Revlimid (lenalidomide)

REVLIMID® (lenalidomide) is an immunomodulatory drug (IMiD®). It was first approved by the U.S. Food and Drug Administration (FDA) in 2006 for use with the steroid dexamethasone in adult patients with myeloma who had received at least one prior therapy. In 2015, the FDA expanded this indication to a broad approval of Revlimid for use throughout the myeloma disease course, from diagnosis through relapse. 

How Does It Work?

Revlimid is an immunomodulatory agent taken by mouth (orally) in capsule form. Revlimid has multiple actions, including the following:  

• Targeting and killing myeloma cells. To kill myeloma cells, Revlimid acts by binding to cereblon (CRBN), the primary molecular target of all immunomodulatory agents.  
• Enhancing the function of the immune system, and activating specialized white blood cells (WBC) – both the T cells (T lymphocytes) and natural killer (NK) cells. Revlimid helps immune cells recognize and destroy myeloma cells. 
• Preventing new myeloma cell growth by inhibiting vascular endothelial growth factor (VEGF). Revlimid can alter the levels of growth factors called cytokines and interleukins. 

Revlimid in the Frontline Setting 

The most important initial decision is when to begin treatment for your myeloma. Treatment controls myeloma bone breakdown and tumor growth. It also impacts the diverse effects caused by the monoclonal protein (myeloma protein, M-protein) and the cytokines stimulated by the M-protein. The urgency of treatment depends upon the exact problems faced by an individual patient. This is why the experience and expertise of a myeloma specialist is of such importance.  

If you are newly diagnosed with myeloma, we suggest that you read the IMF’s publication Patient Handbook for the Newly Diagnosed. This booklet will help you to better understand this complex disease.  

Revlimid is an important component of a growing list of FDA-approved myeloma treatment options in the frontline setting, including the following (listed in alphabetical order): 

• Darzalex® (daratumumab), Revlimid and dexamethasone (DRd) for patients ineligible for an autologous stem cell transplant (ASCT).  
• Darzalex Faspro® (daratumumab and hyaluronidase-fihj), Revlimid, and dexamethasone (DRd) for patients who are ineligible for ASCT.  
• Velcade® (bortezomib), Revlimid, and dexamethasone is currently considered the standard of care for patients with newly diagnosed myeloma. See the note below about the D-VRd regimen.  

In June 2024, at the annual meeting of the American Society of Clinical Oncology (ASCO), an analysis was presented of minimal residual disease (MRD) status and depth of response (DpR) in the PERSEUS clinical trial. This trial evaluated the use of Darzalex [with subcutaneous (SQ) injection of Darzalex Faspro] in combination with VRd [D-VRd] in ASCT-eligible patients with newly diagnosed multiple myeloma (NDMM). The results showed that D-VRd induction therapy and consolidation therapy, and Darzalex plus Revlimid maintenance therapy improved progression-free survival (PFS) and increased the  DpR compared to VRd induction/consolidation and Revlimid maintenance. 

The MRD-negative rates were higher with D-VRd, and the rates increased over time. Sustained MRD negativity for 12 months was also higher with D-VRd. The study concluded that D-VRd and Darzalex maintenance can be considered a new standard of care for ASCT-eligible patients with NDMM. At this time, D-VRd is not formally approved by the FDA. Yet, it is included by the National Comprehensive Cancer Network (NCCN) in its guidelines for the management of myeloma. 

For more information about the drugs that are part of Revlimid-containing frontline combination therapies, read the following IMF publications from our Understanding series: 

• Understanding Dexamethasone in the Treatment of Myeloma  
• Understanding DARZALEX® (daratumumab) and DARZALEX FASPRO® (daratumumab + hyaluronidase-fihj)  
• Understanding VELCADE® (bortezomib) injection  
• Understanding the VRd Regimen for Newly Diagnosed Myeloma  

If a particular frontline therapy is not working for you, many other treatment options are available. Discuss your options with the doctor. However, it is not advisable to rapidly skip from one treatment regimen to another. 

Revlimid in the Relapsed or Refractory Setting 

Revlimid is an important component of a growing list of FDA-approved myeloma treatment options in the relapsed or refractory setting, including the following (listed in alphabetical order): 

• Darzalex (daratumumab), Revlimid (lenalidomide), and dexamethasone (DRd) for myeloma patients who have received at least one prior therapy 
• Empliciti® (elotuzumab), Revlimid, and dexamethasone (ERd) for patients who have had from one to three prior therapies 
• Kyprolis® (carfilzomib), Revlimid, and dexamethasone (KRd) for patients who have received one to three prior lines of therapy 
• Ninlaro® (ixazomib), Revlimid, and dexamethasone (IRd) for patients who have had at least one prior therapy.  

For more information about some of the drugs that are part of Revlimid-containing combination therapies for relapsed/refractory myeloma, read the following IMF publications from our Understanding series:  

• Understanding EMPLICITI® (elotuzumab)  
• Understanding KYPROLIS® (carfilzomib) injection  
• Understanding NINLARO® (ixazomib) capsules 

If You Are Planning to Proceed to Stem Cell Transplant 

In December 2023, a plenary session at the annual meeting of the American Society of Hematology (ASH) presented the results from the IsKia phase III clinical trial of 302 patients with NDMM who were eligible for ASCT. 

Patients were randomized to two study arms with 151 patients in each arm. One arm received Kyprolis® (carfilzomib) and Revlimid® (lenalidomide) plus dexamethasone [KRd] and the other arm received Sarclisa + KRd [Isa-KRd]. 

The study assessed efficacy and safety of Isa-KRd as pre-ASCT induction and post-ASCT consolidation. Compared to KRd alone, the addition of Sarclisa to KRd [Isa-KRd] induction and consolidation significantly increased the rates of MRD-negativity in every treatment phase and with no new safety  concerns, including in patients with high-risk multiple myeloma (HRMM).

Newly diagnosed myeloma patients who are eligible for autologous stem cell transplant (ASCT) should know that longer-term use of Revlimid can affect their blood-making stem cells.

The collection of stem cells for use in ASCT should occur within 4 cycles of a Revlimid-containing therapy. For more information, read the IMF publication Understanding Stem Cell Transplant in Myeloma. 

Revlimid in the Post-ASCT Maintenance Setting 

Revlimid is the only treatment approved by the FDA as a maintenance therapy following ASCT. Two important clinical trials evaluated Revlimid in this setting and demonstrated survival benefit:  

• the phase III CALGB (Alliance) 100104 study  
• the IFM 2005-02 study 

Clinical trial data from several studies has shown that Revlimid maintenance therapy following ASCT significantly increases both progression-free survival (PFS) and overall survival (OS). This is true even if a patient has high-risk myeloma; their OS is superior to that of patients who do not receive Revlimid maintenance. The proportion of patients who are MRD-negative with Revlimid maintenance has also increased.  

However, Revlimid maintenance therapy post-ASCT can increase the risk of second primary malignancies (SPM) that arise among patients exposed to both Revlimid and melphalan, used in ASCT. Studies of early Revlimid maintenance revealed that second hematologic cancers occurred in 7.5% of patients who received Revlimid maintenance compared to 3.3% of patients who received no maintenance.  

The incidence of hematologic plus solid tumor cancer (SPM) was 14.9% compared to 8.8% over a follow-up period of almost 10 years. Given the evident advantages but potential risks of post-ASCT maintenance therapy with Revlimid, each patient must discuss the pros and cons of this course of treatment with the doctor treating their myeloma. The doctors must evaluate the patient’s individual risk factors and the response to transplant before making a recommendation. Patients who are receiving Revlimid maintenance therapy must be carefully monitored.  

Revlimid in the Setting of Smoldering Myeloma 

Currently, several active and recruiting clinical trials are bringing Revlimid to a new treatment setting in myeloma, intermediate-risk and high-risk smoldering multiple myeloma (SMM). These clinical trials are investigating several approaches to treating SMM. The data from these clinical trials will help assess the possible benefits and risks of treating SMM with these different strategies. For more information, visit the National Institutes of Health (NIH) website clinicaltrials.gov or contact the IMF InfoLine at 1.818.487.7455 or [email protected]. 

How Is Revlimid Taken? 

Revlimid is an oral drug. Since you do not need to be at the doctor’s office or in a clinic or hospital to receive Revlimid, it is your responsibility to take Revlimid as directed by your doctor.  

• Make sure to read the booklet Understanding Revlimid.  
• Follow any other materials your doctor provides.  
• Read and download/order the related IMF Tip Card on Revlimid. 
• Read and download/order the IMF Tip Card the Adherence to Oral Cancer Therapy. 

Revlimid is taken as capsules that are swallowed with water. Revlimid is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg capsules. The standard treatment dose in myeloma is 25 mg taken 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.  

All patients must follow these instructions: 

• Swallow Revlimid capsules whole with water 1 time a day. Do not open, break, or chew your capsules.  
• Revlimid may be taken with or without food.  
• Take Revlimid at about the same time each day.  
• Do NOT open the Revlimid capsules or handle them any more than needed. If you touch a broken Revlimid capsule or the medicine in the capsule, wash the area of your body right away with soap and water.  
• If you miss a dose of Revlimid and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, you must contact the doctor treating your myeloma for instruction. 

Patients with renal (kidney) disease may take Revlimid, but the dosage must be adjusted according to the level of remaining kidney function. Your doctor must follow the “Recommended Dosage for Patients with Renal Impairment” included in the Revlimid prescribing information. 

Dose Reductions with Revlimid  

The standard treatment dose for Revlimid is one 25 mg capsule each day for 21 days of a 28-day Cycle. Your physician may consider reducing the dose because of lowered blood cell counts. In addition, there may be cumulative side effects such as fatigue or slight neuropathy. Your physician may decide that dose reduction is appropriate, lowering first to 20 mg, then to 15 mg, then to 10 mg, and even to 5 mg or 2.5 mg if necessary.  

Results from clinical trials show that with dose reductions after 12 months or longer of Revlimid therapy, treatment benefit is retained. Long remissions following dose reduction were reported in two clinical trials, MM009 and MM010. In these two clinical trials, Revlimid and dexamethasone were compared to dexamethasone alone in myeloma patients who had relapsed after 1 to 3 prior lines of therapy. Patients who had dose reductions after 12 months or more of Revlimid had significantly longer PFS than those who had never had dose reductions at all. These patients were better able to remain on therapy. 

The dose of Revlimid is also reduced as part of maintenance therapy, commonly dosed at 10 mg daily on a 28-day schedule.

It is important to  

• communicate openly with your doctor or healthcare professional, 
• follow your prescribed dose and schedule of medication, and  
• keep regular appointments to maintain your Revlimid treatment schedule. 

Warnings and Precautions with Revlimid

While most of the side effects associated with Revlimid are manageable and predictable, some potential side effects of Revlimid are serious enough to require an FDA-mandated “Boxed Warning” on the package insert. A Boxed Warning is the strictest warning put in the labeling of prescription drugs when there is reasonable evidence of an association with a serious hazard from the drug.

In the current prescribing information for Revlimid, the Boxed Warnings are the risks of thrombocytopenia, neutropenia, and embryo-fetal toxicity.

For patients taking the combination of Revlimid and dexamethasone, the Boxed Warnings include an increased risk of arterial and venous thromboembolism (VTE, blood clots, and pulmonary embolism, a blood clot that travels to the lung), myocardial infarction (heart attack), and stroke. See Heart and Lung Complications to learn more about these issues. 

Your blood counts will be monitored if you are taking Revlimid in combination with dexamethasone or as maintenance therapy:  

• Weekly for the first 2 cycles 
• On Days 1 and 15 of cycle 3 
• Every 28 days (4 weeks) thereafter

A dose interruption and/or dose reduction may be required. 

Hepatotoxicity  

The evidence from clinical trials suggests that Revlimid may be associated with drug-induced liver injury. Risk factors may include pre-existing viral liver disease, elevated baseline liver enzymes, and other medications that a patient may be taking. Liver failure, including fatal cases, has occurred in patients treated with Revlimid and dexamethasone (Rd).  

Prevention and treatment of hepatotoxicity  

Your doctor will monitor your liver enzymes periodically. Your Revlimid treatment will be stopped if your liver enzyme tests show that they are higher than normal. After the enzymes return to your normal baseline levels, treatment at a lower dose may be considered.  

Thrombocytopenia (decreased platelet level)  

Patients taking Revlimid may experience thrombocytopenia, a lowered level of blood cells called platelets. Platelets help the blood to clot. “The “normal” level varies from laboratory to laboratory. For example, the “normal” level is ≥ 150,000 platelets per microliter of circulating blood. 

If the platelet count is less than 50,000, bleeding problems could occur. Major bleeding is usually associated with a reduction to less than 10,000. 

Prevention and treatment of thrombocytopenia  

Your doctor will monitor your platelet counts as well as your other blood counts during your treatment with Revlimid (see the above monitoring schedule). Be sure to report any unusual bleeding or bruising. In Revlimid maintenance therapy studies, severe thrombocytopenia occurred in up to 38% of patients. Your dose of Revlimid may be interrupted and/or lowered until your platelet count improves. If necessary, your doctor may order a platelet transfusion or a medication to stimulate the production of platelets. For more information, visit Myelosuppression.

Neutropenia (low level of neutrophils) 

Neutrophils, the most abundant type of white blood cell, are the body’s “first responders” in fighting infections. Having too few neutrophils can therefore lead to infection. In the maintenance therapy studies, severe neutropenia was reported in up to 59% of Revlimid-treated patients. Fever is the most common sign of neutropenia. If you have a fever, you need to contact your doctor immediately. 

Prevention and treatment of neutropenia  

Your neutrophil count will be monitored frequently while you are being treated. Your dose of Revlimid may be interrupted and/or lowered if your neutrophils are too low. The treatment of neutropenia depends on its cause and severity. Contact your physician immediately if you experience fever, sore throat, or mouth sores. Fever in patients with neutropenia warrants immediate medical attention as it indicates potential infection.  

If you are showing signs of infection, then 

• you may be given antimicrobial therapy 
• your doctor may also give you a white blood cell growth factor (G-CSF, or granulocyte colony stimulating factor) to increase production of your white blood cells

The neutropenia accompanying infections may be brief and may resolve after the infection has cleared. Mild neutropenia generally has no symptoms and may not need treatment. For more information, visit Myelosuppression.

Venous thromboembolism (VTE) 

Venous thromboembolism (VTE) is a condition that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE).  

DVT is a condition that occurs when a blood clot (thrombus) forms in one or more of the deep veins in the body, usually in the lower extremities. A blood clot from a DVT can break loose (embolize) and travel to the heart or lungs. An embolus is very dangerous and potentially life-threatening. DVT can occur without any symptoms, or it can cause leg pain or swelling. 

PE is a condition that occurs when a blood clot in the vein breaks loose, travels through the bloodstream, and lodges in a lung, blocking blood flow. 

Blood clots in the arteries, veins, and lungs occur more often in people who take Revlimid than in the healthy population. The risk is even higher for people with multiple myeloma who take dexamethasone with Revlimid. Heart attacks and strokes are also more frequent in people who take Revlimid with dexamethasone. 

Prevention and treatment of venous thromboembolism  

The Boxed Warning for Revlimid states that anti-thrombotic prophylaxis (preventive therapy with a blood thinner) is recommended. The type and dose of blood thinner will be tailored to your risk factors. Before taking Revlimid, tell your doctor and/or nurse:  

• If you have had a blood clot in the past.  
• If you have high blood pressure, smoke, or if you have been told you have a high level of fat in your blood (hyperlipidemia).  
• About all the medicines you take, since certain other medications can also increase the risk for blood clots.  

You are strongly advised to seek immediate medical care if you experience any of the signs or symptoms of VTE, heart attack, or stroke.  

Signs or symptoms of VTE may include the following: 

• difficulty breathing 
• warmth, swelling, redness, and/or pain in an extremity 

Signs or symptoms of a heart attack may include the following: 

• chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen) 
• breaking out in a sweat 
• shortness of breath 
• feeling sick to your stomach or vomiting 

Signs or symptoms of a stroke may include the following:  

• sudden numbness or weakness, especially on one side of the body, 
• severe headache 
• confusion 
• problems with vision, speech, or balance 

A doctor will diagnose your condition and determine if treatment is needed. Treatment depends upon both the location of the VTE and its underlying cause. 

Embryo-fetal Toxicity 

Animal studies have shown that Revlimid can cause severe birth defects or the death of a developing fetus. The FDA therefore required that a risk management program be established. The goals of the Revlimid Risk Evaluation and Mitigation Strategy (known as REVLIMID REMS®) are as follows:  

1. To prevent the risk of embryo-fetal exposure to Revlimid.  
2. To inform prescribers, patients, and pharmacists about the serious risks and safe-use conditions for Revlimid. 

Patients who can become pregnant must undergo mandatory pregnancy testing and give informed consent before taking Revlimid. Female patients of childbearing potential and all male patients are also required to complete a monthly phone survey. Since most female myeloma patients are beyond the age of childbearing, they are enrolled in the REMS program by their physicians with a lower risk classification. These patients must only do the phone survey once every six months. They will, however, have monthly counseling with the specialty pharmacy that dispenses their Revlimid. 

Other Possible Side Effects When Taking Revlimid

In addition to the Boxed Warning side effects, patients must be aware of  other side effects when taking Revlimid.  

Side effects experienced by patients in clinical trials with Revlimid included the following: 

• diarrhea 
• fatigue 
• anemia 
• constipation 
• peripheral edema (swelling of the ankles and feet) 
• insomnia, muscle cramps and/or spasms 
• abdominal pain 
• back pain 
• nausea 
• fever 
• upper respiratory tract infection 
• gastroenteritis (“stomach flu”) 
• rash 
• Itching 
• shortness of breath 
• dizziness 
• decreased appetite 
• tremor (shaking or trembling) 

The following are the most common side effects that should be reported to, and managed by, your doctor. 

Diarrhea  

Diarrhea is defined as 3 or more loose stools per day. Severe diarrhea is defined as 7 or more loose stools per day requiring treatment with intravenous fluids or hospitalization. Diarrhea can be a troubling side effect of long-term Revlimid therapy that can severely affect quality of life and may lead to discontinuation of therapy if not well managed.  

Revlimid modulates the immune system throughout the body to fight myeloma, including the immune system in the gut. The good news/bad news is that development of severe diarrhea among Revlimid-treated patients is associated with improved overall survival. It is also a sign of Revlimid’s immune control of the myeloma.  

Prevention and treatment of Revlimid-related diarrhea 

Tell your doctor if you are having diarrhea while taking Revlimid. Your doctor will determine 

• if your diarrhea is Revlimid-related and caused by bile acid malabsorption (BAM), or  
• if it is caused by other medical problems. 

Revlimid’s modulation of the gut affects absorption of bile acids. BAM occurs when the intestines cannot process bile acids properly.  

Revlimid-related diarrhea can be significantly improved or resolved by doing the following:

• reducing intake of dietary fat
• taking a bile acid sequestrant prescription medication such as cholestyramine (brand names include Cholestyramine Light®, Prevalite®, Questran®, Questran Light®), colesevelam (Welchol®), or colestipol (Colestid®) 

If you have Revlimid-related diarrhea and cannot take a bile acid sequestrant, you should discuss your Revlimid dose with your doctor.  

Fatigue 

Fatigue is commonly associated with cancer and with cancer therapy. Fatigue that is related to cancer and its treatments is 

• different from and more severe than normal fatigue, 
• tends to last longer, and 
• includes the feeling of overall weakness. 

The medical term for this feeling is asthenia. For more information about this debilitating side effect, read the IMF publication Understanding Fatigue. 

Prevention and treatment of fatigue  

The effects of fatigue may be minimized by maintaining: 

1. A moderate level of activity 
2. A healthy diet and proper fluid intake 
3. A consistent sleeping schedule 
4. Regular visits with your doctor to monitor your red blood cell count (low red blood cells, or anemia, can cause fatigue) and to discuss any of fatigue-inducing issues 
5. A review of potential side effects of other medications contributing to fatigue 

Anemia (low red blood cell count)  

Red blood cells contain hemoglobin, a protein that contains iron and transports oxygen from the lungs to the body’s organs and tissues. A low level of red blood cells results in low levels of oxygen in the body. This may cause shortness of breath and feelings of exhaustion.  In the phase III FIRST clinical trial for newly diagnosed myeloma, 44% of the patients experienced anemia. For 18%, the anemia was severe. 

Prevention and treatment of anemia  

Your doctor will determine which treatment regimen for anemia is best suited to and safest for you.  

The following are options for treatment of anemia:  

• interruption, reduction, or discontinuation of your dose of Revlimid 
• blood transfusions 
• erythropoietic (red blood cell-making) medication 

Rash  

In the phase III FIRST clinical trial, 26% of the patients experienced a rash. For 7%, the rash was severe. Most Revlimid-related rash is mild to moderate in severity. It might present as patchy, raised spots on the skin, sometimes with hives in that area, which might be associated with itching.  

Prevention and treatment of rash 

Mild rash may be treated with topical steroid and/or topical or oral antihistamines (such as Benadryl® [diphenhydramine]). If you develop a rash while taking Revlimid, report it to your doctor and/or nurse right away. Your doctor may interrupt or discontinue Revlimid if you have a moderate to severe skin rash.  

Although it is rare, some Revlimid-related rashes can become very severe and life-threatening. Patients with a prior history of severe rash associated with Thalomid® treatment should not receive Revlimid.  

Decreased appetite 

In the phase III FIRST clinical trial, 23% of the newly diagnosed patients experienced a decreased appetite. Of those, only 3% had weight loss or malnutrition.  

Prevention and treatment of decreased appetite 

View the National Cancer Institute’s Eating Hints: Before, During, and After Cancer Treatment to view and download the accompanying pdf. This publication includes the following helpful suggestions to maintain your weight and meet your nutritional needs:  

• Eat plenty of protein and calories when you can.  
• Eat at the time of the day when you have some appetite.  
• Eat what appeals to you, even if it’s the same thing again and again.  
• Drink liquid meal replacements for extra nutrition.  
• Don’t worry if you can’t eat at all some days. Tell your doctor if you are not able to eat for more than one day.  
• Drink plenty of non-alcoholic liquids. It's even more important to drink on days when you cannot eat. 
• Drink 8-12 cups of liquid a day.

Revlimid and Dexamethasone Toxicities

The major studies that were the basis of Revlimid’s approval in the relapse setting used a combination of Revlimid and dexamethasone. It is important to be aware that additional toxicities can occur with this combination versus Revlimid alone.

Side effects that may occur with Revlimid and dexamethasone include the following:

• muscle weakness
• anxiety
• agitation
• cardiac arrhythmias
• nausea
• increased blood sugar
• elevated liver enzymes
• constipation and/or diarrhea

The use of dexamethasone in myeloma is discussed in a separate IMF booklet, Understanding Dexamethasone in the Treatment of Myeloma. 

Revlimid prescribing information, including updated renal dosing guidelines

Dosing guidelines from the FDA and the EMA.

Patient Assistance

Celgene's patient support program

Celgene's Patient Support Coordinators assist patients and healthcare providers to navigate the challenges of reimbursement, provide information about co-pay assistance, and answer general questions about Revlimid.

Fast Track for First Prescription™

Celgene has developed a new program called Fast Track for First Prescription™ to help eligible patients receive their first prescriptions for a Celgene product quickly and efficiently. Fast Track is an optional service of Celgene Patient Support that facilitates communication between doctors, patients, insurance providers, risk management programs, pharmacies, and co-pay foundations. To be eligible, patients must be receiving their first prescription of either Revlimid or Pomalyst, must have documented proof of insurance, and must be registered in a Celgene risk management program and have a valid authorization number. For more information on the program, call the IMF InfoLine at 1-800-452-2873.