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Celgene's Revlimid Makes Stronger Case for European Front-Line Approval

The upcoming American Society of Hematology (ASH) annual meeting is important for Celgene (CELG - Get Report) and its multiple myeloma drug Revlimid. Investors got a first look last week at a research abstract for the so-called MM-020 study of Revlimid in newly diagnosed multiple myeloma and results were as good as Celgene bulls could have hoped for.

Expanded European approval of Revlimid in front-line multiple myeloma is an important growth driver for Celgene. The company has already failed once to garner the support necessary to expand Revlimid's label, which makes data from the MM-020 study especially important. 

In June 2012, European regulators identified two main issues which prevented Revlimid expansion into front-line use. While Revlimid demonstrated a clear benefit on progression-free survival (PFS), there was no survival benefit. This wasn't really Celgene's fault because the Revlimid studies were early and the majority of multiple myeloma patients were still alive when the data were submitted to European regulators. 

The more significant knock against Revlimid was data from the studies showing an imbalance in the diagnosis of secondary primary malignancies (SPM.) Patients treated with Revlimid were more likely to develop future cancers compared to the patients in the control group. 

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One could argue that the PFS benefit of Revlimid was so great that these imbalances would not matter in the long run.  That argument, however, would require a convincing and statistically significant survival benefit.  Given the early nature of the Revlimid data, Celgene could not make this case and thus had to withdraw the European application.

There has been a long bull/bear debate over the reasons for the SPM imbalance observed in the Revlimid studies. It's not important delve into those details, but the key for the bull thesis was twofold.  First, Revlimid had an overall survival trend and a robust PFS benefit even if you counted the development of an SPM as a progression event. In other words, Revlimid maintained a statistically significant, event-free survival benefit over the control group.  

Second, bulls argue Revlimid is not the cause of the SPMs. The blame lies with melphalan, the drug administered to multiple myeloma patients alongside Revlimid. In Europe, the Revlimid-melphalan combination is more widely used than in the U.S., which which why Celgene use it as the basis for a European registration trial. 

Celgene could wait for the original trials to develop mature OS data but that would be a time consuming process. Luckily for Celgene, investors, and patients, we have the MM-020 trial data, which can shed light on the effect of Revlimid in the frontline setting.  

The MM-020 trial enrolled 1,623 newly diagnosed myeloma patients over 65 who were ineligible for stem cell transplant. These patients were divided into three arms: Revlimid and dexamethasone until disease progression (arm A -- continuous maintenance), Revlimid and dexamethasone for 18 months (arm B -- fixed duration maintenance) and melphalan-prednisone-thalidomide (MPT) for 18 months (arm C -- control arm.)  The primary endpoint was PFS between arms A and C with numerous secondary endpoints that included overall survival.

Note melphalan is not being used in the MM-020 study, which should help clarify the SPM controversy.

According to the research abstract for the MM-020 study released on Nov. 7, the hazard ratio for the PFS primary endpoint was 0.72 and statistically significant, which translates into a strong, 28% reduction in the risk of tumor progression. There was a trend towards a survival benefit, with an overall survival hazard ratio of 0.78, signifying a 22%  reduction in the risk of death. 

Most important was that the rate of hematological SPM was 0.4% in arm A and 2.2% in arm C. The solid tumor SPM rate was 2.8% in both arms. Unlike previous studies, the imbalance in SPM favors Revlimid in the MM-020 study.  This is more evidence that melphalan was the cause of the SPM imbalance in the previous studies.

We'll get a fuller presentation of the MM-020 study  data at the ASH meeting in December, but it's hard to imagine that the new SPM data combined with the strong PFS benefit and trend in OS will not be compelling for the European regulators. I expect them to expand Revlimid's approval into the front-line setting for multiple myeloma patients who are transplant ineligible.

Sobek is long Celgene.

David Sobek has been writing on biotech for a number of years through various outlets with a general focus on small cap oncology and antibiotics companies. He received his PhD in political science from Pennsylvnia State Univeristy in 2003 and a BA in international relations from The College of William and Mary in 1997.

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