The U.S. Food and Drug Administration (FDA) has ex­panded the of­ficial­ly ap­proved use of Revlimid to include the treat­ment of newly diag­nosed multiple myeloma.

Previously, Revlimid’s approval in the U.S. and elsewhere in the world was for the treat­ment of myeloma patients who have re­ceived at least one prior therapy.

With the expanded U.S. approval, there no longer is any re­striction regard­ing prior therapies in the FDA-approved pre­scrib­ing in­for­ma­tion for Rev­limid (lena­lido­mide).

The new edition of the pre­scrib­ing in­for­ma­tion says simply that “Revlimid in combination with dexa­metha­sone is indicated for the treat­ment of patients with multiple myeloma.”

The FDA decision to expand Revlimid’s approved use was announced in a press release issued earlier today by Celgene (NASDAQ:CELG), the U.S. pharmaceutical company that developed and markets Revlimid globally.

Celgene also is awaiting a final decision on an application to have Revlimid’s approved use in Europe ex­panded.  In December, a European advisory committee voted in favor of expanding the drug’s approval to include transplant-ineligible newly diagnosed myeloma patients (see related Celgene press release).  The committee’s positive vote makes it likely that the application for expanded use will be approved, probably within the next several weeks.

In addition to the change in Revlimid’s approved use, the new edition of the drug’s U.S. pre­scrib­ing in­for­ma­tion contains other updates, most of which are related to the use of the drug in newly diagnosed myeloma patients.

There are changes to the drug’s dosing rec­om­men­da­tions, a warning that Revlimid may impact stem cell collection, altered language about how often blood cell counts should be tested in patients taking Revlimid, and expanded language about Revlimid and the risk of secondary cancers.

Of these changes, the altered dosing rec­om­men­da­tions may have the greatest impact on Revlmid’s use in the U.S.  The new rec­om­men­da­tions specifically call for treat­ment with Revlimid and dexa­metha­sone (Decadron) to continue “until disease progression or unacceptable toxicity,” regardless of whether the patient is newly diagnosed or relapsed.

Previously, the primary rec­om­men­da­tion regarding Revlimid’s dosing was that treat­ment with the drug should be “continued or modified based upon clinical and laboratory findings.”

Revlimid already is widely used in the U.S. in newly diagnosed myeloma patients. In those patients, it often is used in a three-drug combination that includes Velcade (bortezomib) and dexa­metha­sone, or in a two-drug combination with just dexa­metha­sone.

The extensive use of Revlimid in newly diagnosed U.S. myeloma patients has occurred because “off-label” pre­scrib­ing – that is, use of a drug outside its officially approved patient population – is permitted and widely practiced in the U.S.

Off-label pre­scrib­ing is not, however, generally permitted in most European countries, and Revlimid is there­fore not commonly used outside of clinical trials in European newly diagnosed myeloma patients.

Thus, although the change in Revlimid’s approved use may slightly expand its use in newly diagnosed U.S. patients, the change – if it is approved – is likely to have the greatest impact in Europe.

Dr. Kenneth Shain, a myeloma specialist at the H. Lee Moffitt Cancer Center in Tampa, Florida, told The Beacon that the expansion of Revlimid’s approved use is “very exciting news.”

“Revlimid has been a critical drug in the care of myeloma patients for almost a decade,” Dr. Shain added.  “Its efficacy, tolerability, and oral delivery have marked a great leap forward in anti-myeloma therapies … It is excellent to see that barriers to upfront use of Revlimid are being removed."

Expanded Approval Based On Results Of “FIRST” Trial

The results of the so-called “FIRST” clinical trial were the primary impetus for the FDA’s decision to expand Revlimid’s approved patient population.  The trial was a large Phase 3 study that tested three different treat­ment regimens for newly diagnosed myeloma patients ineligible for stem cell transplantation:

1. Continuous therapy with Revlimid and dexa­metha­sone until disease pro­gression
2. Revlimid and dexa­metha­sone therapy for a fixed duration of 72 weeks
3. Melphalan (Alkeran), prednisone, and thalidomide (Thalomid) (MPT) therapy for a fixed duration of 72 weeks.

The results of the trial were first presented at the 2013 annual meeting of the American Society of Hema­tol­ogy (see related Beacon news article), and also were published last fall.

In the trial, patients treated with continuous Revlimid and dexa­metha­sone had significantly longer pro­gression-free survival and overall survival than patients treated with MPT, the primary comparator regimen.

Median progression-free survival was 25.5 months in the continuous Revlimid-dexa­metha­sone arm of the trial and 21.2 months in the MPT arm.  Median overall survival was 58.9 months in the continuous Revlimid-dexa­metha­sone arm and 48.5 in the MPT arm.

The most common severe side effects observed in the patients treated with continuous Revlimid and dexa­metha­sone were reduced blood cell counts, pneumonia, and fatigue or general weakness.

Other Key Changes In The Revlimid Prescribing Information

The changes in Revlimid’s U.S. pre­scrib­ing in­for­ma­tion beyond the change in the drug’s approved patient population focus on dosing, the timing of stem cell collection, testing for low blood cell counts, and the risk of secondary cancers.

The change in Revlimid’s dosing rec­om­men­da­tion has already been sketched above.  The new rec­om­men­da­tion emphasizes continuous therapy, regardless of whether a patient is newly diagnosed or relapsed.  “Treatment should be continued,” the pre­scrib­ing in­for­ma­tion states twice, “until disease progression or unacceptable toxicity.”

The dosing rec­om­men­da­tions also note that, in patients eligible for a stem cell transplant, stem cell mo­bil­i­za­tion and harvesting “should occur within 4 cycles of a Revlimid-containing therapy.”

This reflects another significant change in the pre­scrib­ing in­for­ma­tion, which is an entirely new section of the document focused on the possible impact of Revlimid on stem cell mobilization.  The full text of the new section uses some technical language, which is explained immediately below.  The text is as follows:

A decrease in the number of CD34+ cells collected after treat­ment (> 4 cycles) with Revlimid has been reported. In patients who are ASCT [autologous stem cell transplantation] candidates, referral to a transplant center should occur early in treat­ment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a Revlimid-containing treat­ment or for whom inadequate numbers of CD 34+ cells have been collected with GCSF alone, GCSF with cyclophosphamide or the combination of GCSF with a CXCR4 inhibitor may be considered.

(“CD34+ cells” is an alternative description for “stem cells.” GCSF is an abbreviation for drugs known as granulocyte colony stimulating factors, of which Neupogen (filgrastim) is a commonly used example. “CXCR4 inhibitor” refers to a class of drugs used to assist in stem cell mobilization; Mozobil (plerixafor) is the best known of those drugs.)

The new Revlimid pre­scrib­ing in­for­ma­tion also calls for slightly increased monitoring of patient blood cell counts when treat­ment with Revlimid and dexa­metha­sone is initiated.  It says, in particular, that

Patients taking Revlimid in combination with dexa­metha­sone for multiple myeloma should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required …

The final significant change in the pre­scrib­ing language concerns the risk that treat­ment with Revlimid may cause secondary cancers to develop.  The new language is more detailed than previously was the case, stating:

In clinical trials in patients with multiple myeloma receiving Revlimid, an increase of invasive second primary malignancies [SPM], notably AML [acute myeloid leukemia] and MDS [myelodysplastic syn­dromes], has been observed. The increase of cases of AML and MDS occurred predominantly in newly diagnosed multiple myeloma patients receiving Revlimid in combination with oral melphalan (fre­quen­cy of 5.3%) or immediately following high dose intravenous melphalan and ASCT (fre­quen­cy of up to 5.2%). The fre­quen­cy of AML and MDS cases in the Revlimid / dexa­metha­sone arms was ob­served to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting.

Patients who received Revlimid-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration Revlimid-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treat­ment with Revlimid.

The full text of the new U.S. Revlimid pre­scrib­ing in­for­ma­tion is available at the Revlimid.com website. The previous version of the pre­scrib­ing in­for­ma­tion is available at the FDA’s website.