PS: Welcome at this ecancer filming. We are here at the International Myeloma Workshop in New Delhi, India, where we hear a lot of exciting news about multiple myeloma. We are here together, sitting next to me is Professor Michele Cavo from Bologna in Italy and Peter Voorhees from North Carolina in the United States and Dr Evangelos Terpos from the University of Athens in Greece. Welcome colleagues. So we will discuss a couple of important issues that have been raised at this workshop and we would like to start with the current treatment standards for newly diagnosed myeloma patients, especially the transplant eligible patients or the younger patients. Dr Cavo has a lot of experience in that field so I would like to ask him to present the most recent data that have been obtained in this topic and in particular the most recent studies that are ongoing or have been presented for the first time. Dr Cavo.

MC: Autotransplant for younger and fit patients with newly diagnosed myeloma still remains the gold standard of therapy. This is based on two recently reported large phase III European trials comparing up front transplant versus transplant delayed at the time of relapse. In both the studies the primary study endpoint was progression free survival and both of them provided a clear demonstration that patients who were randomised to receive upfront autotransplant had a significantly better progression free survival in comparison with the control group.

PS: So those initial treatments for patients that are transplant eligible, in fact they consist of several stages, like induction, the transplant itself, maybe consolidation and maybe maintenance therapy. So what’s your opinion about the transplant phase high dose melphalan? Should we give it to every patient based on your experience?

MC: Up to now high dose melphalan still remains the standard of care. Several trials are exploring the possibility to add several agents, old agents as well as novel agents, for example, the second generation proteasome inhibitor carfilzomib. However, these trials are still ongoing and the conclusion is that at this time melphalan still remains the gold standard therapy.

PS: And is there also a second transplant in all patients or some subgroups?

MC: This is a matter of discussion and this issue was addressed in two phase III trials, one conducted in Europe and the second one in the US. The EMN02 trial is the largest so far reported including a proteasome inhibitor and an IMiD which was designed at prospectively comparing standard dose versus high dose intensification therapy including single versus double transplant and consolidation versus not consolidation therapy. The results of the first interim analysis were reported and showed that for those patients who were randomised to a double transplant there was a benefit in terms of extended progression free survival. The benefit was mostly seen in patients with poor prognosis such as, for example, those with high LDH values or revised ISS stage 2/3. But the highest hazard ratio in this study was seen for patients with a high risk cytogenetic profile. For this population receiving a double transplant translated into a two times longer median progression free survival in comparison with that seen for patients who were randomised to a single autologous stem cell transplantation. Although the study still needs to be evaluated with a more mature follow-up, the first conclusion at this time is that it is likely that it is placed for double transplant, particularly in patients with poor prognosis and in patients with a high risk cytogenetic profile.

PS: Thank you. This study also looked at the role of consolidation and there is another trial, an American trial, the STAMINA trial, that also looked at the role of different intensification or consolidation phases. Can you comment on that? This is all very recent data.

MC: The STAMINA trial was reported at the last ASH meeting. The design of the trial was based on a randomisation for patients with newly diagnosed disease to receive a single autotransplant followed by lenalidomide maintenance or a single autotransplant followed by four cycles of VRd consolidation and then lenalidomide maintenance or a double autotransplant with lenalidomide maintenance. Disappointingly, no difference in progression free survival and overall survival was seen between the three arms of the study.

PS: So there is probably more… we need more time for those trials to mature before we have a final answer.

MC: Yes and I can also add that several inconsistencies between the EMN and the STAMINA trial can be appreciated. The induction before transplant was different in the two studies, all the patients in the EMN received VCD while more than 50% of patients in STAMINA did get VRd as induction therapy. But, more importantly, the pre-planned months of induction before the first transplant was in the range between 2-3 months in the EMN trial while it was extended up to one year in the STAMINA trial. It is likely that for those patients who were exposed to a prolonged administration of VRd this very intensification therapy may be abrogating the value of consolidation. This is a possible explanation on the conflicting results seen between the two trials: the STAMINA negative in terms of the role of consolidation, the EMN positive in terms of the value of consolidation therapy.

PS: Thank you. I think we have to move on from symptomatic myeloma to asymptomatic myeloma, also called smouldering myeloma. Dr Voorhees, you gave a talk and summarised the current experience with treating smouldering myeloma patients. Can you summarise this for us?

PV: Sure. I think that there are a number of different issues that are important to address in the landscape of smouldering multiple myeloma. First off, there’s a very strong need to refine the model systems that we have in place to identify those patients with smouldering multiple myeloma that are at higher risk to progressing to active disease versus those patients that have disease biology that’s much more in line with that of an MGUS patient. There are multiple models that are out there now, the Mayo Clinic models and the PETHEMA models are the ones that are most commonly utilised but it’s safe to say that there’s probably some degree of heterogeneity there. In that regard it’s very encouraging that the International Myeloma Working Group is actually getting ready to embark on a very important study where they’re going to take large datasets of patients with smouldering multiple myeloma, capture as much data on those patients as they can and really sit down, look at the data and determine what factors place patients in a higher risk category to evolve into active myeloma. Because at the end of the day those are the patients that we worry about the most; those are the patients that probably have disease biology that’s more in line with that of an active myeloma patient and those are the patients that should be considered for clinical studies in smouldering multiple myeloma whereas those patients that have more of an MGUS phenotype are probably better served with observation.

So it’s important to note that the Spanish study of lenalidomide versus observation for patients with high risk smouldering multiple myeloma was a positive study so, not surprisingly, we all expected to see a dramatic improvement in time to progression with early intervention. Many of us were perhaps surprised at the magnitude of benefit that was seen with regards to overall survival in that particular study. Now, we can certainly argue about some of the study design issues - it was a relatively small study, there may have been differences in disease biology, it’s important to recognise that bone imaging these days, more advanced bone imaging of smouldering multiple myeloma patients will pick up patients with active disease that would have been missed by plain radiographs. Dr San Miguel made a very good point at the meeting a couple of days ago that their current CESAR trial, approximately 20% of the patients that are screened to participate in that particular trial wind up not being able to go on the study because they have occult lytic bone disease that was missed by plain films. So that’s important to recognise.

The other important issue with that particular study was that patients who were assigned to lenalidomide dexamethasone were allowed to have dexamethasone added back into their therapy at the time of lenalidomide maintenance if they had biochemical progression, not progression to active disease but biochemical progression, whereas those patients that were assigned to observation did not have the benefit of receiving therapy for biochemical progression. Nonetheless, with those caveats aside, it was a very powerful study. It’s the first study that has ever shown a survival advantage in this particular situation and that’s what has really fuelled the interest in newer studies in smouldering multiple myeloma.

So there are a number of different initiatives that have recently launched which are basically utilising the lenalidomide dexamethasone backbone for patients with higher risk smouldering multiple myeloma. Dr Ghobrial had presented at ASH and will be presenting updates at this meeting of the combination of lenalidomide, dexamethasone and elotuzumab for patients with high risk smouldering multiple myeloma. Very encouraging data thus far - approximately 83% overall response rate and very impressive progression free survival with very early follow-up. There are a number of other studies looking at immunotherapy type approaches for smouldering multiple myeloma. There’s a lot of interest in the checkpoint inhibitors, for example the MD Anderson group is looking at pembrolizumab as monotherapy in smouldering multiple myeloma. Now, pembrolizumab may not have done terribly well as monotherapy in relapsed refractory patients but it would be very interesting to see how it performs in patients with smouldering disease by itself. There’s another initiative looking at the combination of lenalidomide dexamethasone and another checkpoint inhibitor, nivolumab, that’s ongoing and enrolling patients as well.

PS: So is there any place for proteasome inhibitors in this disease?

PV: Absolutely. Again, I do think that we need to better define high risk smouldering multiple myeloma because at the end of the day as we add more drugs to therapy we add more toxicity and we need to make sure that we’re treating the right patients. That said, there are two studies, one of which is already enrolling patients and another one that will open later this year, that are taking a very comprehensive curative approach to smouldering multiple myeloma. The first is the CESAR trial which is being run out of Spain and the second study is an IMF study, a Black Swan research initiative that is being spearheaded by the IMF group. All of this is basically rooted in Ola Landgren’s work with carfilzomib, the proteasome inhibitor cafilzomib, lenalidomide and dexamethasone in high risk smouldering multiple myeloma. While he was at the NCI he treated twelve patients, a very small number so we have that caveat aside, but with just eight cycles nine out of twelve patients achieved MRD negative status by next generation sequencing methodology, so very encouraging results. So the CESAR trial is basically taking patients who have high risk smouldering disease and ultra-high risk disease and treating them with KRd induction, transplant, KRd consolidation followed by len-dex maintenance therapy. They’ve enrolled 60 out of the 90 patients so we should get a readout of that study in the near future.

The ASCENT trial is very similar, in this case it’s going to be induction therapy with KRd daratumumab. They will then either go on to transplant or additional cycles of KRd-dara. There will be an intensification process out back where they get more KRd-dara followed by one year of carfilzomib-len-dara maintenance. Again, it will be very interesting to see what the rate of MRD is in this scenario and whether patients are effectively cured.

PS: So one last and quick question – should patients with smouldering myeloma, high risk smouldering myeloma, be treated outside the context of a clinical trial?

PV: I don’t think so. The general approach that many have taken in the United States is to observe. For those patients that have high risk disease observe them closely. There is a lot of emerging data on evolving phenotype of smouldering multiple myeloma. The Mayo Clinic group is actually presenting data at IMW basically looking at a rate of rise in their M protein and a rate of decrease in their haemoglobin that predicts a very high risk of progression within one year. So for those patients that have high risk disease that have an evolving phenotype you could make a very strong case for using lenalidomide and dexamethasone in that situation.

PS: OK, so thank you. In the interests of time we move on. Dr Terpos, you have been much involved in diagnosing and treating comorbidities or complications of multiple myeloma like bone disease.  Have you seen any new data here at the Myeloma Workshop?

ET: Bone disease is the most common complication of multiple myeloma, it’s approximately present in 80% of patients at diagnosis. With the new test, as you mentioned, like the whole body low dose CT or the PET-CT we manage to diagnose lytic lesions in approximately 80-85% of the patients at diagnosis. As you mentioned, Jens Hillengass is going to present some of the data of the study that we are conducting together on behalf of the International Myeloma Working Group comparing the whole body low dose CT with conventional radiography in patients both with asymptomatic myeloma according to the conventional radiography and symptomatic disease. In this study Jens showed that approximately 20% of the patients who had no lytic lesions with conventional radiography have lytic lesions with whole body low dose CT. Thus these patients are considered as having active myeloma and need treatment.  So I think that we have done a lot of improvement in the diagnostics of bone disease. We have the PET-CT also and the…

PS: Sorry, if I may interrupt you, what do you recommend now for diagnosing bone disease?

ET: We totally recommend the whole body low dose CT as a not so much expensive like the PET-CT technique which gives very low radiation and can diagnose the lytic lesions in approximately 80-85% of patients with multiple myeloma.

PS: That’s very clear and good advice. So when we move to treating bone disease are there any new developments?

ET: We have the new development of a new drug, a monoclonal antibody targeting RANK ligand. The receptor activator of nuclear factor-kappa B ligand is the most potent osteoclast activator and in the myeloma microenvironment it’s overexpressed and presses the osteoclast to work more and destroy the bone. So even now the most potent drugs that we have targeting bone are the bisphosphonates that inhibit the osteoclast function. Now we have one very potent osteoclast inhibitor and the name is denosumab, it’s an anti-RANK ligand monoclonal antibody and in this meeting we have the first randomised trial comparing denosumab with zoledronic acid. This is the first report in this meeting and it’s going to be reported by Noopar Raje on Saturday morning, seven o’clock I think. In this study more than 1,700 patients were randomised to receive either the standard dose of zoledronic acid, 4mg every four weeks, compared to denosumab in 120mg given subcutaneously every four weeks again.

PS: And this is myeloma patients only?

ET: Myeloma patients only, 1,700 patients, one of the largest studies in the field of multiple myeloma ever conducted. We had a lot of stratification regarding patients receiving autologous transplantation or not receiving the transplant, receiving novel agents or not receiving novel agents and also we had stratification regarding Japan or no Japan region in order to have the different genomes of the different nations.

PS: So what’s your recommendation on the duration of treatment? This has been for discussion many times.

ET: Yes, as far as zoledronic acid or bisphosphonates, because also pamidronate is giving very good results in this setting, we can say that for patients who have not achieved a complete response or very good partial response the International Myeloma Working Group recommendation is to give the treatment for two years and then if the patient continues to have only a partial response or less than partial response they have to continue on the bisphosphonates. If the patient has achieved complete response or very good partial response then the recommendation is that the treating physicians can stop treatment. We have also a study led by Noopar Raje published in Clinical Cancer Research last year showing that if we give the bisphosphonates in this category of patients every three months compared to every month the results are also similar. So for patients in complete response or very good partial response we may stop the bisphosphonates because of the side effects.

PS: OK, so last question and quick answer please, should we resume these therapies once the patient has progression or relapse?

ET: Yes, the answer is yes, we have to resume definitely the bisphosphonate. And just to say a few words about the denosumab study because in the abstract we have the first results and also there was an urgent press release regarding this study saying that the primary endpoint of the study, which is the non-inferiority of denosumab versus zoledronic acid, has been achieved and we have in the abstract the first result for the PFS which is in favour of denosumab. We have to say that although this was not the primary endpoint of the study this is something very promising.

PS: Thank you very much, gentlemen, for giving these very useful comments.