Patients Starting Treatment:

Treatment Options

Revlimid

Revlimid in Newly Diagnosed/Previously Untreated Patients

What clinical trials are available?

What is Revlimid?

Revlimid (also called lenalidomide) is an oral cancer drug that is used for the treatment of multiple myeloma. It is part of a class of drugs called Immunomodulatory drugs or IMiDs^®. IMIDs work against cancer cells by impacting the functioning of the immune system.

Revlimid is chemically related to Thalidomide, another IMID, but has been found to be more potent in the laboratory and has different side effects. For example, significant sleepiness, constipation and painful nerve problems (neuropathy), common side effects of Thalidomide, are seen much less frequently with Revlimid.

In addition to multiple myeloma, Revlimid is also used to treat another disease (myelodysplastic syndrome or MDS).

Revlimid is made by the Celgene Corporation.

How is Revlimid used in multiple myeloma?

Revlimid is a commonly used drug in all stages of multiple myeloma.

Although it can be used alone, it is usually used in combination with another anti-myeloma drug, dexamethasone (dex). This combination is called Revlimid-dex. The combination of Revlimid plus dexamethasone has been shown to be more effective than either drug taken alone.

Revlimid-dex is approved by the FDA for the treatment of multiple myeloma patients who have received at least one prior therapy. It is also commonly used for newly diagnosed or untreated patients.

Revlimid is now being studied for use as maintenance therapy following high-dose chemotherapy and stem cell transplant. Maintenance therapy is treatment that is given to patients in remission in order to reduce the risk of relapse.

In addition, Revlimid is also being studied in combination with other myeloma drugs (eg, Velcade) as well as other new drugs in development.

How does Revlimid work?

Revlimid works in multiple ways to slow or kill myeloma cells, although the exact way in which it works is not completely understood. It directly affects the tumor cells. It is also known to affect the blood vessels and other substances surrounding a tumor (known as the tumor microenvironment) which help to feed the cancer cell's growth.

How long is Revlimid-dex taken?

Revlimid is a capsule that is taken every day for 3 weeks with a 1 week rest period. It is available in several strengths (5mg, 10mg, 15mg and 25mg capsules). The typical starting dose is 25 mg once a day. The minimum dose is 5 mg daily.

Dexamethasone is a pill that is taken along with Revlimid. The dose of dexamethasone is usually 40mg and may be given in two different ways — on a high-dose schedule or on a low-dose schedule.

Dexamethasone Dosing — High-dose or low-dose?

The initial studies with Revlimid-dex used dexamethasone in a high-dose schedule (considered to be the "standard" dose)and as a result, the high-dose schedule is FDA approved for use in combination with Revlimid.

However, more recent studies have shown that the combination of Revlimid and low-dose dex in newly diagnosed or untreated patients significantly improves survival with fewer side effects as compared Revlimid and high-dose dexamethasone. Therefore, low-dose dexamethasone is being used more frequently. In particular, the combination of Revlimid and low-dose dexamethasone is recommended in patients over 65.

Your doctor will recommend the right dose for you.

High-dose dexamethasone is typically taken only on certain days of the month, at a starting dose of 40mg (usually given as ten 40mg strength pills). For the first four months, it is taken on days 1-4, 9-12 and 17-20 of each month. Starting at month 5, dexamethasone is only taken on days 1-4 of each month. Each month or 28-days of therapy is known a treatment cycle (usually called a 28-day treatment cycle). LEARN MORE »

Low-dose dexamethasone is given once a week. The starting dose of dexamethasone is 40 mg. LEARN MORE »

It is important to take Revlimid-dex exactly as your doctor has prescribed. If you miss or forget to take a dose, do not double the dose the next day. Re-start your therapy at your regular dose.

In addition, a blood thinner such as aspirin is typically taken along with Revlimid-dex to reduce the chance of developing a blood clot.

Your dose may be changed depending upon your response to therapy and side effects.

How long is the treatment with Revlimid-dex?

The length of treatment with Revlimid-dex is determined on an individual basis and may depend on a number of factors including:

Response to therapy
Side effects
Whether the treatment plan includes high-dose chemotherapy and stem cell transplant (following Revlimid-dex)
Patient preference

Patients who expect to proceed to high-dose chemotherapy and stem cell transplant may only receive a few cycles of Revlimid-dex, until they achieve a response. Other patients may choose to continue Revlimid-dex indefinitely, as long as the treatment is working and side effects are manageable. You and your doctor will discuss the length of treatment that is right for you.

What are the possible side effects with Revlimid-dex?

It is important to remember that side effects of all treatments are based on the individual and vary from patient to patient. Most side effects of Revlimid-dex can be easily managed.

The most common side effects of Revlimid-dex seen in large clinical studies are:

Low blood counts (also one of the most serious side effects)
Constipation
Muscle cramps
Diarrhea (see more details below)
Fatigue
Insomnia

Update from recent studies: Increased diarrhea in patients taking Revlimid-dex for an extended period of time (>8 months)

In studies with more than 700 patients, patients taking Revlimid-dex for more than 8 months experienced significantly more diarrhea than patients taking dex alone (39% vs 28% with dex alone).
In the majority of patients, diarrhea started after taking Revlimid-dex for 19 months.
In most cases, the diarrhea was mild or moderate and could be managed with Imodium^® (loperamide, Mc-Neil-PPC, Inc). However, the dose of Revlimid needed to be reduced for some patients.

The most serious side effects that may occur while taking Revlimid-dex are low blood counts, blood clots, rare rash or skin reactions and possible birth defects.

Low blood counts: Two types of blood cells may be reduced while taking Revlimid:
- Platelets: substances in the blood responsible for clotting. (low levels of platelets are also known as thrombocytopenia).
- Neutrophils: a type of white blood cell that plays an important role in the immune system (low levels of neutrophils are called neutropenia).

Symptoms of low blood counts

Symptoms of low platelet counts are:

Easy bruising
Unexplained bleeding
Bleeding that does not stop easily (after 5 minutes of pressure)
Small red or purple spots on the lower legs

Symptoms of low neutrophil counts are:

Frequent infections
Severe or unusual infections
Fever

Call your doctor if you experience any of these symptoms.

Your doctor will monitor your blood counts. Typically, blood counts will be checked every 2 weeks for the first 12 weeks of therapy and at least monthly thereafter.

If your blood counts drop significantly, your doctor may temporarily stop or reduce your dose of Revlimid. If your counts are very low, your doctor may add another drug to help increase your blood counts (eg, colony-stimulating factor known as G-CSF).

Serious blood clots in the veins or lungs (deep vein thrombosis, DVT or pulmonary embolism): These types of blood clots are potentially life-threatening. However, the risk of blood clots is decreased when patients take blood thinners along with their Revlimid-dex therapy.

IMPORTANT SAFETY INFORMATION: Revlimid-dex and blood clots

When Revlimid-dex was initially studied, more patients taking
Revlimid-dex (11%) developed serious blood clots as compared to patients taking dex alone (4%). Patients in these studies were not taking any kind of blood thinner.

As a result, it is now recommended that all patients taking Revlimid-dex also receive a blood thinner to reduce the chance of developing blood clots.

The most commonly used blood thinner for patients on Revlimid-dex is aspirin. Other types of blood thinners are Coumadin^® or heparin. Researchers are investigating which type of blood thinner is most effective in combination with Revlimid-dex.
Your doctor will recommend the type of blood thinner that is right for you.

Symptoms of serious blood clots may include swelling, tenderness, pain and redness in the leg. Tell your doctor right away if you experience any of the following

Shortness of breath
Arm or leg swelling
Chest pain

Some patients may be at greater risk of blood clots (even without taking Revlimid-dex). Risk factors include:

History of blood clots or family history
Recent surgery (particularly hip, pelvic, knee and some gynecologic procedures)
Fractures
Prolonged bed rest or inactivity (eg, hospitalizations, long plane or car trips)
Pacemakers or catheter in a major vein (used to give some types of cancer drugs)
Pregnancy or childbirth within the last 6 months
Taking estrogen (eg, hormone replacement therapy, birth control pills)
Certain medical conditions where blood clots are more likely
Older age, overweight or smoking

Very serious rash or skin reaction (Stevens-Johnson syndrome and toxic epidermal necrolysis): A few cases of very serious skin reactions or rashes have been seen in patients taking Revlimid. In these types of skin reactions, blisters may appear on a large percentage of the body.

Although, it is not clear whether or not Revlimid actually causes these problems, it is important to be aware of them because they can be life-threatening. Call your doctor immediately if you notice any type of unusual rash or skin reaction.

Possible birth defects: Although, Revlimid does not appear to cause the type of severe birth defects seen in the past with Thalidomide. Women who are pregnant or who plan to become pregnant must not take Revlimid. This precaution is due to its similarity to Thalidomide, and some signs of birth defects in animals. A program called RevAssist(SM)has been created to prevent exposure to Revlimid during pregnancy.

Doctors and pharmacists must register with RevAssist in order to prescribe and dispense Revlimid.
Patients must register and meet all the conditions of the program in order to take Revlimid.

In addition, dexamethasone by itself can cause side effects. Possible side effects of dexamethasone alone include: stomach problems, vomiting, headache, dizziness, insomnia, restlessness, depression, anxiety, acne, increased hair growth, and easy bruising.

Please tell your doctor or nurse if you experience any side effects.

LEARN MORE »

How are side effects of Revlimid-dex managed?

Management of side effects depends on the type and severity of the problem. Some side effects such as mild or moderate diarrhea can be managed with additional medications.

More serious side effects may require you to stop Revlimid-dex either temporarily or permanently. In many cases, Revlimid-dex is stopped temporarily, until the side effect improves, and then re-started at a lower dose. Studies have shown that Revlimid-dex is still effective at lower doses. LEARN MORE »

What types of patients can benefit from Revlimid-dex?

Although Revlimid in combination with dexamethasone has been FDA approved in myeloma only for patients who have received at least one prior therapy, this drug has also been shown to be effective in a wide range of patients including:

Newly diagnosed/untreated myeloma and relapsed or refractory myeloma
Older patients (?65 years old) as well as younger patients
Patients whose disease has certain high-risk features such as
chromosome 13, chromosome 14 or 17 deletions or with an elevated ß2-microglobulin level .
Patients who previously received Thalidomide (although efficacy is slightly reduced)
Patients who have received several prior therapies (heavily-pretreated)
- One study showed that some of these patients responded for a long period of time (4 or more years)
Patients who previously received high dose chemotherapy and stem-cell transplant
Patients with reduced kidney function (renal impairment)
- In one study, 78% of patients with moderate to severe renal impairment showed improved renal function within 4 months of treatment.

IMPORTANT SAFETY INFORMATION:
Reduced Kidney Function (Renal Impairment) and Revlimid-dex

Patients with reduced kidney function may be a greater risk of serious side effects with Revlimid-dex, particularly,

Neutropenia (decline in a type of white blood cells): impacts the body's ability to fight infection. In one study, patients experienced a type of severe neutropenia that is associated with fever, called febrile neutropenia, which is potentially life-threatening.
Thrombocytopenia (drop in platelet counts): impacts the body's ability to form blood clots, resulting in an increased risk of bleeding.

Patients with reduced kidney function taking Revlimid-dex need to be carefully monitored. Patients with moderate or severe kidney problems may need to start with a lower dose of Revlimid. The dose of Revlimid-dex may need to be further reduced if serious side effects occur. LEARN MORE »

Is Revlimid-dex effective in treating newly diagnosed/untreated myeloma?

Two large clinical studies have shown that Revlimid-dex significantly improves survival in patients with newly diagnosed/untreated myeloma.

One study showed that Revlimid plus high-dose dex was more effective than high-dose dex alone. However, there were more side effects with Revlimid high-dose dex. LEARN MORE »

Another important study showed that patients taking Revlimid plus low-dose dex had significantly improved survival and fewer side effects than patients taking Revlimid plus high dose dex.
- One year after the beginning of treatment, 96% of patients taking Revlimid low-dose dex were alive and 88% were alive 2 years later.
  - There was no difference in survival time between patients who went on to high dose chemotherapy plus stem cell transplant and those who took Revlimid plus low-dose dex for an extended period of time (more than 4 months).
- The incidence of serious (grade ¾) side effects was much lower with Revlimid plus low-dose dex versus Revlimid plus high-dose dex (30% versus 50%).
LEARN MORE »

Based on these two studies, the combination of Revlimid-dex has become a commonly used option for newly-diagnosed/untreated patients. Many doctors recommend the combination of Revlimid and low-dose dex, particularly in patients over 65.

How is Revlimid being studied in combination with other agents (besides dexamethasone) for the treatment of newly diagnosed/untreated myeloma?

Large national studies (Phase III) are evaluating the efficacy and safety of combinations of Revlimid with other myeloma drugs.

Revlimid in combination with Velcade and dexamethasone (also known as REV-VEL) is being compared to Velcade and dexamethasone in 440 patients eligible for high-dose chemotherapy and stem cell transplant.
- Data from a small early study indicated that this combination may be very effective and with manageable side effects. 98% of patients responded to this treatment with 30% achieving a complete response. This response rate is one of the highest seen in newly diagnosed patients.
Revlimid in combination with melphalan and prednisone (MP-R or R-MP) is being studied in patients over 65 years old (who are typically NOT eligible for high-dose chemotherapy and stem cell transplant).
- The goal of these studies is to improve on an older treatment--the combination of melphalan and prednisone (also know as MP). Two large studies are underway. One study with 450 patients will compare MP-R to MP. Another study with 450 patients will compare MP-R to MP plus Thalidomide (also known as MP-T).
- Researchers believe that Revlimid plus MP may be effective because the combination of MP and Thalidomide, a drug that is chemically similar to Revlimid, has been proven to be very effective.
- In addition, promising results have been seen with MP-R in some small studies in relapsed and refractory patients. In one recent study, 69% of patients responded and 31% had a substantial reduction in M-protein (CR or VGPR).

In addition, several other combination treatments are being studied including:

Revlimid, Velcade, dex, plus Cytoxan (a chemotherapy drug used for many cancers)
Revlimid-dex plus Clarithromycin (Biaxin^™), an antibiotic. This combination is known as BiRD (Biaxin, in addition to Revlimid-dex).

How is Revlimid being studied as maintenance therapy?

Several studies are evaluating the use of Revlimid as a treatment following remission with the goal of reducing the risk of relapse. In particular, one large national study is evaluating Revlimid as maintenance therapy following high-dose chemotherapy and stem cell transplant.

How is Revlimid being studied in newly diagnosed asymptomatic patients?

A large national clinical trial is studying the effectiveness of Revlimid compared to observation in high risk asymptomatic patients. Typically, these patients are not given any myeloma treatment.

To find a clinical trial, call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.

For more information on Revlimid, visit www.revlimid.com.

Reviewed by:
S. Vincent Rajkumar, MD
Professor of Medicine
Mayo Clinic, Rochester, MN