COMMENTARY

Recent Advances in Multiple Myeloma Therapy

Antonio Palumbo, MD; Jesús San Miguel, MD, PhD; Meletios Dimopoulos, MD; Thierry Facon, MD; Philippe Moreau, MD

Disclosures

April 11, 2012

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Talking About Multiple Myeloma

Professor Philippe Moreau: Good morning. Today, we have a panel of 5 for a discussion about the treatment of multiple myeloma, focusing especially on the results presented during the American Society of Hematology (ASH) meeting in San Diego in December 2011. My name is Philippe Moreau. I work in Nantes, France, and I have 4 very famous experts with me: Thierry Facon from the IFM (Intergroupe Francophone du Myélome) group working in Lille, France; Jesús San Miguel, who is one of the heads of the Spanish myeloma group, Meletios Dimopoulos, head of the Greek group working on myeloma; and Antonio Palumbo, one of the leaders of the Italian group.

We are going to discuss some presentations that were of interest at the last ASH meeting. First of all, I would like to ask Thierry Facon his opinion of an important improvement in the treatment of patients not eligible for high-dose treatments -- the elderly patients. What is your opinion on outstanding presentations during this meeting?

Lenalidomide Maintenance in Elderly Patients?

Professor Thierry Facon: We had an update on the lenalidomide front-line study (MM-015).[1] The topic of maintenance in elderly patients is emerging, so this is important. Lenalidomide maintenance therapy is not approved, but we now have the final results of the melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance study.[1] This will probably translate into routine practice in the next year because it is probable that this therapy will be approved by the European Medicines Agency.

Professor Moreau: Do you think that it will be approved for all patients above the age of 65, or do we have a subgroup of patients who benefit most from this maintenance therapy?

Professor Facon: That is a very good point. It will be approved only in patients aged 65-75 years, on the basis of the results of that particular study.

Professor Moreau: Would you like to comment, Antonio? You are the principal investigator of this study. Do you think that the study will lead to the approval of the drug?

Professor Antonio Palumbo: I do not know the approval path, so I cannot comment on the approval. I agree with what Thierry said. This trial was very important to show the clinical role of a maintenance approach after induction in elderly patients. That was the major finding from this study.

Adding Bortezomib: The VISTA Trial

Professor Moreau: Jesús, you presented the updated results of a very important international phase 3 randomized study[2] that was presented several times during the meeting, but the final presentation reported a very long follow-up. Would you like to comment on the results of the VISTA study?

Professor Jesús San Miguel: Yes. It was a large randomized trial comparing melphalan/prednisone (MP) vs bortezomib plus melphalan/prednisone (VMP). With a median follow-up of 5 years (4.5 years from the last patient enrolled), there was a significant overall survival benefit of more than 1 year (13.3 months) in favor of the experimental arm (VMP group). This benefit was observed across group analyses.

In addition, this study has shown something that is very important about the paradigm of using a more conventional approach (MP up front) and reserving the other drugs until the time of relapse. This study has clearly shown that it is better to use an optimized treatment up front.

The third message of the study was that for the first time, in the analysis of risk for second primary malignancies with the use of bortezomib (in this case, in combination with MP), it showed that the incidence is the same as in the control arm.

Professor Moreau: You presented interesting results on cytogenetics in this study. Would you like to comment on this?

Professor San Miguel: The study was not sufficiently powered to analyze the role of cytogenetics because the number of patients with high-risk cytogenetics was very small (22 patients in 1 group and 24 in the other). Initially, we saw an advantage for the experimental arm vs the MP group, but now with longer follow-up, the incidence of second primary malignancies was exactly the same. One could argue that at the time of relapse, fewer patients were receiving bortezomib, but this is not the right answer. The right answer is that no difference in risk for second primary malignancies was seen in this study.

On top of this, we have the data from the Spanish trial, also in the elderly patients, in which we were unable to overcome the prognosis of high-risk cytogenetics. This is a challenge for the elderly community.

Professor Palumbo: That is an important message, although quite disappointing.

Professor San Miguel: Yes, this is a challenge.

Professor Moreau: You presented the VISTA study, which used a biweekly dose of bortezomib, but would you discuss the results of VMP with once-a-week administration? We have heard about some results with this schedule.

Professor Meletios Dimopoulos: We had an update of the weekly administration of bortezomib.[3]This clearly indicated (especially in older patients) that not only is weekly bortezomib associated with better tolerance, but at the end of the day, the cumulative dose of bortezomib is higher. The complete response (CR) rate is the same, and there might even be a trend toward a better CR rate, especially with a maintenance phase in these trials. So, clearly, weekly administration of bortezomib is the way to go in older patients, and discussions are occurring about treating even older and frailer patients with weekly doses of bortezomib.

Early vs Late Autologous Stem Cell Transplant

Professor Moreau: Let's move now to the younger patients: patients who are eligible for high-dose therapy and autologous stem cell transplantation. We have heard, Antonio, another presentation from your group[4] -- a prospective comparison of melphalan/prednisone/lenalidomide vs melphalan (200 mg/mg2 MEL200) in tandem with autologous stem cell transplantation following an induction phase with lenalidomide-dexamethasone (len-dex). Would you like to give a summary of your results?

Professor Palumbo: This study addressed the question of early vs late transplant. Today, early transplant should be considered the standard because the study that compared the conventional approach (a novel agent vs an autologous transplant approach including a novel agent) clearly showed that the use of the autologous transplant significantly improves progression-free survival (PFS). We do not yet have data in terms of overall survival, but there is a clear advantage in terms of PFS. For the younger patient, a strategy including a novel agent as induction, consolidation with high-dose melphalan in tandem with stem cell support, and maintenance should be introduced as quickly as possible.

Professor Moreau: Your median follow-up at the time of the presentation was 26 months. Do you think, considering the difference in terms of PFS, that this could translate into an overall survival advantage? You also have a maintenance phase in this study. Patients were randomly assigned to receive, or not receive, maintenance. Do you think that could influence overall survival?

Professor Palumbo: It should translate to increased overall survival. It is a matter of time, and with follow-up, we will see an advantage in overall survival. Maintenance should not create an issue because both arms are balanced, so conventional approach and transplant patients receive maintenance (or not) in equal proportion.

High-Risk Smoldering Myeloma

Professor Moreau: We can speak about another very interesting presentation, which could change the future of our clinical practice. I would like to ask Thierry to comment on a Spanish presentation, and then Jesús can add important points about high-risk smoldering multiple myeloma. We have heard the results of a study[5] comparing no treatment (which is our current standard of care) with a len-dex combination in patients with high-risk smoldering multiple myeloma. Maria Mateos presented on behalf of her group that there was a survival advantage in favor of len-dex. What do you think of those results, Thierry?

Professor Facon: First of all, it was a very good trial, and a very good idea, so this is a great debate. It is a matter of controversy, as well, so we have a lot of questions. Basically, the study was len-dex with some kind of maintenance vs observation, and patients who received len-dex had a PFS advantage and a survival benefit. We still have some discussion about whether the survival benefit is meaningful, and so forth, but on the other hand, the difference in terms of delaying progression is very important. Some patients in the control group who progressed had renal insufficiency and bone disease -- events that are really not good for patients.

We have some questions about the definition of high-risk smoldering myeloma, so we may have discussion about that. Do we need emerging techniques to more adequately define the population? The other point is, we may use something different from len-dex -- either lenalidomide as a single agent, or we might even have the provocative discussion about transplant in high-risk smoldering myeloma. This trial was well designed. This is a good question and will be an open question probably for some years. People usually say, "In routine practice, this is still abstention." We will see more and more studies in these smoldering myeloma patients.

Professor Moreau: With respect to your point on the definition of "high risk," Jesús, you used flow cytometry to define high-risk patients. This technique is difficult to use in a multicenter setting. Do you think that we need to change the definition of high-risk smoldering to include something that will be available in all centers?

Professor San Miguel: This is a very important topic because we probably need to redefine "smoldering." We think that there are some smoldering myeloma patients that behave like monoclonal gammopathy of undetermined significance and should not be called "smoldering," but there are some smoldering patients who have early myeloma, and for these patients we need to do the research to identify them properly and be sure that imaging techniques are appropriate and needed. We will also need a trial to analyze patients with an abnormal MRI to determine whether the intervention is adequate.

My feeling is that to treat early myeloma is going to be positive, because these patients may be cured. We need to identify them appropriately and conduct the right trials.

Professor Moreau: That is interesting. Maybe it will change our way of treating patients in the future.

To close this debate, I have a couple of questions about novel therapies. We have heard a lot about novel agents. What were the outstanding or interesting results from ASH?

Novel Agents and Combinations

Professor Dimopoulos: Significant data indicate that carfilzomib, a novel proteasome inhibitor, will have a role in myeloma.[6] The study that compared carfilzomib with len-dex vs len-dex in relapsed, refractory myeloma has completed accrual.

Pomalidomide is another interesting agent that may induce responses in 25%-30% of patients with myeloma who are refractory to both bortezomib and lenalidomide.[7] We are very eager to see the data from the randomized trial, which compares high-dose dexamethasone vs pomalidomide and low-dose dexamethasone.

The third agent of interest is elotuzumab, and based on the update that we heard at ASH[8] on len-dex with elotuzumab, ongoing trials are assessing this combination, in both the relapsed, refractory setting and in the front-line setting.

Professor Moreau: Thierry and Antonio, would you like to speak about MLN9708? Carfilzomib may come on the market very soon, and interesting studies have been completed with pomalidomide. We have phase 3 data for elotuzumab, but only early development for MLN, an oral proteasome inhibitor. What would you like to say?

Professor Facon: We have few data, but MLN is a promising agent. It is a novel proteasome inhibitor, which will be useful for patients, especially (but not only) elderly patients.[9] The drug is effective as a single agent. The combination of lenalidomide, low-dose dexamethasone, and MLN is also promising, so the drug may be combined with MP, lenalidomide, or low-dose dexamethasone.[10]We will have a phase 3 trials for potential approval of MLN in the next few months and years.

Professor Moreau: What do you think about the toxicity profile of this drug?

Professor San Miguel: It is very good. As a general comment, we will have a more complex treatment approach in the near future because we will have, basically, 3 proteasome inhibitors -- bortezomib, carfilzomib, and MLN -- with different profiles, so we should use them accordingly in different ways. We already have 3 immunomodulatory drugs: thalidomide, lenalidomide, and pomalidomide. So, in the immunomodulatory setting, we will have to make the appropriate choice of drug according to the patient's condition. We will have elotuzumab, which is a completely new class of drug, but also the histone deacetylase (HDAC) inhibitors. We will have at least 2 HDAC inhibitors, vorinostat and panobinostat, and probably more are coming.

Thus, another 4 completely different classes of drug will be available. It will not be easy to choose and exactly position all the different drugs in the different settings.

Professor Facon: It is very good for patients to know that the proteasome inhibitor MLN is being analyzed in relapsed, refractory patients. It has always been the tradition to have solid data, but in this case, almost in parallel, there is a pilot study up front. This is very important for the patients, because the myeloma community is trying to move as quickly as possible to have the best possible data to help them.

Professor Moreau: We can think of having very effective oral combinations with MLN and len-dex front line, which will be a revolution not only for the elderly but also for young patients. I would like to thank you all for your fruitful comments and very interesting points about ASH 2011. Thank you very much.

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