMA chimeric antigen receptor (CAR) T cell therapy, bb21217, data of which were presented at the 2018 ASH Meeting?

Importantly, it didn’t damage people’s quality of life (QoL). The QoL study that was done with it didn’t show a difference between the 2 arms, and of course, it was placebo-controlled. For the first time, we are able to address that question.We can safely say now that you can treat people for a prolonged period with an oral PI, ixazomib, that it is well tolerated, and that all subgroups of patients benefit with a significant improvement in PFS. We have to wait to see if that translates to an improvement in OS because the patients are doing so well.BCMA is an interesting target in myeloma. We have lacked an antibody target in myeloma before daratumumab (Darazalex), so BCMA becomes something interesting that you can target therapy to; it is one way of therapies targeting BCMA-specific CAR T cells. That seems to be functional in myeloma. There were good responses, and there was a significant improvement in survival of about 11.5 months; that was achieved with very little toxicity. The CAR T-cell approaches do have toxicity in that a proportion of patients can become very unwell and need intensive care support, but most of the time, it seems to be well tolerated.

How do you envision CAR T cells impacting the myeloma landscape?

What data are you looking forward to coming down the pike?

You can view this as sort of pilot study that says CAR T cells directed against BCMA actually work in myeloma, and we should see this as an increasingly well used approach as a particular kind of efficacy for high-risk patients, which still remain a clinical problem.There are a lot of treatments available for myeloma, and yet we can still do better. The majority of patients do relapse. There are a lot of side effects from the treatment, so a highly efficacious cellular therapy could replace many of the current therapies that are available and lead to long-term survival at a limited cost from toxicity. It is up to us now to find ways using them, design clinical trials, and put them into specific segments of disease where we see a benefit from these drugs in the short-term.There are a number of clinical trials that are going to come out in the near future for myeloma. The [updated] results of the selinexor compound will be interesting. It will be interesting to know whether that outperforms standard therapy in the randomized studies that are being conducted. There are a couple of new drugs available for myeloma, but underneath it all, we are all expectant to see the next generation of CAR T-cell studies reported.

Morgan G, Dimopoulos M, Gay F, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. In: Proceedings from the 2019 Transplantation & Cellular Therapy Meetings; February 20-24, 2019; Houston, TX. Abstract 23.

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