Patients Starting Treatment:

Treatment Options - Revlimid


Important Information about Revlimid
Celgene, the manufacturer of Revlimid, is working closely with the FDA to review data related to the occurrence of secondary malignancies in three recent trials of Revlimid when used with melphalan. The FDA advises patients not to stop taking Revlimid without speaking to your doctor. Read the FDA announcement.

Revlimid® (lenalidomide)

Overview

Revlimid in Newly Diagnosed/Previously Untreated Patients

Links

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 partly by impacting the functioning of the immune system.

Revlimid is chemically related to Thalomid® (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.

In addition, the combination of melphalan and prednisone plus Revlimid followed by Revlimid maintenance has been shown to be effective in newly diagnosed/untreated patients over 65 years old who are ineligible for high-dose chemotherapy followed by stem cell transplantation.

Revlimid has also been shown to extend remission and survival time when used as maintenance therapy following high-dose chemotherapy and stem cell transplantation.

Further, 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 has increasingly become the standard approach.

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

Increased diarrhea in patients taking Revlimid-dex for an extended period of time (>8 months) has been seen.

  • 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. A low level of neutrophils is 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. One study has shown no major differences between these options. Since aspirin is more convenient, it is an appropriate choice for many patients. In some cases, where patients are at higher risk of blood clots, low molecular weight heparin may be recommended.
  • 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 Thalomid®. Women who are pregnant or who plan to become pregnant must not take Revlimid. This precaution is due to its similarity to Thalomid, and some signs of birth defects in animals. A program called RevAssistSM 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 »

 

Does Revlimid cause second cancers?

There have been reports of new second cancers (also called second primary malignancies or SPMs) developing in a small number of myeloma patients who received maintenance therapy, in 3 large clinical studies. In all of these studies Revlimid was used in combination with melphalan. The types of second cancers seen include MDS (myelodysplastic syndrome, a form of preleukemia) and AML (acute myelogenous leukemia). Two of the 3 trials evaluated the use of Revlimid following high-dose chemotherapy with melphalan and stem cell transplant, and one assessed the role of Revlimid following MPR (standard dose melphalan plus prednisone and Revlimid). Additionally, an analysis of 9 studies including nearly 2500 patients showed that patients who received melphalan in combination with Revlimid or Thalomid had approximately double the risk of a second malignancy compared to those who did not receive these drugs (2% versus 1%). While the risk of second cancer is higher among those receiving Revlimid, the total number of patients developing the cancer was still very small.

There have been no additional second cancers in other studies with Revlimid where melphalan was not part of the treatment. Overall, the information available to date indicates that therapy with Revlimid significantly decreases the risk of myeloma disease progression. Hence, some doctors believe that the benefits of Revlimid therapy may outweigh any potential risk of second cancers.

The MMRF urges patients not to make any changes to their treatment regimens without speaking to their doctor, and if you are a candidate for maintenance therapy, to discuss the options, including these emerging data on safety and effectiveness with your doctor before making any decisions.

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 Thalomid (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 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.
    • Two years after the beginning of treatment, 96% of patients taking Revlimid low-dose dex were alive and 87% 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).
  • Similar results were seen regardless of age.
  • 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.

 

Is Revlimid plus melphalan and prednisone effective in treating newly diagnosed/untreated myeloma?

Preliminary results from a large study, with over 450 patients, have shown that Revlimid in combination with melphalan and prednisone followed by Revlimid maintenance therapy (MPR-R) is more effective than MP alone in patients over 65 years old. MP is an older treatment for patients who are ineligible for high-dose chemotherapy and stem cell transplantation.

In this study, three groups of patients were compared:

  1. Patients who received MP-R for 9 treatment cycles and then continued Revlimid alone (maintenance or continuous therapy) (MPR-R group)
  2. Patients who received MP-R for 9 cycles only (MPR group)
  3. Patients who only received MP alone (MP group)

The results of this study showed that:

  • Patients taking MP-R followed by Revlimid maintenance therapy (MPR-R) had significantly improved response rates and experienced a longer period of time without progression of their myeloma compared to those taking MP alone.

  • 77% of patients taking MPR followed by Revlimid maintenance therapy (MPR-R) achieved a response compared to 50% of patients taking MP alone. Notably this included complete response rates of 10% for MP-R versus 3% for MP alone.

    • In patients 65-75, the time without disease progression was 31 months for those taking MPR-R versus 15 months for those taking MPR. However, the magnitude of the benefit in those over 75 years old was lower; time without disease progression was 19 months for those taking MPR-R versus 15 months for patients taking MP alone

Although the results described above are promising, the effect on overall survival is not yet known. It is also not known how MPR-R compares with other regimens used in the treatment of elderly patients such as Revlimid plus low-dose dexamethasone, or MP plus Thalomid. A study with 450 patients who are not candidates for high dose chemotherapy followed by stem cell transplantation is underway comparing MP-R to MP plus Thalomid (also known as MP-T).

 

Is Revlimid effective as maintenance therapy following high dose chemotherapy and stem cell transplantation?

Two large studies have shown that patients who received Revlimid as maintenance therapy following high-dose chemotherapy and stem cell transplantation have a significantly longer remission time compared with those who did not receive any maintenance treatment. Revlimid maintenance therapy was taken at a dose of 10-15 mg/day in these studies—which is lower than the typical dose of 25 mg/day.

  • One study, conducted in the United States, showed that maintenance therapy with Revlimid significantly prolonged the time until disease progression. In addition, the overall survival rate was higher for patients who received Revlimid. This is the first study to show a survival benefit with Revlimid maintenance therapy.

  • The other study, conducted in France, showed that in patients who received Revlimid as maintenance therapy, there were fewer patients who had progression of their myeloma after 3 years of follow-up. However, in this study there has been no improvement in the overall survival among those receiving Revlimid.
  • The other study, conducted in France, showed that in patients who received Revlimid as maintenance therapy, there were fewer patients who had progression of their myeloma after 3 years of follow-up. Further, there appeared to be a trend toward improved survival as well.

There was a small increase in second new cancers in these studies, which did not affect the overall benefit of Revlimid on disease progression. Thus, some researchers believe that the benefits of maintenance therapy with Revlimid may outweigh the risks of a second new cancer.

Patients who have undergone a stem cell transplant should discuss with their doctors the pros and cons of maintenance therapy with Revlimid.

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


Data from a small early study indicates that the combination of Revlimid in combination with Velcade and dexamethasone (also known as RVD) may be very effective.

  • Importantly, 100% of patients responded to this treatment with 39% achieving a complete response or near complete response. This response rate is one of the highest seen in newly diagnosed patients.
  • The impact on survival of this treatment on survival is very encouraging. 97% of patients were alive 18 months after initiation of treatment.
  • Further, there appeared to be no difference in outcome between the patients who went on to receive high dose chemotherapy following by stem cell transplantation and those who did not.
  • Although side effects with this combination were manageable, many patients developed neuropathy. In most of these patients, it was mild and in all cases it was reversible.

A large national study (Phase III) is evaluating the efficacy and safety of Revlimid in combination with Velcade and dexamethasone (RVD) versus Revlimid and dexamethasone in patients eligible for high-dose chemotherapy and stem cell transplant.

In addition, several other combination treatments with Revlimid 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).
  • Revlimid-dex, plus Carfilzomib (a new type of proteasome inhibitor).
  • Revlimid-dex plus Doxil® (lipsomal doxorubicin HCL injection). This combination is known as PLD.

Is Revlimid effective in newly diagnosed asymptomatic patients?


Recently, results from a study conducted in 119 asymptomatic patients with smoldering myeloma, who were at high risk of progression to symptomatic myeloma (i.e. development of myeloma symptoms and/or organ damage) were reported. In this study, high risk asymptomatic smoldering myeloma was defined as those patients with more than 10% of plasma cells in the bone marrow, M protein greater than 30g/L, greater than 95% abnormal plasma cells, or abnormal light chains.

In this study, Revlimid-dex prolonged the time to the development of symptomatic myeloma and improved overall survival. Patients were treated with Revlimid at the 25mg dose for 9 months then continued treatment with a lower dose of Revlimid (10mg).

  • The overall response rate was 81%
  • After an average of 29 months of follow-up, the overall survival rate was 98% in patients who received Revlimid-dex compared to 87% of patients taking placebo.

Typically, patients with asymptomatic myeloma are not given any myeloma treatment. The use of Revlimid for high-risk asymptomatic smoldering myeloma is still experimental and there is insufficient data on the benefits and risks of therapy at this time. However, patients with high-risk asymptomatic smoldering myeloma, as defined in this study, may wish to discuss the option of Revlimid treatment with their doctor which is currently available as part of a large national study.

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:
Shaji Kumar, MD
Associate Professor of Medicine
Mayo Clinic
Rochester, MN