PVd Regimen Highlighted as New Standard in Relapsed/Refractory Myeloma

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.”

OncLive: Can you discuss the background of this study?

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.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.

What did you find when you looked at PFS?

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 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.

Did the 3-drug combination also produce superior response rates?

The patients [who progressed on lenalidomide maintenance but were not refractory] derived quite a remarkable clinical benefit. It was on the order of more than 10 months. That was quite striking to us. It had a hazard ratio of around 0.5, which suggests it's clinically meaningful. And, the P value was also highly significant.If you looked at the response rates in the study group overall, it was about 82% for the 3 drugs and around 60% for the control group, which is very typical for bortezomib and dexamethasone.

Do you have data on OS or tolerability?

Did you see any significant difference in the incidence of secondary cancers?

What was very interesting in the first relapse group was that 90% of patients responded to the 3 drugs, which is very high compared with the control, which was significantly lower. The most important thing is that the 90% response rate represents a very high response rate in early relapse, so we were very encouraged by that.The data are too immature for survival information. We did look at quality of life, including minimal residual disease, and that data are currently cooking. What I can say about tolerability, though, is that we didn't see any unexpected safety signals; generally speaking, the 3-drug regimen was well tolerated with manageable toxicities. There were more for the 3 drugs as you might expect, compared with the 2, which primarily consisted of neutropenia and low platelet count. But, again, these were manageable. In fact, we only saw neutropenic fever in the 3-drug regimen in only 3% of patients and, it was manageable with appropriate antibiotic therapy and growth factor support. [The patient made a] full recovery.Interestingly enough, no. We saw some skin cancers that were a little more common in the IMiD-based treatment but, again, these were typically basal cell [or] squamous. There were none that were of any particular clinical significance. In fact, we only saw 1 case of myelodysplasia in the 3-drug regimen and that patient had had a lot of melphalan before but for transplant, so that was probably the explanation for that.

Do these findings establish this combination as the new standard of care?

Overall, the safety profile was very encouraging. There were no unexpected signals, rates of neuropathy were manageable, very low rates of thromboembolism, and no cardiac signal, which is important.A new standard of care for first relapse, and certainly 1 to 3 prior regimens too, and a platform on which we can build because the combination could be very rationally added to an antibody, for example, or even to other drugs. In fact, at [the 2018 ASCO Annual Meeting] our own group under the leadership of Dr Andrew Yee has looked at pomalidomide/bortezomib/dexamethasone with elotuzumab (Empliciti) in a very heavily treated, high-risk group of patients. A very meaningful response rate has been seen although the data remain early.

Once lenalidomide fails a patient, what do you reach for? Pomalidomide has already been approved after 2 or more lines of therapy. This brings it up to 1 or more. In that context, especially in the ex-US setting, it's very important to have this large, high level phase III information to obtain regulatory approval. Obviously, in US practice, people are using pomalidomide in first relapse left, right, and center, but from a regulatory point of view and especially outside the United States, this is tremendously important.

What other types of agents will be used in combination with this platform?

We are very excited by the promise of ixazomib (Ninlaro) with pomalidomide, for example. Carfilzomib (Kyprolis) with pomalidomide is a very effective regimen; I use it myself off-protocol in the context of relapsing disease. But what is attractive about bortezomib is that it is a very well-established proteasome inhibitor in this space. Also, especially in the ex-US situation—and I say this carefully because cost is problem for many healthcare systems—the pomalidomide/bortezomib/dexamethasone platform is a value proposition. You can partner it with other drugs and at the same time, not generate a cost that is in any way prohibitive.Both carfilzomib and ixazomib partner very well with pomalidomide. The important message though is that there are other drugs that could be rationally partnered with pomalidomide/bortezomib/dexamethasone. We saw a lot of data at this meeting on venetoclax (Venclexta), for example. We saw data on other small molecules in development.

In that context, we will see this platform being partnered with because it's very well tolerated. You always have to worry about overlapping toxicities. In this particular combination with using subcutaneous bortezomib and being proactive with neuropathy management, it was generally manageable.

Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low&#8208;dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36 (suppl; abstr 8001).