Expert Highlights Phase III Results That Establish PVd as New Standard in Relapsed/Refractory Multiple Myeloma

Danielle Ternyila

In an interview with&nbsp;<em>Targeted Oncology</em>, Paul G. Richardson, MD,&nbsp;clinical program leader and director of Clinical Research in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute,&nbsp;discussed the results from the OPTIMISMM trial. He also shared his insight on the significance of these findings and what he expects to see in the future for this patient population.

Paul G. Richardson, MD

In results from the phase III OPTIMISMM trial, the 3-drug regimen of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) significantly improved progression-free survival (PFS) compared with the 2-drug regimen of bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma who have prior exposure to lenalidomide (Revlimid).

This trial was conducted on a global scale, enrolling approximately 560 patients in Europe, Canada, and the United States. As pomalidomide has been approved for the treatment of patients

following 2 prior therapies, including lenalidomide and bortezomib, the goal was to find a regimen that could benefit patients who progressed on lenalidomide.

Findings from this trial were collected in an early analysis and demonstrated some significant results, according to Paul G. Richardson, MD. There was an 82% response rate in the experimental arm, compared with around 60% in the control arm. The 3-drug regimen was also very well tolerated.

In an interview withTargeted Oncologyduring the 2018 ASCO Annual Meeting, Richardson, clinical program leader and director of Clinical Research in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, discussed the results from the OPTIMISMM trial. He also shared his insight on the significance of these findings and what he expects to see in the future for this patient population.

TARGETED ONCOLOGY: Can we start by discussing the rationale for this study?

Richardson:The background to the OPTIMISMM trial is that we have demonstrated that there is synergy between immunomodulatory treatments and proteasome inhibitors, and that’s been a paradigm of myeloma therapy now 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 to the phase III setting and demonstrate improvement in clinical benefit compared to 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 and II studies, and not only was it safe, but it was also very active as well. It was a very rational build to move 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. As you may know, pomalidomide was originally approved in patients where lenalidomidehad failed them and they were progressing, and therefore, pomalidomide was a viable next step in terms of immunomodulatory treatment.

This goal was to say now, in modern myeloma treatment, most patients receive lenalidomide-based treatment upfront, certainly in the United States, and now increasingly around the world. What's 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? Once lenalidomide has failed a patient, what's the rational next choice? Our goal here was to establish that this combination could be effective, well tolerated, and active in this setting.

TARGETED ONCOLOGY:How was the trial designed?

Richardson:The trial compared pomalidomide, bortezomib, and dexamethasone to a reasonable control at the time that the trial was designed, which was bortezomib and dexamethasone. We knew that was both active and well tolerated, generally. Very 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, then from 9 cycles onwards, and maintenance strategy followed. Patients had to have had prior lenalidomide obviously, and the majority of them were not only exposed to lenalidomide, but also refractory to it at 70%. Because the control regimen consisted of bortezomib and dexamethasone, obviously it wasn’t fair for patients who were refractory to bortezomib to be put into this trial, so they were not eligible. Having said that, if you were on bortezomib maintenance, which is just every 2 weeks, you could actually be a candidate for the trial.

Basically, we randomized about 570 patients across a large number of centers. It was a real global effort and a fantastic world partnership with colleagues in Europe, Canada, the US, and all over the world. I will also emphasize that our European partners are fantastic in particular because they really helped with enrollment, although encouragingly, the US actually enrolled 122 patients which was quite good. For a phase III study, I think that shows that the US can meaningfully contribute. I particularly want to acknowledge my colleagues at my own center because we were actually the lead enroller, not just in the US but globally as well so it was a big effort in the US to contribute to the study.

TARGETED ONCOLOGY:What were the findings?

Richardson:First and foremost, we saw that the PFS benefit for the 3 drugs over the 2 was quite striking and quite early, because we actually did an earlier analysis than planned by the protocol amendment. 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. Very importantly, though, when you looked at those patients who had only had 1 prior line of treatment, say for example lenalidomide, bortezomib, dexamethasone, a stem cell transplant, and then lenalidomide maintenance, those patients who progressed on maintenance were lenalidomide refractory in the first-line. Those sorts of patients derived really quite a remarkable clinical benefit of over 10 months. That was quite striking to us. It had a hazard ratio of around 0.5, which suggested it was clinically meaningful, very meaningful. The Pvalue was also highly significant.

If you looked at the response rates in the trial, for 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. What was very interesting was in the first relapse group, 90% of patients responded to the 3 drugs, which was very high, compared to the control, which was significantly lower. The most important thing is that a 90% response rate represents a very high response rate in early relapse. We were very encouraged by that.

Now obviously the data are too immature for survival information. We don't have that yet, but we did look at quality of life, we are looking at various correlatives, including MRD, and all that data is currently sort of 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 to the 2, primarily consisting of neutropenia and low platelet count. Again, these were manageable. In fact, we only saw neutropenic fever in the 3-drug regimen in only 3% of patients. Again, it was manageable with appropriate antibody therapy, growth factor support, and full recovery.

TARGETED ONCOLOGY:Did you see any significant difference in other primary cancers?

Richardson:Interestingly enough, no. We saw some skin cancers that were a little more common in the immunomodulatory drug-based treatment, but again, these were typically basal cell squamous, nonethat were really of any particular significance, clinically, in the big sense. In fact, we only saw 1 case of myelodysplasiain the 3-drug regimen, and that person had had a lot of melphalan before the transplant, and a lot of oral melphalan, so that was probably the explanation for that. Overall, the safety profile was very encouraging, no unexpected signals, manageable neuropathy, very low rates of thromboembolism, and no cardiac signal, which is important.

Our conclusions were [this is] a new standard of care for first relapse, and certainly for 1 to 3 prior regimens too. This is obviously a platform upon which we can build, because the combination could be very rationally added to an antibody for example, or even to other drugs, too. In fact, our own group, under the leadership of Andrew J. Yee, MD, has looked at pomalidomide, bortezomib, and 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 does remain early.

TARGETED ONCOLOGY: Can you speak to how these findings are going to demonstrate how to care for these patients?

Richardson:Essentially, 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. I think 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 the US practice, people are using pomalidomide in first relapse left, right, and center. But I think from a regulatory point of view, and especially outside of the United States, this is tremendously important. I think that obviously we are very excited by the promise of ixazomib (Ninlaro) with pomalidomide, for example. Carfilzomib (Kyprolis) with pomalidomide is a very effective regimen that I often use myself and off protocol in the context of relapsing disease. I think what's attractive about bortezomib is it's a very well established proteasome inhibitor in this space, and also from a practical ex-US situation, it is obviously — and I say this carefully because cost is a challenge for many healthcare systems – the pomalidomide/bortezomib/dexamethasone platform is a value proposition if you excuse the term, because you can partner it with other drugs and at the same time not generate a cost that is in any way, for certain healthcare systems, prohibitive.

TARGETED ONCOLOGY: Do you see any other agents or treatment regimens on the horizon as a result of these findings?

Richardson:Monoclonal antibodies, first and foremost, different types of proteasome inhibitors, and I stress, for example, both carfilzomib and ixazomib partner very well with pomalidomide. Obviously, ixazomib has the advantage of being all oral. Carfilzomib is particularly active. I think the important message, though, is there are other drugs beyond this that can be rationally combined with pomalidomide, bortezomib, and dexamethasone. We saw a lot of data at this meeting on venetoclax, for example. We saw data on other small molecules in development. I think in that context, we will see this platform being partnered, because it's very well tolerated. You always have to worry about overlapping toxicities and if any of these become prohibitive. Obvious ones are cardiac, vascular, and obviously, neurotoxicities are always a worry. In this particular combination with using subcutaneous bortezomib and in particular being very proactive in neuropathy management, it was generally manageable.

TARGETED ONCOLOGY: Is there anything else you want to mention?

Richardson: