Three-Drug Combo Improves Multiple Myeloma Response

Paul G. Richardson, MD


June 30, 2014

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Multiple Myeloma News From Milan

Hello. My name is Dr. Paul Richardson, and I am the RJ Corman Professor of Medicine at Harvard Medical School and Clinical Director of the Dana-Farber Cancer Institute in Boston, Massachusetts. Welcome to this edition of Medscape Oncology Insights on multiple myeloma. Today I will highlight key data in myeloma, presented here at the 19th Congress of the European Hematology Association (EHA) in Milan, Italy, and will update you on other important studies recently reported at the American Society of Clinical Oncology (ASCO) meeting in Chicago.

These 2 meetings have taken place very close to each other in time, which provides a very nice forum for emphasizing the studies that have had the greatest impact. In fact, the results of some important phase 3 trials reported first at ASCO are being updated here at the EHA meeting in Milan.

Leveraging Histone Deacetylase Inhibition

I particularly wish to bring your attention to the results of the PANORAMA 1 study.[1] This was a prospective, randomized trial conducted in more than 34 countries and 220 centers, comparing a 3-drug combination of panobinostat, bortezomib, and dexamethasone with a combination of bortezomib, dexamethasone, and placebo. This large phase 3 trial in relapsed/refractory multiple myeloma was designed to evaluate the impact of 3 drugs vs 2 drugs. Bortezomib and dexamethasone are an important backbone in our treatment paradigm in relapsed disease, and panobinostat is an oral histone deacetylase inhibitor given 3 times a week (2 weeks on and 1 week off).

The preclinical rationale for this approach is quite strong. Histone deacetylase (HDAC) inhibition has been shown to block a key rescue pathway when proteasome inhibition occurs through the aggresome -- the key escape pathway within myeloma cells that has been identified as a very important target. The other exciting aspect of HDAC inhibitor activity is the epigenetic effects, which appear to stabilize the genome and have an effect directly on the mutational thrust of myeloma.

That being the case, several studies are looking at HDAC inhibition in myeloma. Vorinostat showed initial promise as the first drug in which this was tested. Unfortunately, phase 3 results[2] were disappointing, largely because of challenging side effects encountered with the regimen that was used, which consisted of vorinostat given concomitantly with bortezomib but without dexamethasone.

In the context of panobinostat, there are some important differences. First and foremost, preclinically is one of the most potent HDAC inhibitors. Second, in a very comprehensive phase 1/2 program, we were able to identify a dosing schedule that was reasonably well tolerated and provided a good partnership with bortezomib and dexamethasone. It was against this backdrop that the PANAROMA I study was developed, carried out, and completed, with results reported this year at ASCO[3] and now at EHA.[1]

PANORAMA: Viewing Success

We were able to show that there is a clinically significant median 4-month progression-free survival benefit associated with 3 drugs compared with 2 drugs. Of greatest importance, the quality of responses was higher as well with the 3-drug regimen, with an approximately 30% rate of near-complete response and complete response for the 3-drug regimen compared with about half of that rate for the 2-drug regimen. Moreover, the overall trend in response rate was very favorable. Although the study is not yet mature enough to comment on overall survival, we are very hopeful that next year we will be able to present results on overall survival as well.

When we looked at subgroups of patients, we were able to show that the greatest benefit occurred in patients who were relapsed and refractory, in patients with high-risk cytogenetics, and in patients who had received bortezomib and lenalidomide previously, as well as each drug individually. This suggests that this 3-drug platform could be very important going forward for relapsed patients in whom these drugs have been used before, and who are at higher risk for the development of resistance.

Another very important aspect of the trial is the construct of a twice-weekly schedule of bortezomib administered intravenously. It might well be that administering the drugs in a different way -- for example, using bortezomib subcutaneously -- can dramatically improve tolerability of this regimen. The effectiveness was very impressive in this study, but some of the side effects were quite challenging, including thrombocytopenia, gastrointestinal disturbances, and fatigue. The good news is that with supportive care and dose reduction, these side effects proved generally manageable. We are very hopeful going forward that with these weekly schedules of subcutaneous bortezomib, we will be able to manage some of the side effects encountered.

Next Wave of HDAC Inhibitors

A new wave of HDAC inhibitors is coming, and one of the best examples of this is rocilinostat (ACY-1215),[4] which is arguably more potent and more targeted in that it specifically targets HDAC-6. It also has a more favorable side-effect profile, so it may be an exciting new agent in the future.

Other highlights of the meetings include the continuing story and strength of the monoclonal antibodies. We have seen dramatically positive data on the antibody direct tumor map that targets CD38.[5] We have seen the Sanofi compound (called SAR for short and which also targets CD38) show equally promising results, both as a monotherapy[6] and in combination with lenalidomide.[7]

These monoclonal antibodies add to the already established armamentarium of elotuzumab, which at the moment is undergoing phase 3 testing with the goal of approval in the not-too-distant future. It means we could have up to 3 new monoclonal antibodies that may be highly effective either as monotherapy, in combination, or obviously used in both ways in the future. These are very exciting times in myeloma, with continued progress.

It is particularly exciting to see the original platforms of proteasome inhibition and immunomodulation being continually built upon. At the meetings we have seen plenty of examples of this, both with pomalidomide-based combinations,[8,9,10] which continue to show remarkably good tolerability profiles and excellent outcomes, as well as exciting new data on carfilzomib,[11,12] which also continues to show great promise. When one adds to the exciting data on the monoclonal antibodies and the renaissance of the HDAC inhibitors, the future for our patients continues to look very bright.

On that note, I would like to thank you for joining me for this edition of Medscape Oncology Insights. This is Dr. Paul Richardson, reporting from EHA in Milan, Italy. Thank you for your kind attention.


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