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PVd Regimen Highlighted as New Standard in Relapsed/Refractory Myeloma

Published: Friday, Jul 13, 2018

 Paul Richardson, MD
Paul Richardson, MD
Findings from the phase III OPTIMISMM trial established the combination of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) as a new standard of care in patients with relapsed/refractory multiple myeloma with prior exposure to lenalidomide (Revlimid), said Paul Richardson, MD.

In results presented at the 2018 ASCO Annual Meeting, the median progression-free survival (PFS) was 11.20 months with PVd compared with 7.10 months with bortezomib and low-dose dexamethasone (Vd) alone (HR, 0.61; 95% CI, 0.49-0.77; P <.0001). In subgroup analyses, the PFS benefit with pomalidomide was observed regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy.

Investigators found that PVd improved PFS regardless of lenalidomide-refractory status, with an HR of 0.65 among refractory patients and an HR of 0.48 among those who were not refractory. The time to next treatment was 22.24 months with PVd versus 8.51 months with Vd (HR, 0.42; 95% CI, 0.33-0.54; P <.001). The median follow-up was 16 months.

“What we saw, first and foremost, is that the PFS benefit with the 3 drugs over the 2 was quite striking and quite early,” said Richardson, lead author and clinical program leader and director of clinical research with the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “We did an early analysis that was planned by protocol amendment and, even going early to look, we saw a difference. The difference was around 4.5 months in favor of the 3 drugs over the 2.”

In an interview with OncLive, Richardson discussed the combination’s efficacy and tolerability, as well as the possibility of pairing PVd with other agents to boost outcomes without increasing toxicity in multiple myeloma.

OncLive: Can you discuss the background of this study?

Richardson: We have demonstrated that there is synergy between immunomodulatory (IMiD) treatments and proteasome inhibitors. That's been a paradigm in myeloma treatment for some time.

This study was building on the concept that pomalidomide combined with bortezomib is, clinically, at least additive, if not synergistic. In that context, could we take that forward into the phase III setting and demonstrate improvement in clinical benefit compared with standard approaches in relatively early relapse?

Preclinically, pomalidomide and bortezomib are highly synergistic in the laboratory. Clinically, we were able to demonstrate that it was a safe combination in phase I/II studies. Not only was it safe, but it was also very active. Therefore, it was a very rational [idea] to bring it into the phase III setting.

Most importantly, we wanted to figure out how patients who have had prior lenalidomide do in the context of this combination. Pomalidomide was originally approved in patients in whom lenalidomide had failed them—they were progressing on lenalidomide, and therefore pomalidomide was a viable next step in terms of immunomodulatory treatment.

In modern myeloma treatment, most patients receive lenalidomide-based treatment upfront, certainly in the United States and now increasingly around the world. What is even more important is that lenalidomide maintenance has been shown to convey clinical benefit. As a result of that, when patients unfortunately progress on lenalidomide, what's next?

Our goal here was to establish that this combination could be effective, well tolerated, and active in this setting.

The trial compared pomalidomide, bortezomib, and dexamethasone with a reasonable control at the time the trial was designed, which was bortezomib and dexamethasone. We knew that was both active and generally well tolerated.

Importantly, in the design, we required that patients continued on treatment. In other words, there wasn't a fixed duration of therapy. Treatment continued for a full 8 cycles and then from 9 cycles onward, a maintenance strategy followed.

Patients had to have had prior lenalidomide, obviously, and the majority of them, 70%, were not only exposed to lenalidomide, but were also refractory to it.

Because the control regimen consisted of bortezomib and dexamethasone, it wasn't fair to put patients who were refractory to bortezomib in this trial—so they were not eligible. Having said that, if you were on bortezomib maintenance, which is just every 2 weeks, you could be a candidate for the trial.

We randomized about 570 patients across a large number of centers. It was a real global effort—there was a fantastic world partnership with colleagues in Europe, Canada, the United States, and all over the world.

What did you find when you looked at PFS?

What we saw, first and foremost, is that in fact, the PFS benefit with the 3 drugs over the 2 was quite striking and quite early.

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