Celgene, the company that markets Revlimid in the United States and inter­nationally, announced this morning that it has withdrawn its applica­tion in Europe to have the drug approved for use as initial therapy for newly diagnosed myeloma patients as well as for maintenance therapy.

The company also is postponing until next year a similar application it had intended to file in 2012 with the U.S. Food and Drug Administration (FDA).

The European application was withdrawn due to concerns raised by regulators about the link between Revlimid ^[1] (lenalidomide) and second cancers ^[2] (also known as second primary malignancies).

Celgene's announcement came as a surprise to many observers -- so much so that Celgene's stock declined more than 11 percent today.

The announcement means that near-term European use of Revlimid in newly diagnosed patients will be noticeably less than previously expected.  It also indicates that concerns about risks associated with Revlimid maintenance therapy are continuing to persist.

In both Europe and the United States, Revlimid's only officially approved use as a myeloma treatment is for patients who have received at least one previous therapy.

In the United States, however, the drug can legally be used "off label" to treat newly diagnosed myeloma patients, and it very often is.  A recent Beacon survey ^[3] of its readers -- a majority of whom live in the U.S. -- found that 45 percent of them received Revlimid as one of their initial myeloma therapies.

Restrictions on the off-label use of drugs in Europe, however, mean that newly diagnosed European myeloma patients are treated much less frequently with Revlimid

Revlimid also is not specifically approved to be used as maintenance therapy.  Nevertheless, its use as maintenance therapy has increased in the U.S. since initial results from three clinical trials showed that such treatment nearly doubles time to relapse.  One of the three trials also has shown an overall survival benefit to Revlimid maintenance therapy (see related Beacon ^[4] news).

It is data from these three trials -- known as the MM-015, IFM, and CALGB studies -- upon which the European application for Revlimid's expanded use was based.

It is also these three studies that have shown that Revlimid maintenance therapy -- either after stem cell transplantation, or after melphalan ^[5] (Alkeran)-prednisone ^[6]-Revlimid initial therapy -- increases the risk of a myeloma patient developing second cancers.

Both U.S. and European regulators have carried out reviews of Revlimid's safety during the past year, focusing on the drug's link to second cancers.  Neither review led to any restrictions being placed on Revlimid's use.  Both reviews, though, led to additional warnings being added to Revlimid's official U.S. and European prescribing information (see related Beacon news about the U.S ^[7]. and European ^[8] investigations).

When it announced the end of its review of Revlimid's safety, the European Medicines Agency (EMA) said that it "has confirmed that the benefit-risk balance for Revlimid (lenalidomide) remains positive within its approved patient population," and it noted that "the benefits of Revlimid, particularly improved survival, continue to outweigh the risks."

Today's announcement by Celgene, however, makes clear that a key part of the above statement from the EMA is the text that reads ""within its approved patient population."

Although the EMA appears comfortable with Revlimid's benefit-risk profile when the drug is used to treat myeloma patients who have had one previous therapy, the agency apparently is less convinced of Rev­limid's benefit-risk profile when the drug is used as maintenance therapy or to treat newly diagnosed patients.

Celgene issued a brief press release ^[9] early this morning announcing its decision to withdraw Revlimid's European application and providing an update about pomalidomide's ^[10] regulatory status in the United States and Europe (see related Beacon ^[11] news).

Later in the morning, Celgene executives hosted a conference call to provide further information about the recent developments and answer questions about them.

In a prepared statement at the beginning of the call, Celgene Chief Executive Officer Robert Hugin said that “In response to the need for more follow-up and mature data from the MM-015, IFM, and CALGB studies to allow [European authorities] to reach a clear benefit-risk conclusion, we have withdrawn the Revlimid newly diagnosed multiple myeloma application."

Mr. Hugin added that, despite the withdrawal of the European application, Celgene is "proceeding with submissions for Revlimid in newly diagnosed multiple myeloma in Switzerland, Australia, and other core markets."

For more information, see the complete compilation of Beacon articles with information about the Revlimid safety controversy ^[2]  as well as the complete text (below) of Mr. Hugin’s statement about the withdrawal of Revlimid's European application.

Partial Text of Statement By Robert Hugin, Chief Executive Officer, Celgene Corporation
(made during publicly broadcast conference call, June 21, 2012)

In response to the need for more follow-up and mature data from the MM-015, IFM, and CALGB studies to allow the CHMP [Committee for Medicinal Products for Human Use] to reach a clear benefit-risk conclusion, we have withdrawn the Revlimid newly diagnosed multiple myeloma application.  Our intention is to re­submit the application at the earliest possible time.

As we responded to each specific set of questions and discussed the progress of the application with our CHMP assessors, the 180-day questions made it clear that the follow-up and maturity of the studies with respect to the potential impact of second primary malignancies [SPMs] on the current survival trends had become a principle concern.

Based on these questions, we explored multiple approaches to more precisely define the positive benefit-risk ratio for Revlimid across the patient populations presented in our application.

Included in our responses were analyses that separated induction from maintenance indications and limited the potential approval to a subset of patients not eligible for stem cell transplant.

While there is strong consensus regarding the clinical benefits demonstrated by the studies in our applica­tion, discussions during and after our oral explanation further defined the need for additional follow-up to ensure that the current benefit-risk profile is not negatively impacted by SPMs.

We are proceeding with submissions for Revlimid in newly diagnosed multiple myeloma in Switzerland, Australia, and other core markets.

In the United States, we are currently reevaluating the timing and scope of our Revlimid newly diagnosed submission to the FDA and now anticipate submitting an application in 2013.

We are disappointed with this delay, but are very confident in the strength and importance of the data from these three trials, as evidenced by their recent publication in the New England Journal of Medicine.

These studies join the growing body of clinical evidence from a current total of seven completed Revlimid-based Phase 3 studies in multiple myeloma demonstrating positive patient benefits.  In addition, there are approximately 15 ongoing Phase 3 trials evaluating Revlimid in combination with virtually every investiga­tional drug in development for myeloma.

We are committed to ensuring the broadest access possible to Revlimid for myeloma patients around the world.