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Spring 2005 Volume 6, Issue 4:
Update on Lenalidomide (CC-5013; Revlimid®)
By S. Vincent Rajkumar, MD
There has been intense research to develop a safer and more effective version of thalidomide. Lenalidomide (CC-5013; Revlimid®) is the first analog (close cousin) of thalidomide to enter clinical trials. It may prove to be more effective and safe
S. Vincent Rajkumar, MD
Associate Professor of Medicine
Mayo Clinic
Rochester, Minnesota

Over the last five years, numerous clinical trials have shown that thalidomide is effective in the treatment of multiple myeloma. In fact, thalidomide plus dexamethasone (Thal/Dex) has rapidly become one of the more commonly used regimens for the initial treatment of myeloma. Given this success, there has been intense research to develop a safer and more effective version of thalidomide. Lenalidomide (CC-5013; Revlimid®) is the first analog (close cousin) of thalidomide to enter clinical trials. It may prove to be more effective and safer than thalidomide. Like thalidomide, it is taken by mouth, as a capsule, and does not carry the type of side effects commonly associated with cancer chemotherapy like nausea, vomiting, and hair loss.

Initial studies with lenalidomide, as with most new drugs to treat cancer, were carried out in the laboratory on myeloma cells and in animal models of myeloma. In these studies, the drug was found to be several-fold more powerful than thalidomide. This led to several clinical trials in patients with multiple myeloma.

The first clinical trials were conducted to determine the correct dose of the drug and to establish its safety (Phase I trials). These trials were carried out at the University of Arkansas (Little Rock, AR) and the Dana-Farber Cancer Institute (Boston, MA). These studies showed that the maximum tolerated dose of lenalidomide was 25mg daily. Importantly, in both trials, patients with advanced multiple myeloma responded to the treatment. At least a 25% drop in the M protein (M spike; paraprotein level) was seen in 50-60% of the patients. These results were particularly impressive because most patients had failed other effective regimens, and some had already failed thalidomide.

With the success of these initial trials, a larger trial was conducted to more accurately determine the response rate with lenalidomide in patients with relapsed and refractory myeloma (Phase II trial). This trial was conducted jointly at the Dana-Farber Cancer Institute, Mayo Clinic (Rochester, MN), St. Vincent’s Hospital (New York, NY), and the H. Lee Moffitt Cancer Center (Tampa, FL). Of 101 patients treated, approximately 25% achieved a partial response to therapy which is a 50% or higher reduction in M protein level. Overall about 35% of patients had a drop in their M spike by at least 25%.

Lenalidomide Exceeds Expectations in Relapsed and Refractory MM

The Independent Data Monitoring Committee (IDMC) responsible for overseeing two clinical trials of lenalidomide (CC-5013; Revlimid®) found a statistically significant improvement in time to disease progression – the primary endpoint of these Phase III trials – in patients receiving Revlimid plus dexamethasone compared to patients receiving dexamethasone alone. The trials have been unblinded many months earlier than originally projected. Celgene Corporation is allowing all patients in these studies to get Revlimid if they want to. Plans are under way to offer expanded access to Revlimid for patients with previously treated myeloma (subject to appropriate regulatory approval).

Lenalidomide was in the news recently when two large randomized studies showed that the combination of lenalidomide plus dexamethasone (Rev-Dex) is significantly more effective than dexamethasone alone. These studies are referred to as Phase III trials, in which patients were assigned to either of the two treatments being studied by a computer program similar to a coin toss. All patients had relapsed/refractory myeloma. Over 700 patients participated in these Phase III trials. The time from diagnosis to myeloma progression was much longer in patients receiving lenalidomide plus dexamethasone compared to dexamethasone alone. These results are very exciting and suggest that lenalidomide is a very active drug to treat multiple myeloma. These studies will hopefully lead to approval of the drug by the Food and Drug Administration when the final efficacy and safety data are reviewed.

As with thalidomide, the effectiveness of lenalidomide in patients at the relapsed and refractory stage has led to clinical trials in newly diagnosed myeloma, as first-line treatment. In a recent Mayo Clinic trial, over 80% of patients with newly diagnosed myeloma responded to the combination of lenalidomide plus dexamethasone (Rev-Dex). There were far fewer serious side effects compared to the Thal-Dex regimen. As a result, Rev-Dex promises to be one of the major treatment options when patients are first diagnosed with myeloma. Since lenalidomide is not commercially available, the Rev-Dex regimen is currently available to patients only as part of clinical trials. In the United States, two large trials are available to patients with newly diagnosed myeloma. These trials are coordinated by the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group (SWOG), and are available through many centers nationwide. Please visit the IMF website at www.myeloma.org or call 800-452-CURE (2873) to learn more about clinical trial enrollment.

Lenalidomide is dispensed as capsules. The most common dosing used in multiple myeloma is 25 mg given orally daily on days 1-21 and repeated every 28 days (days 22-28 are rest days). Doses are then modified based on side effects. The main side effects are low blood counts. Unlike thalidomide, significant sedation, constipation, or neuropathy is not common with this drug. Although no birth defects have been reported with lenalidomide, stringent precautions to prevent pregnancy and to prevent pregnant woman from receiving this drug are required.

The mechanism by which lenalidomide works is not fully known. It belongs to a class of drugs called “immunomodulatory drugs” (or “ImiDs”). It is felt to work by boosting the immune system to help fight the cancer cells more effectively. Lenalidomide is also directly toxic to the myeloma cells and likely interferes with the blood supply that is needed for cancer cells to grow.

Lenalidomide is not commercially available, but will hopefully be approved in the near future. It is a very promising and effective addition to the treatment of myeloma. Besides trials in newly diagnosed myeloma discussed above, ongoing trials are testing combinations of lenalidomide with other active anti-myeloma agents such as bortezomib (VELCADE®). In addition to myeloma, lenalidomide has also shown efficacy in a certain form of myelodysplastic syndrome, another disease involving the bone marrow.

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