Conference Coverage: EHA 2018
Paul G. Richardson, MD discusses EHA 2018 Abstract S847 – OPTIMISMM: Phase 3 Trial of Pomalidomide, Bortezomib, and Low‐Dose Dexamethasone vs Bortezomib and Low-Dose Dexamethasone in Lenalidomide-Exposed Patients with Relapsed/Refractory Multiple Myeloma
Blake Morrison (Interviewer): Good afternoon it’s Saturday at EHA 2018. I’m Blake Morrison with the World Myeloma Forum. I’m here with Paul Richardson. Dr. Paul Richardson from the Dana Farber Cancer Institute, world renown for myeloma research. He’s here to talk to us about a really interesting trial from OPTIMISMM. It’s a triplet versus doublet therapy in lenalidomide refractory disease. So why don’t you tell us a little bit about this study.
Paul Richardson, MD: Thank You Blake and good afternoon everyone it’s an absolute pleasure to be here. I think the essence of the OPTIMISMM trial (EHA Abstract S847: Phase 3 Trial of Pomalidomide, Bortezomib, and Low‐Dose Dexamethasone vs Bortezomib and Low-Dose Dexamethasone in Lenalidomide-Exposed Patients with Relapsed/Refractory Multiple Myeloma) is summarized by the fact that lenalidomide based therapy is being used upfront now as a standard of care certainly in the United States and increasingly elsewhere. And lenalidomide is now being used as part of maintenance both in transplant eligible and transplant non-eligible patients.
So there the goal of OPTIMISMM was really to establish a real-world platform that could address this area of relative unmet medical need. In other words, when lenalidomide fails what do we do. So, we built the platform on the premise that obviously after IMiDs runs out of benefit a protosome inhibitor based approach makes sense. Obviously, we have great data from the synergy of IMiDs and proteozome inhibition from the original VTD/RVD KRD, IRD concepts and combining palm with bortezomib had been shown in our phase 1 to experience to be safe well tolerated and very importantly very active. We also knew that you could combine pomalidomide successfully with carfilzomib, you can combine it with ixazomib, but obviously we wanted to provide a real-world platform. So, the idea was to take forward a triplet versus a doublet in lenalidomide exposed and lenalidomide refractory patients. One to three prior lines of therapy.
This was a global effort, really a tremendous international team, and essentially what we also built into the design was that patients continued on therapy. So, it reflected the paradigm of continuous treatment. There was no fixed duration of therapy. People got pomalidomide bortezomib and dexamethasone for up to their eight to nine cycles, similarly for bortezomib Dex up to eight to nine cycles, and then at that inflection point converted to maintenance strategies in both arms. I think this was the strength of the trial, because obviously,
1. a lot of recent phase threes have one been in patients in whom lenalidomide exposure has been minimal and
2. there’s been fixed duration to the control arms at least which has led to some difficulty in exactly interpreting the impact in the in the clinic of what the comparisons might mean.
We enrolled approximately 570 patients – five hundred sixty-six to be exact – and we were very pleased to see a very equal distribution in characteristics, the beauty of a randomized trial, 100% were lenalidomide exposed, and 70 percent of the patients were truly lenalidomide refractory. which is important. We did allow prior bortezomib exposure, but they could not be refractory to therapeutic bortezomib for obvious reasons because then the equipoise of the control arm wouldn’t apply. So, with that in mind we’ve did our analysis for the primary endpoint, we looked early Blake, because we’ve had data from studies like castor which showed that the PFS for bortezomib Dex was around seven months and therefore we by protocol amendment did an interim look earlier than originally planned. So, with an early look, which obviously has its risks, we were very pleased to see that the PFS benefit was significant and clinically meaningful. Basically, a four-month difference in favor of the triplet with a PFS of approximately 11 months versus 7 months for the control group. What was particularly striking though, was if you looked at the first relapse population, if you looked at those patients in first relapse, the PFS benefit was 20 months versus 10 months. And that group of patients, in particular, had about a 10-month difference in their favor. Which is very important. And the clinical question that’s arisen is, you know, what about the lenalidomide refractory patients in that first line. We were very pleased to see that the PFS for the control group was 9 months but actually for the triplet it was 17.8 months with a hazard ratio of 0.55.
So, you know, really exciting data that in first relapse but not only can you improve clinical benefit by a solid 10 months in everyone, but even if you’re lenalidomide refractory, you get a significant clear or gain. So, if you look at response rates as obviously a surrogate for this kind of clinical benefit, 80% overall for PVD versus 50% overall for VD in first relapse, 90% for PVD, 60% for VD.
I think what’s really nice about that is that it, sort of, confirms the synergy that you and I have known about for a long time between IMiDs and proteasome inhibitors and at the same time in a very manageable practical context.
Blake Morrison (Interviewer): So, two questions. It establishes the IMiD to IMiD and ability to sequence within the class. A question about tolerability, is there major differences between the two arms in terms of patients tolerating the triplet versus doublet therapy?
Paul Richardson, MD: Great question. There was no unanticipated safety signals. What we saw was basically the duration of therapy was much longer as you’d expect for PVD. So therefore, obviously you have to take that into context when you look at the aggregate toxicity data. But suffice to say, neutropenia was probably the biggest difference. But it was manageable. Our rates of febrile neutropenia were just 3% so that reflects that. Deep vein thrombosis very low rates but there with a triplet not with VD. But again, very low rates and manageable neuropathy. A little higher for PVD than VD but again not huge. And so, in general, you looked at a very comparable safety profile for both groups. Then when we looked at subgroups. What was really interesting, you know, for patients with high risk cytogenetics, renal dysfunction, older age, the benefits were consistently good across all groups. Which is very important obviously from a practical point of view.
Blake Morrison (Interviewer): Is MRD testing being done in this patient line of therapy?
Paul Richardson, MD: Yes, it is. MRD testing is cooking so as other correlative science.
Blake Morrison (Interviewer): I’m presuming you’re going to look at overall survival (OS) as well as an ultimate end point on this study?
Paul Richardson, MD: As a secondary endpoint, yes. But obviously that’s going to, thank goodness for the benefit of patients, that’s going to be a long time.
Blake Morrison (Interviewer): It’s going to be interesting watching this study continue mature and generate interesting data. Thank you very much for sharing what you did today, we really appreciate you stopping by.
Paul Richardson, MD: It’s my pleasure Blake and thank very much.
Dr. Francesca Gay discusses EHA 2018 abstract #PF560: Carfilzomib in Combination with Bendamustine and Dexamethasone in Relapsed/Refractory Multiple Myeloma: A Multicenter Phase Ib/II Trial of the European Myeloma Network Trialist Group (EMNTG)
Dr. Karim Iskander discusses EHA 2018 abstract S849 – Once-Weekly vs Twice-Weekly Carfilzomib Dosing Plus Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Results Of The Randomized Phase 3 Study A.R.R.O.W.
Dr. Bringhen discusses EHA 2018 abstract PS1293: Doublet vs Triplet Lenalidomide-Containing Regimens Followed by Maintenance: Subgroup Analysis by Frailty Status After a Median Follow-Up of 5 Years (EMN01 Phase III Study). The study challenges the “one-size-fits-all” approach to treating patients with multiple myeloma. This subset analysis of a large randomized phase III trial, demonstrated that that fit patients benefit from triplet full-dose regimens, while intermediate and frail patients benefit from a gentler doublet regimen.
Dr. Dinmohamed from the Netherlands Comprehensive Cancer Organisation (IKNL) discusses abstract PS1301 from the EHA meeting in Stockholm: Treatment and Survival of Patients with Primary Plasma Cell Leukemia: A Nationwide Population-Based Study Among 179 Patients Diagnosed in the Netherlands from 1989 to 2015
Dr. Gay discusses EHA 2018 Abstract S109: Updated Efficacy and MRD Data According To Risk-Status in Newly Diagnosed Myeloma Patients Treated with Carfilzomib Plus Lenalidomide or Cyclophosphamide: Results from the FORTE Trial