Following on from their discussion around the treatment of smoldering multiple myeloma patients, Professor Maria-Victoria Mateos (University Hospital of Salamanca, Salamanca, Spain) and Professor Paul Richardson (Dana-Farber Cancer Institute, Boston, USA) focus on advances in the treatment of relapsed/refractory multiple myeloma (RRMM) at IMW 2017 in Delhi.
First discussed was the update to the POLLUX trial presented at IMW. After median 17.3 months of follow-up, the addition of daratumumab to lenalidomide and dexamethasone (DRd) demonstrated significantly prolonged PFS compared to lenalidomide and dexamethasone (Rd).
As well as showing “the best PFS in a Phase III RR trial”, the DRd combination also resulted in positive overall and complete response rates.
With the updates of the trial focusing on depth of response and the role of MRD, MRD negativity was observed in over three times as many patients receiving DRd verses Rd, with no MRD-negative, high-risk patients progressing during the study.
Prof Richardson and Prof Mateos then focused discussion on the use of mAbs combined with Pomalidomide and Dexamethasone (POM-D) as a backbone in the treatment of RRMM. A multi-arm, phase 1b study presented at IMW 2017 evaluated daratumumab with POM-D in patients with two or more prior lines of therapy.
Deep, durable responses were observed across all subgroups and the results showed a safety profile consistent with individual therapies, with the exception of a higher incidence of neutropenia.
Another mAb evaluated in combination with POM-D is Isatuximab, with preliminary data presented at IMW suggesting that the combination is well tolerated and clinically active in patients with heavily treated RRMM. With a number of novel agents and combinations producing promising results in RRMM, the options for patients are set to expand.
This is the second part of a larger discussion covering smoldering myeloma which can be viewed here.
This programme has been supported by an unrestricted educational grant from Janssen Pharmaceuticals (A Johnson & Johnson Company).
PR: We’ll change gears and, if you don’t mind Marivi, now we’ll move on to an area where we both work very actively which is in relapsed and relapsed refractory disease. I wondered if you might like to discuss with our audience our joint work with daratumumab, particularly in the context of the POLLUX study, as a first step?
MVM: Yes. So you know that the POLLUX is a [?? 0:24] phase III randomised trial in which lenalidomide and dexamethasone, one of the previous, or one of the old standards of care for relapsed and refractory myeloma patients, was compared with len-dex plus daratumumab, the CD38 monoclonal antibody. Approximately 500 relapsed and refractory myeloma patients after one prior line of therapy were included in this study. Daratumumab plus lenalidomide and dexamethasone was given as continuous therapy and an update of the trial was presented at the last ASH meeting and it will be also presented here in Delhi in the International Myeloma Workshop. With a median follow-up of approximately 18 months so we can observe a significant benefit in terms of progression free survival for dara plus RD. At the present time I would say that it’s the best progression free survival curve we’ve seen in a phase III randomised trial in relapsed and refractory myeloma patients with a very low hazard ratio. This is important but for me it’s also very important the overall response rate and, more importantly, the complete response rate because 46% of the patients achieve a complete response and this was something unusual for relapsed and refractory myeloma patients. Even I would say that we are not seeing this complete response rate in the upfront setting with a bortezomib based combination. So the complete response rate clearly translated into a significant benefit in terms of progression free survival. But the other important message coming from the POLLUX and I would say also from the CASTOR, in which daratumumab was combined with bortezomib and dexamethasone, is the role of minimal residual disease. Because if we put together POLLUX and CASTOR so we will have probably almost 1,000 relapsed and refractory myeloma patients in which minimal residual disease has been evaluated. The main message is that this study consolidated the role of minimal residual disease as an important surrogate marker predicting progression free survival. In fact, if you look at the progression free survival curves for patients achieving minimal residual disease negative, regardless of the treatment, experimental or control arm, almost 100% of the patients are free of progression. This is the clear message but when you look at the number of patients who achieved minimal residual disease negative it’s much higher when daratumumab was added to len-dex or bortezomib and dexamethasone. So we have to try to achieve this minimal residual disease negative status for all of our patients, not only in the upfront, also in the relapsed setting and, of course, if we add, in this case, daratumumab to backbone regimens a higher number of patients are going to reach this objective.
PR: I completely agree with you. I think the MRD data are particularly striking, aren’t they, and you’re absolutely right that certainly in the relapsed refractory setting to see MRD negativity correlating with disease control for prolonged periods is very, very exciting. It is interesting to me in the MRD world, though, that for example in the upfront setting with follow-up you lose disease control over time and we see up to 20% of MRD negative patients in the upfront setting, for example, relapsing after three years or so. So I think we need further follow-up with our current work to understand that. But I completely agree with you, the results with daratumumab combination therapy are unprecedented and the hazard ratios are the best we’ve ever seen and these are yet to combine the two drug classes, the IMiD proteasome inhibitor plus monoclonal antibody platform, which is so exciting. In that context, upfront, now we’re looking at combinations like lenalidomide, bortezomib and dexamethasone with daratumumab upfront. We already have the MAIA data which I know you’re involved with which is RD plus or minus dara upfront. So there’s a whole wealth of information that’s going to come through that’s going to be very, very promising, I believe, and very exciting in terms of daratumumab use. However, in the relapsed refractory setting we do recognise that dara can fail and what I’m very impressed by is that actually new combinations, be it with pomalidomide and dara, have been studied and I’d love your thoughts on that. Then I can perhaps talk about some of our other work with other antibodies in the same space.
MVM: Yes, of course because we think that after bortezomib and after lenalidomide, so pomalidomide and dexamethasone, is or was one of the standards of care based on the NIMBUS trial. However, in the future pomalidomide and dexamethasone will be again a backbone to which other novel agents are going to be added. So I would like to ask you by the new agents that we can add to pomalidomide and dexamethasone and specifically for the monoclonal antibodies targeting CD38 that you can discuss the role of dara and also the role of other CD38 monoclonal antibodies in this setting.
PR: Absolutely Marivi. So my take on it, I think we’ve both very much on the same page, is that dara plus pom the results are very promising. Obviously then there will be the opportunity to integrate a proteasome inhibitor into that platform and carfilzomib, for example, comes to mind as does ixazomib. So in that context the tolerability profiles will matter because we have to recognise that daratumumab, by targeting CD38, obviously has effects on blood counts which are relevant, fatigue. Very interestingly also there’s this endothelial targeting that may occur that may be relevant to certain proteasome inhibitor drugs that we use, particularly carfilzomib. Now, with that in mind I’m impressed that the pomalidomide data are as encouraging as we see with lenalidomide. The flip of that in terms of other CD38 targeting agents in the same space, we’ve been very pleased with the performance of isatuximab, so-called SAR with a long number that I can never remember but isatuximab is obviously its generic name. This targets CD38 in exactly the same way as obviously daratumumab does but there are important differences between the antibodies. One of the most important practically is the infusion time. What we’ve been very pleased with with daratumumab on the one hand being long for the first and then shorter for subsequent is that with isatuximab it’s relatively short to start with at around four hours and then you cut down to around two. What’s really interesting also is you can give it every two weeks. So from a patient perspective there’s enormous convenience to that approach. What’s also exciting to me is there doesn’t seem to be a huge difference in their activities. Interestingly, there is some preclinical evidence that isatuximab may have more ectoenzymic or pro-apoptotic function than, for example, other monoclonals in the same space. Having said all of that, they seem very comparable and at 10mg/kg which is obviously not dissimilar from the 16mg/kg that we use for dara we’re seeing promising activity with pomalidomide as a backbone. That’s actually forming the platform for a phase III trial combining pom-dex versus pom-dex isatuximab. In our work that we’re going to present here at the International Myeloma Workshop as an oral session later today we will show basically very encouraging results overall, about two-thirds of patients responding. They are heavily pre-treated, median number of prior lines is essentially five, and what we are struck by is that it is manageable in terms of its side effect profile. One thing is clear is myelosuppression and that applies to dara too but again it’s manageable.
MVM: Yes, because the frequency of grade 3/4 neutropenia is higher than the control arm, higher than we expect with pomalidomide and dexamethasone alone but you are right because this is not translating to a significantly higher frequency of severe infections or other complications.
PR: Yes, I think we have to be a bit careful about that because in the context of the relapsed refractory patients I’ve treated on the study I’m very proactive with their infectious management. I think you’re absolutely right, it’s not unmanageable but I would speculate that it might be higher because in the more advanced patients they’re more vulnerable. Given all of that though, thank goodness we’re seeing responses in patients who are frankly extremely refractory. These are median fives and certainly speaking to my own patients in the trial several have been in the situation where if this combination had failed them they would be in a hospice. To see them actually doing well despite all the side effect management challenges, which are manageable, is really gratifying.
MVM: And do you use any specific antibiotic prophylaxis?
PR: Great question. Obviously we use acyclovir to prevent reactivation of herpes zoster because that’s real with all the CD38s. We are just proactive, in other words at the first sniffle, at the first cough, particularly upper respiratory tract symptomatology, we dive in with antibiotics and we have a very low threshold for evaluating people in the emergency room or in the clinic if they report any symptomatic issues that may suggest infection. But, again, it’s manageable. We have certainly not had in our centre any treatment related mortality from the combination which has obviously been an important feature. In terms of some closing comments we’re very pleased with the excitement around monoclonal antibodies, aren’t we? It’s been an absolute pleasure in the daratumumab space to be seeing how that is going and at the same time to see next generation or arguably just subtly different antibodies come into the same space that could enhance therapeutic benefit.
MVM: Yes, of course we will have a lot of new monoclonal antibodies because at the end if we use the CD38 monoclonal antibodies at the beginning, so probably in the upfront setting or in first relapse, are we are going to challenge our patients with the same monoclonal antibodies? Probably we will use another different monoclonal antibody targeting another antigen present on the surface of the plasma cells so probably the bone marrow microenvironment.
PR: That’s an excellent point to close on. In terms of where we are with the antibodies we not only have exciting ones in the same class but we have ones that are completely different. Certainly speaking from my own practical experience we’ve been able to use elotuzumab-based combinations after daratumumab failure and see responses although it’s obviously not just the antibodies, it’s the other drugs as well. But you’re absolutely right, Marivi, the new targets like BCMA are going to be very, very attractive for different classes of antibody.
PR: So at that point we will probably close up. Just to say thank you very much to our audience for listening in on our discussion today and we hope very much that what we’ve discussed has been helpful and informative.