Paul G. Richardson, MD


December 23, 2011

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Hello. My name is Dr. Paul Richardson. I am Clinical Director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, and Associate Professor of Medicine at Harvard Medical School.

It really is my pleasure to welcome you to this edition of Medscape Oncology Insights on multiple myeloma (MM). Today I would like to report to you on a number of key studies on MM presented here at the 2011 Annual Meeting of the American Society of Hematology (ASH) in San Diego, California.

Promising New Agent

The first thing that I want to tell you about is an exciting new investigational agent, MLN9708, an oral proteasome inhibitor, which we have studied in the phase 1 setting in patients with relapsed and refractory MM.[1] The results of this trial have shown that with an appropriate dose escalation to 2 mg/m2 of this drug, administered on a twice-a-week schedule, the drug is well tolerated. We have shown that the characteristics of the agent (so-called pharmacokinetics and pharmacodynamics) are particularly attractive, and at the same time, the side-effect profile has proven manageable.

This agent (an oral proteasome inhibitor, the first of its type to enter clinical study) is actually less toxic than some of its counterparts. In particular, MLN9708 may produce much less neuropathy as part of its side-effect profile. In any event, our results to datesuggest that this is indeed the case.

We have been able to demonstrate encouraging activity, especially at the maximum tolerated dose. Of 46 evaluable patients, we have already seen that approximately 15% of these patients are responding, and we have seen some complete responses as well. This first presentation of MLN9708, as it is called, is particularly interesting and exciting because it brings to the fore the possibility of an oral proteasome inhibitor that is showing a favorable side-effect profile. Some of the side effects were important to note, such as skin rash, but these are generally manageable. Already, with just this drug alone (combined with no other drugs) we are seeing some evidence of activity.

My colleagues in the same study group presented results from a combination approach, using MLN9708 with the drug lenalidomide and dexamethasone.[2]Very excitingly, this combination has been shown to be exquisitely active. In the upfront setting, no less than 100% of patients treated so far have responded to this oral combination approach incorporating a proteasome inhibitor, lenalidomide and dexamethasone.

A Gift From the Sea

We also presented the results of an intravenous proteasome inhibitor called marizomib.[3]Marizomib is of a totally different class and, in fact, is derived from a marine organism. Marizomib is particularly potent as a proteasome inhibitor. In the laboratory, it is probably the most potent of clinically usable agents that we have seen to date. Phase 1 studies of marizomib have been comprehensive. We have conducted studies both in the United States and in Australia. At this meeting, we presented the results of the Australian and American studies combined. When you are dealing with such a potent molecule, it is obviously very important to start at a low dose and follow a cautious schedule. After a long and protracted study (because it has been very important to get the dose correct), we found that twice-a-week dosing with 0.4-0.5 mg/m2 appears to be the optimal dosing schedule to test this drug.

In terms of side effects, we have seen no peripheral neuropathy and very manageable myelosuppression (in fact, very little of that). Most important, of the nonhematologic side effects have been some fatigue, muscle cramping, and central nervous system effects, which are very transient and manageable. Of greatest importance, the doses that we defined as the maximum tolerated doses appear to be well tolerated. We do not see any significant peripheral neuropathy.

The activity of this drug, especially when you combine it with dexamethasone, shows encouraging responses of 15%-20% in very sick, heavily pretreated patients. At this stage in the development of the drug, we are encouraged by the quality of the responses we have seen, including some very good partial responses, even in very sick patients.

Putting this together, we think it is an excellent platform for going forward in combination therapy. Preclinical studies show that this drug in combination with lenalidomide, for example, is particularly active in the preclinical setting. We are very optimistic as we go into the clinic with this combination that we will have yet another proteasome inhibitor to use and potentially help our patients.

The reason that this is so important is that several classes of proteasome inhibitors are not available. They include the boronate peptides, such as bortezomib, and the MLN9708 compound, which is the oral equivalent. We now have marizomib, which is the beta-lactone class, and very exciting data have been presented[4,5,6]at this meeting on carfilzomib, a drug of the epoxy ketone class. This not only has encouraging single-agent activity with minimal peripheral neuropathy, but it also shows excellent activity combined with lenalidomide and dexamethasone.

A Potent New Immunomodulator

In the same session we heard some other exciting data. One of the most important presentations of the meeting included results about the use of pomalidomide.[7] Pomalidomide is the most potent of the available immunomodulators. In the laboratory it is clearly more potent than thalidomide and is also more potent than lenalidomide. Of note, at a molecular level, pomalidomide combines the best features of both thalidomide and lenalidomide and thus, perhaps, it is the most potent immunomodulator. What is particularly exciting, though, is its tolerability profile, which appears to be remarkably good. No significant neuropathy is associated with its use. It doesn’t produce the same degree of gastrointestinal dysfunction and muscle cramping that we sometimes see with lenalidomide, recognizing that lenalidomide is very well tolerated. Having said that, we have been very pleased to see that pomalidomide is consistently able to engender responses in patients who have failed to respond to lenalidomide and bortezomib.

It was our pleasure to present on behalf of colleagues the results of our relapsed and refractory trial of pomalidomide and low-dose dexamethasone.[7] This was a very large, randomized phase 2 trial involving more than 200 patients from multiple centers. These were relapsed and refractory patients with myeloma, meaning that they had not only relapsed in terms of their disease but their salvage treatment was failing. They had not benefited from salvage and they were resistant not only to lenalidomide but also to bortezomib. We were able to show in this highly refractory population a partial response, or better, of 34% for the combination of pomalidomide and low-dose dexamethasone. When we added those patients who received a minimal response or better, the number improved even more, exceeding 40%.

We believe that this is a very active and exciting combination. We were able to show survival data because the study is now relatively mature. We were also able to show encouraging progression-free survival data and activity across all patient groups -- not just patients who were refractory to lenalidomide with prior bortezomib failure but also patients who were what were called "double refractory," or refractory to both lenalidomide and bortezomib. Moreover, the side-effect profile of this combination continues to look very encouraging, with low rates of deep vein thrombosis (with the appropriate thromboprophylaxis), minimal peripheral neuropathy, and myelosuppression as an important but very manageable side effect.

Thus, we are very optimistic about this combination, particularly given its activity in this area of exquisite unmet medical need.

Phase 3 trials are ongoing in Europe with this combination, and here in the United States we plan to go forward with a combination of pomalidomide, dexamethasone, and bortezomib, which, of course, we think will be a very active and exciting combination compared with bortezomib and dexamethasone alone. Those studies are expected to get started as soon as next year.

Enhancing Bortezomib Activity

During that same afternoon session here in San Diego, we presented a number of other important data. These studies aimed to improve upon bortezomib with the addition of other drugs. I would like to touch on 2 presentations.

The first is the combination of bortezomib with panobinostat.[8] Panobinostat is a deacetylase inhibitor, a very important and broad class of drugs. There are multiple agents in this group, including panobinostat, vorinostat, another drug called romidepsin (which belongs to a different drug class altogether), and, finally, other small molecules that are coming into the clinical research arena and that also appear to be quite specific for certain HDAC subtypes.

The panobinostat project focused on combination strategies with bortezomib. The phase 1 studies established that bortezomib and panobinostat can be safely combined and were particularly helpful in documenting the schedule of the drug -- specifically, that bortezomib is given on a classic schedule: days 1, 4, 8, and 11. Panobinostat, which is an oral drug, is given 3 times a week, 2 weeks on, 1 week off, and dexamethasone is partnered with the bortezomib.

In that phase 1 study we were able to show a very exciting signal, not only with respect to the overall response rate; in bortezomib-refractory patients, by adding the panobinostat, we were able to restore responsiveness to the bortezomib platform.

We then launched a phase 2 trial to prospectively validate that finding in the multicenter setting.[9] Our results did exactly that. They demonstrated that in about one third of patients who were truly refractory to bortezomib (and all were relapsed and refractory) we were able to consistently show a response rate and favorable tolerability profile. Not only was response encouraging, but we were able to see some high-quality responses as well, including near-complete remissions, which is particularly remarkable if one considers that these patients were truly bortezomib refractory. This wasn't simply a retrospective approach. Patients were prospectively evaluated for refractoriness before being allowed to participate in the trial, so we believe that this is rigorous, and the results we have seen are robust.

The side-effect profile, which proved generally very manageable, was interesting. Recognizing that some gastrointestinal side effects and thrombocytopenia can be challenging with this combination, we were able -- with appropriate dose reduction, schedule changes, and so forth -- to demonstrate that these side effects were generally manageable.

Obviously, one single-arm phase 2 trial is not enough to prove the point, and a very encouraging and exciting presentation was given by my colleague, Dr. Jesus San-Miguel,[8] who gave an update on the PANORAMA-1 program. This phase 3 study is moving along very rapidly and has almost completed its accrual. Patients are assigned to either panobinostat; bortezomib and dexamethasone; or bortezomib, dexamethasone, and placebo. This large, multicenter, international trial has been very successful in terms of its enrollment, so we expect results to emerge relatively soon, in the next year or so.

Overcoming Bortezomib Resistance

What else can we add to increase the activity of bortezomib and enhance its effects? The last presentation I wanted to share with you was about a very interesting and novel agent.This drug is called perifosine, and it is an alkylphospholipid. Perifosine is orally bioavailable and is a very interesting compound. It targets the AKT pathway but it also has effects on what we call JNK, as well as on NF kappa B. Exactly how it works is somewhat complex. It appears to have a pan-AKT effect. That may, in fact, be very important to its activity, and it has other effects on these other proteins that control the protein degradation cycle.

With that construct, combination of perifosine and bortezomib is being developed with the goal of overcoming bortezomib resistance. If bortezomib sensitivity is preserved, this should enhance its efficacy.

We presented the results of our phase 1/2 trial[10] in which all patients had to have received prior bortezomib. Approximately half the patients were bortezomib refractory and the other half had received prior bortezomib but would not be considered traditionally refractory to treatment. First and foremost, we were able to demonstrate that you could combine the drugs safely and that a continuous daily oral dose of 50 mg was remarkably well tolerated in this population. Furthermore, in the phase 2 portion of the study we were able to show a very consistent response rate. About one third of patients responded, and what was particularly interesting was the durability of the responses, progression-free survival, and overall survival.

In aggregate, we found that progression-free survival was 7-8 months for this group of patients. Bortezomib-naive patients who receive only bortezomib typically have a median progression-free survival of 6 months, so in a bortezomib-exposed or heavily pretreated relapse-and-refractory population, to see this improvement in progression-free survival is particularly interesting.

Moreover, we looked at actual median overall survival, because in phase 1/2 trials, a frequent and appropriate question is, what maturity do you have around your data? This study is now quite mature, and we were able to show median survivals of approximately 2 years, which in a relapsed and relapsed/refractory population is quite encouraging.

Of course, this single-arm phase 2 trial, just like the PANORAMA-2, doesn't make the grade. What makes the grade is a randomized phase 3 trial. Just as PANORAMA-1 is making great progress, we have another phase 3 trial ongoing that compares perifosine, bortezomib, and dexamethasone with bortezomib and dexamethasone. This is a multicenter, international effort. It is accruing very nicely, and we anticipate that we will complete enrollment in the next year or so. We hope to have a read on this study in the next several years.

Closing Remarks

In summary, the meeting has proved to be a very exciting one, with multiple exciting abstracts presented. I have shared with you just a few of these abstracts to give you a flavor of how we are trying to continue to make progress (particularly in the relapsed/refractory setting), how we are looking at second-generation and third-generation drugs that show considerable promise, and, at the same time, how we are attempting to make existing platforms, such as bortezomib and lenalidomide, work that much better. Thank you for your kind attention. Thank you for joining me today in this edition of Medscape Oncology Insights. This is Dr. Paul Richardson reporting from ASH 2011 in San Diego, California.


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