Warfarin Institute of America
DEDICATED TO YOUR HEALTH SINCE 2000
Treatment of Multiple Myeloma
SPECIAL NOTE
Bennett et al reported in an article in the Journal of the American Medical Association that there have been over 1,100 reports of blood clots in people taking either thalidomide or lenalidomide. These usually happened when the person was also taking dexamethasone or prednisone. Some of these even happened when the person was taking warfarin. Multiple Myeloma causes people to be very prone to blood clots. The American Society of Clinical Oncology now recommends that people taking thalidomide or lenalidomide should be on warfarin. It is my practice that that they should be monitored every two weeks. I monitor without regard to any other therapy. People with this condition tend to not feel very good. It is when they feel their worst that the monitoring needs to be done the most. Please do not neglect to have your INR checked every two weeks if you are on either thalidomide or lenalidomide.
Al Lodwick, RPh, CACP
The next section was written by Jenny Meyer
Multiple myeloma is a cancer of the plasma cells. A plasma cell is a type of white blood cell (WBC) that is made in the bone marrow and it normally produces antibodies which help fight infections. Other cells that are produced in the bone marrow include red blood cells (RBC) and platelets. WBCs are important to the immune system, RBCs play a vital role in tissue oxygenation, and platelets are essential for clot formation. Under normal circumstances, these cells divide, differentiate, and die when needed. However, once a plasma cell becomes abnormal, it can no longer function as originally designed. The abnormal cells (“myeloma cells”) divide uncontrollably and eventually form tumors in the bone marrow. They are often present in multiple bones, hence the name, multiple myeloma. As the abnormal cells increase in number, they displace RBCs and platelets, leading to anemia and thrombocytopenia (low platelets). The abnormal plasma proteins also damage the bone as they accumulate in the bone marrow. Rather than producing normal antibodies, myeloma cells produce M proteins (an abnormal type of antibody which does not help fight infections; the type of antibody produced determines the type of multiple myeloma). These M proteins bind various proteins in the blood and can lead to “hyperviscosity syndrome”.
Multiple myeloma is a relatively uncommon cancer, but is the second most common blood cancer after Non-Hodgkin’s Lymphoma. About 16,570 new cases are expected in 2006, with nearly 11,310 deaths anticipated. Currently, more than 50,000 people live with the disease in the US. Risk factors (these increase your chance of getting the disease) include age (>2/3 of people are over age 65), gender (men are 50% more likely than women to get this disease), race, radiation or petroleum or Agent Orange exposure, and obesity. It is unknown whether family history is a risk factor, but it is believed that certain gene mutations play a role in the development of the disease.
Diagnosis of multiple myeloma involves a series of tests. The first step is usually testing the blood and urine for the presence of M proteins. If these are present, it can be presumed that multiple myeloma is also present. For confirmation, a bone biopsy or aspiration is performed. Additionally, x-rays, CT scans, MRIs, and PET scans can be used.
Before treatment can be started, the disease must be staged. There are two different staging systems that are currently being used. The first is called the Durie-Salmon System and is based on four factors: the amount of M protein present, the amount of calcium in the blood, the severity of bone damage on x-ray, and the amount of hemoglobin in the blood. This system utilizes three stages: I (few myeloma cells present), II (moderate number of myeloma cells), and III (large number of myeloma cells). The second system is called the International Staging System and it uses serum b-2 microglobulin and serum albumin levels (these are two specific proteins that are present in the blood). This system also utilizes three stages, however, they are different from the stages of the Durie-Salmon System.
After the disease has been confirmed and staged, the appropriate treatment can be started. Treatment options include radiation, chemotherapy, corticosteroids, thalidomide, biological agents, bisphosphonates, diuretics, and bone marrow/stem cell transplants. These options can be found in another article on this website . One approach that does not involve drug therapy is called plasmapheresis. During this procedure, blood is removed via a vein and the blood cells are separated from the plasma and the blood cells are returned to the body. Since the plasma contains the abnormal M proteins, it is discarded. This procedure has been reported to relieve some of the symptoms associated with multiple myeloma.
The most common symptoms associated with multiple myeloma include bone pain (especially in the spine, hip, and skull), hematological changes (anemia due to low RBCs and thrombocytopenia due to low platelets), nervous system changes (pain and numbness due to vertebral collapse, nerve damage and “hyperviscosity syndrome” due to accumulation of M proteins), kidney damage and failure due to hypercalcemia (high levels of calcium in the blood), and infections due to low WBCs.
At this point in time, multiple myeloma is not curable, but is very treatable. For more information regarding the therapeutic options, please click on the link provided above.
©2006 Jenny Meyer Used by permission
The next section was written by Michael Andrews
There are two categories of treatment for multiple myeloma (MM), primary therapy and alternative therapy. Primary therapies consist of chemotherapy agents and bisphosphonates (such as Fosamax). Chemotherapeutic regimens used in MM are: melphan/prednisone (MP), dexamethasone, vincristine/doxorubicine/dexamethasone (VAD), liposomal doxorubicine/vincristine/dexamethasone (DVD), and thalidomide/dexamethasone. Patients who fail to respond to these therapies or patients with relapsing disease may repeat primary therapy or use alternative therapies such as: cyclophosphamide, etoposide/dexamethasone/cytarabine/cisplatin (EDAP), thalidomide, dexamethasone, and bortezomib.
Thalidomide
(Thalomid) was recently re-introduced to the
Because of the risk of serious birth deformities, thalidomide is only available through a restricted prescribing program known as the System for Thalidomide Education and Prescribing Safety (STEPS). Lenalidomide is also available through a restricted prescribing program known as RevAssist. These programs were designed to help ensure that patients would receive proper education regarding these agents, proper steps would be taken to prevent exposure of human fetuses to thalidomide and lenalidomide, and also help pharmacists and physicians correctly identify appropriate patients for therapy. All female patients of childbearing potential who are considered for therapy with either lenalidomide or thalidomide must enroll in either the RevAssist or STEPS program and have a pregnancy test within 24 hours of initiation of therapy and use 2 forms of reliable (hormonal or intrauterine device) contraception for at least 4 weeks prior to therapy, during therapy, and for 4 weeks after therapy. Pregnancy tests must also be performed every weeks for the first 4 weeks and then every 2-4 weeks thereafter. All sexually mature male patients receiving thalidomide or lenalidomide must also enroll in either the RevAssist or STEPS program and agree to always use a latex condom during any sexual contact with any woman of childbearing potential even if he has undergone a vasectomy.
These drugs have also been shown to cause other serious adverse events such as deep venous thrombosis (DVT), pulmonary embolism (PE), neutropenia, thrombocytopenia, and leukopenia. Other side effects of thalidomide and lenalidomide which have been reported in up to 10% of patients include: rash, insomnia, tremor, weight loss, peripheral edema, dizziness, muscle cramps, back pain, hyperglycemia, blurred vision, cough, dyspepsia, anorexia, upper respiratory tract infection, emesis, fatigue, and constipation. Both thalidomide and lenalidomide have been issued Black Box Warnings from the US FDA for birth deformities, DVT and PE, neutropenia and thrombocytopenia.
Thalidomide and lenalidomide are dangerous and toxic drugs when used inappropriately. When used appropriately, these drugs can effectively treat MM. New restrictions by the US FDA and the drug manufactures help to ensure safe and appropriate use of these drugs. These measures allow patients with MM to experience the benefits of these otherwise dangerous drugs. Patients with resistant forms of MM now have new treatment options for their difficult and potentially fatal disease.
©2006 Michael Andrews Used by permission.
The next section was written by William Shelver
Between 1961 and 1971, the U.S. military in South Vietnam used more than 19 million gallons of herbicides for defoliation and crop destruction. This was done mostly to kill unwanted plants and to remove leaves from trees that otherwise provided cover for the enemy. Heavily sprayed areas included inland forests near the demarcation zone; inland forests at the junction of the borders of Cambodia, Laos, and South Vietnam; inland forests north and northwest of Saigon; mangrove forests on the southernmost peninsula of Vietnam; and mangrove forests along major shipping channels southeast of Saigon. Agent Orange was one such herbicide used in Vietnam. The name, “Agent Orange,” came from the orange stripe on the 55-gallon drums in which it was stored. 1
In the 1970’s some veterans became concerned that exposure to Agent Orange caused health problems. One of the chemicals in Agent Orange contained small traces of TCDD (dioxin), which caused a variety of illnesses in laboratory animals. More recent studies have suggested that the chemical may be related to a number of cancers and other health problems. The VA recognizes diseases such as multiple myeloma, birth defects, non-hodgkins lymphoma, Hodgkin’s disease, diabetes, prostate cancer, as well as respiratory cancer, skin cancer, and other various types of cancer as being caused from exposure to Agent Orange. In 1978, the Veterans Administration set up the Agent Orange Registry health examination program. Veterans who participate in this examination are asked about their possible exposure to herbacides in Vietnam, and a medical history is taken.1 Vietnam veterans who are interested in participating in this program should contact the nearest VA medical center for an examination. The veteran is informed of the results of the examination during a personal interview and gets a follow-up letter describing the findings. Sometimes a follow-up examination or additional laboratory tests are scheduled due to the possibility of previously undetected medical problems being present. This data is then entered into the VA Agent Orange Registry.
Due to the Veterans’ Health Care Eligibility Reform Act of 1996, the VA now supplies hospital care, medical services and may furnish nursing home care to veterans exposed to herbicides in Vietnam. The VA pays compensation to Vietnam veterans with injuries or illnesses incurred in or aggravated by their military service. VA can pay you monthly compensation if you are at least 10% disabled as a result of your military service. You can receive a monthly pension if you are a wartime veteran with limited income and you are permanently and totally disabled or at least 65 years old. There is no time limit to apply for Compensation and Pension benefits. Veterans do not have to prove that Agent Orange caused their medical problems to be eligible for compensation. Instead, the VA must determine that the disability is “service-connected.”1
For more information about the VA’s Agent Orange program call the toll-free helpline: 1-800-749-838. For disability compensation program information, call toll-free: 1-800-827-1000. For detailed information about all VA benefits and services, visit www.va.govSurvivors. Information specific to survivors is available. Select “Benefits,” then “Survivors’ Benefits”, or call 1-800-749-8387, or E-mail GW/AOHelpline@vba.va.gov.
There are also other resources available for Veterans with cancer and their families. Support can come from family and friends as well as health professionals, support groups, or a place of worship. Studies have found that support group participants have an improved quality of life, including their sleep and appetite.2 Cancer support groups are designed to provide a confidential atmosphere where cancer patients or cancer survivors can discuss the challenges that accompany the illness with others who may have experienced the same challenges, including practical problems such as managing side effects or returning to work after treatment. Support groups also provide a safe place for cancer patients to share their feelings. Support programs exist in a variety of formats and include individual or group counseling and support groups. Some groups are formal and focus on learning about cancer or dealing with feelings. Others are informal and social. The length of time groups meet can range from a certain number of weeks to an ongoing program. There are also other forms of support groups called self-help groups. Self-help groups are usually run by nonprofessionals who are affected by a particular situation. People who relate to a particular experience firsthand often have treatment-related tips that will be helpful to the patient. Some find initial diagnosis a difficult time to join a support group because the stories that other patients discuss can be overwhelming and upsetting.
©2006 William Shelver Used by permission
This next section is rather technical but it contains valuable information. It was written by one of my students, Monica Manatt. It contains information about Revlimid (lenalidomide) and then compares it to Thalamid (thalidomide). The conclusion is her personal opinion and is current as of December 2006.
Lenalidomide
GENERIC NAME: Lenalidomide
PROPRIETARY NAME: REVLIMID (Celgene)
THERAPEUTIC CLASS: Immune modulator
SIMILAR DRUGS: Thalidomide
INDICATIONS: Lenalidomide has an FDA labeled indication for multiple myeloma in combination with dexamethasone in patients who have received at least 1 prior therapy. Lenalidomide is also indicated for the treatment of patients with transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.3,4,6 See Table 1 for a comparison of the FDA labeled indications of lenalidomide and thalidomide.
Table 1: Comparison of FDA-Approved Indications for the Immune Modulators:6,8,9
|
Drug |
Trade Name |
Company |
FDA-Approved Indication |
Date of FDA Approval |
|
Lenalidomide |
Revlimid |
Celgene |
1. Myelodysplastic Syndrome 2. 2. Multiple Myeloma
|
1. 12/27/05 2. 6/29/06 |
|
Thalidomide |
Thalomid |
Celgene |
1. Multiple Myeloma 2. Erythema Nodosum (Prophylaxis & Treatment) |
1. 5/26/06 2. 7/16/1998 |
CLINICAL PHARMACOLOGY: The mechanisms of action of both lenalidomide and thalidomide are not fully understood. Lenalidomide is a thalidomide analogue that exhibits anti-neoplastic, immunomodulatory, and antiangiogenic properties. In peripheral blood, lenalidomide inhibits the secretion of pro-inflammatory cytokines and increases the secretion of anti-inflammatory cytokines. It was shown to be effective in inhibiting the growth of Namalwa cells, which is a human B cell lymphoma cell line with a deletion of one chromosome 5. Lenalidomide stops the growth of multiple myeloma cells by inducing cell cycle arrest and apoptosis. It has also been shown to inhibit cyclooxygenase-2 in vitro.3,4,6,7
Since thalidomide has been around and studied much longer than lenalidomide, more possible mechanisms of action have been identified: inhibition of angiogenesis by blocking basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); inhibition of the growth and survival of stromal cells; altering production/activity of cytokines involved in the growth and survival of myeloma cells through various mechanisms including inhibition of cyclooxygenase-2 (COX-2), inhibition of tumor necrosis factor-alpha (TNF–α), down regulation of interleukin 6 (IL-6), increased production of interleukin 10 (IL-10), enhancement of interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 12 (IL-12), inhibition of TNF-α-induced interleukin-8 (IL-8); altering the expression of adhesion molecules located on the surface of tumor cells and bone marrow stromal cells; and stimulation of T-cells, which help the immune system to attack tumor cells directly.3,5,8
PHARMACOKINETICS: In healthy individuals, the time to peak concentration levels of lenalidomide are reached between 0.625 to 1.5 hours. In patients with multiple myeloma, peak concentrations occur between 0.5 and 4.0 hours after the last dose. The Cmax and AUC increase proportionately with the dose following both single and multiple doses. Multiple dosing at the recommended dose does not result in accumulation of drug. In patients with multiple myeloma, the AUC is 57% higher than in healthy male volunteers. When lenalidomide is co-administered with food, the extent of absorption (AUC) does not change, but the maximal plasma concentration is decreased by 36%.3,4,6,7
Lenalidomide binds to plasma proteins approximately 30% of the time in vitro. The metabolic profile of lenalidomide is currently undefined. In healthy volunteers, 67% of lenalidomide is excreted as unchanged drug in the urine. Lenalidomide is excreted as partial or entirely active because the elimination of the drug exceeds the glomerular filtration rate. The elimination half life is approximately 3 hours.3,6,7 Thalidomide is eliminated via the kidneys as well but as <0.7% unchanged drug. The elimination half life for thalidomide varies depending upon the dose given and disease states, such as HIV-positive patients and patients with Hansen’s disease.3,8
Patients with impaired renal function need to be monitored carefully, since lenalidomide is primarily excreted via the kidneys. These patients have an increased risk for adverse reactions. Patients with renal impairment have been excluded in clinical trials.3,6 Dose adjustments are not necessary for patient with renal dysfunction taking thalidomide.3,8 Dose adjustments for lenalidomide do occur when patients have neutropenia and thrombocytopenia.3,6 See Tables 2-4 for dose adjustments of lenalidomide.
Table 2: Dose Adjustments for Lenalidomide for Multiple Myeloma Patients3,6
|
Multiple Myeloma |
Labs |
Action to Taken |
When Labs Improve |
Reoccurrence |
|
Neutropenia |
ANC< 1,000/mcL |
· Stop lenalidomide · Add granulocyte colony-stimulating factor |
ANC≥ 1,000/mcL · Resume at 25 mg daily when neutropenia is the toxicity · Resume at 15 mg daily if other toxicities exist |
· Stop lenalidomide and resume at 5 mg less than pervious dose · Do not dose below 5 mg daily |
|
Thrombocytopenia |
Platelets <30,000/mcL |
· Stop lenalidomide
|
Plts≥ 30,000/mcL · Resume at 15 mg daily |
· Stop lenalidomide and resume at 5 mg less than previous dose · Do not dose below 5mg daily |
|
Toxicities |
Other grade 3/4 toxicities
|
· Stop lenalidomide |
· Restart at next lower dose level when the toxicity is at or below grade 2 |
|
Table 3: Dose Adjustments for Lenalidomide for Myelodysplastic Syndrome Patients with Neutropenia3,6
|
Neutropenic Conditions |
Action to be Taken |
Adjustments to Dose |
|
Neutropenia WITHIN 4 weeks of starting 10 mg daily: baseline ANC ≥ 1000/mcL |
Stop lenalidomide for ANC < 750/mcL |
Resume at 5 mg daily when ANC returns to ≥ 1000/mcL |
|
Neutropenia WITHIN 4 weeks of starting 10 mg daily: baseline ANC < 1000/mcL |
Stop lenalidomide for ANC < 500/mcL |
Resume at 5 mg daily when ANC returns to ≥ 500/mcL |
|
Neutropenia AFTER 4 weeks of starting 10 mg daily |
Stop lenalidomide for ANC < 500/mcL for ≥ 7 days OR ANC < 500/mcL associated with fever |
Resume dose at 5 mg daily when ANC returns to ≥ 500/mcL |
|
Neutropenia DURING treatment with 5 mg daily |
Stop lenalidomide for ANC < 500/mcL for ≥ 7 days OR ANC < 500/mcL associated with fever |
Resume dose at 5 mg every other day when ANC returns to ≥ 500/mcL |
Table 4: Dose Adjustments for Lenalidomide for Myelodysplastic Syndrome Patients with Thrombocytopenia3,6
|
Thrombocytopenic Conditions |
Action to be Taken |
Adjustments to Dose |
|
Thrombocytopenia WITHIN 4 weeks of starting 10 mg daily: baseline Plts ≥ 100,000/mcL |
Stop lenalidomide for Plts < 50,000/mcL |
Resume at 5 mg daily when Plts return to ≥ 50,000/mcL |
|
Thrombocytopenia WITHIN 4 weeks of starting 10 mg daily: baseline Plts ≥ 60,000/mcL and < 100,000/mcL |
Stop lenalidomide when Plts fall to 50% of baseline value |
Resume at 5 mg daily when Plts return to at least 50,000/mcL |
|
Thrombocytopenia WITHIN 4 weeks of starting 10 mg daily: baseline Plts < 60,000/mcL |
Stop lenalidomide when Plts fall to 50% of baseline value
|
Resume at 5 mg daily when Plts return to at least 30,000/mcL |
|
Thrombocytopenia AFTER 4 weeks of starting 10 mg daily |
Stop lenalidomide for Plts < 30,000/mcL OR < 50,000/mcL associated with platelet transfusions |
Resume at 5 mg daily when Plts return to at least 30,000/mcL without hemostatic failure |
|
Thrombocytopenia DURING treatment with 5 mg daily |
Stop lenalidomide for Plts < 30,000/mcL OR < 50,000/mcL associated with platelet transfusions |
Resume at 5 mg daily every other day when platelets return to at least 30,000 without hemostatic failure |
COMPARATIVE EFFICACY:
There has been two dose escalation trials completed for lenalidomide in patients with relapsed and refractory multiple myeloma. The doses tested included 5, 10, 25, and 50 mg a day. There were no dose-limiting toxicities within the first 28 days. After 28 days, grade 3 myelosuppression was seen in patients taking 50 mg a day, leading to a maximal tolerated dose of 25 mg a day.1,2
Two randomized, multicenter, double-blinded, and placebo-controlled studies were conducted to evaluate the efficacy and safety of lenalidomide in patients with relapsed-refractory multiple myeloma. Patients either received lenalidomide plus dexamethasone or dexamethasone alone. Lenalidomide was dosed at 25 mg by mouth daily for 21 days plus placebo for days 22 through 28. Dexamethasone was dosed at 40 mg by mouth daily for days 1-4, 9-12, and 17-20, and then 40 mg by mouth for days 1-4 after 4 cycles had been completed. The primary endpoint for both studies was time to progression of disease, and the doses were decreased based on individual patient toxicities. The combination of lenalidomide/dexamethasone was significantly superior to dexamethasone alone. The median time to disease progression for the lenalidomide group in study 1 (n=341) was 11.1 months vs. 4.7 months for the dexamethasone alone group and 11.3 vs. 4.7 for study 2 (n=351) respectively (P=0.0001). The overall response rates for the lenalidomide group were 59.4% and 59.1% in studies 1 and 2, respectively, vs. 21.1% and 23.9% for the placebo/dexamethasone group (P=0.0001).1,2,3,6,7
A study has not been done comparing lenalidomide to thalidomide. In the studies described above, some of the patients had received and failed thalidomide as a previous therapy. This indicates that lenalidomide is able to overcome conventional drug resistance as well as resistance to thalidomide.2
As for myelodysplastic syndromes, a clinical trial was performed testing the efficacy and safety of lenalidomide in patients with transfusion-dependent anemia in low-risk or intermediate-1 risk with a 5q cytogenic abnormality or with additional cytogenic abnormalities. The 148 patients enrolled received either 10 mg daily or 10 mg daily for 21 days every 28 days. This study was not designed or powered to compare the efficacy of the two dosing regimens. Red blood cell (RBC) transfusion independence was defined as the absence of any RBC transfusion during any consecutive 56 days during the treatment period. Transfusion independence was seen in 99/148 (67%) patients (95% CI [59,74]). The median duration of patients receiving no transfusions was 44 weeks.3,8,7
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: Because of the structural similarity to thalidomide, a known human teratogen, and the lack of sufficient information lenalidomide has a pregnancy category X; therefore, it is contraindicated in women who are pregnant and those of childbearing potential, unless adequate precautions are taken to prevent pregnancy. Lenalidomide is also contraindicated in patients with a hypersensitivity to lenalidomide or any of its components.3,6,7
Lenalidomide can cause an increased risk in developing deep vein thrombosis, pulmonary embolism, neutropenia, and thrombocytopenia. There is a potential increase in the risk of toxicity in patients with renal impairment. Men who are sexually active must comply with mandatory contraception to prevent pregnancy.3,6,7
Lenalidomide has a black box warning for potential birth defects; therefore, there are special prescribing requirements that must be met, including enrolling in a program called RevAssist. Only prescribers and pharmacists registered with the program can prescribe and dispense the product. There are numerous requirements for female patients of childbearing age3,4,6,7
· Effective contraception for 4 weeks prior to therapy, during therapy, during dose interruptions, and 4 weeks after the discontinuation of therapy
· Two reliable forms of contraception should be used unless the patient practices continuous abstinence
· Two negative pregnancy tests before prescribing- 1st within 10-14 days and the 2nd within 24 hours before prescribing
· Pregnancy tests weekly for the 1st 4 weeks and during dose interruptions
· Pregnancy tests every 4 weeks after the 1st 4 weeks for regular menstrual cycles and every 2 weeks for irregular menstrual cycles
Male patients are required to use latex condoms for sexual activity.3,4,6,7
Lenalidomide also has black box warnings for hematologic toxicity (neutropenia and thrombocytopenia) and deep vein thrombosis and pulmonary embolism. Patients with myelodysplastic syndromes should have a complete blood count monitored weekly for the 1st 8 weeks of therapy and then monthly thereafter. Patients also need to be aware of the signs and symptoms of deep vein thrombosis and pulmonary embolism.3,6,7
Thalidomide also has a black box warning for human birth defects and venous thromboembolic events. It has a similar program to lenalidomide that must be followed for prescribing called S.T.E.P.S.3,8
ADVERSE REACTIONS: Lenalidomide was developed with the idea of creating a more potent and less toxic form of thalidomide. In clinical trials, lenalidomide showed less somnolence, constipation, and neuropathies, which are some of the most common toxicities of thalidomide.2 The common and serious adverse effects of lenalidomide therapy documented from clinical trials are listed below in Table 5.
Table 5: Common and Serious Adverse Effects of Lenalidomide3,6
|
Common Adverse Effects |
|
Occurrence Percentage |
|
Cardiovascular |
Peripheral edema |
21.1% |
|
Dermatologic |
Pruritus |
41.9% |
|
|
Rash |
35.8% |
|
Endocrine metabolic |
Hyperglycemia |
15% |
|
|
Hypokalemia |
11.3% |
|
Gastrointestinal |
Abdominal pain |
12.2% |
|
|
Constipation |
38.7% |
|
|
Diarrhea |
48.6% |
|
|
Dyspepsia |
13.9% |
|
|
Loss of appetite |
13.6% |
|
|
Nausea |
23.6% |
|
|
Vomiting |
10.1% |
|
|
Weight decrease |
18.2% |
|
Hematologic |
Leukopenia |
8.1% |
|
Musculoskeletal |
Arthralgia |
21.6% |
|
|
Back pain |
20.9% |
|
|
Cramp |
30.1% |
|
|
Muscle weakness |
15% |
|
Neurologic |
Dizziness |
20.8% |
|
|
Headache |
19.6% |
|
|
Insomnia |
32.1% |
|
|
Peripheral neuropathy |
8.1% |
|
|
Tremor |
19.7% |
|
Ophthalmic |
Blurred vision |
14.7% |
|
Psychiatric |
Asthenia |
23.4% |
|
|
Fatigue |
31.1% |
|
Renal |
Dysuria |
6.8% |
|
Respiratory |
Upper respiratory infection |
14.9% |
|
Serious Adverse Effects |
|
|
|
Cardiovascular |
Deep vein thrombosis |
7.8% |
|
Hematologic |
Anemia |
24.3% |
|
|
Febrile neutropenia |
5.4% |
|
|
Neutropenia |
27.7% to 58.8% |
|
|
Thrombocytopenia |
16% to 61.5% |
|
Respiratory |
Dyspnea |
20.2% |
|
|
Pneumonia |
11.5% |
|
|
Pulmonary embolism |
3.2% |
DRUG INTERACTIONS: Lenalidomide has a moderate interaction with digoxin causing an increase in the plasma drug concentrations of digoxin. Lenalidomide can increase the Cmax of digoxin by 14%; therefore, digoxin levels should be periodically monitored. In contrast, thalidomide has major drug interactions with darbepoetin alpha, dexamethasone, and docetaxel and a moderate drug interaction with zoledronic acid.3
DOSING:
Table 6: Comparative Doses of Lenalidomide vs. Thalidomide3,6,8
|
|
Lenalidomide |
Thalidomide |
|
To treat multiple myeloma in combination with dexamethasone |
25 mg orally daily with water on days 1 to 21 of a 28 day cycle, dose adjust for toxicities |
200 mg orally once daily in a 28 day treatment cycles |
|
To treat myelodysplastic syndrome |
10 mg orally once daily with water |
|
PRODUCT AVAILABILITY:
Table 7: Available Dosage Forms of Lenalidomide and Thalidomide3,6,8
|
|
Lenalidomide |
Thalidomide |
|
Strengths available |
5, 10, 15, and 25 mg |
50, 100, and 200 mg |
|
Dosage form |
Capsules |
Capsules |
COST:
The cost of lenalidomide
for a 21 day supply is approximately $5,670. The cost of a
thalidomide for a month supply is approximately $2,430.4
These prices can vary depending upon the institution.
CONCLUSION: Lenalidomide is an immunomodulator that works to fight against myelodysplastic syndrome and multiple myeloma via numerous possible mechanisms. In myelodysplastic syndrome it has extended independent-transfusion time. This analogue of thalidomide has also shown to be effective in treating multiple myeloma by extending the time to progression of disease even after thalidomide was no longer effective. Lenalidomide is not a cure, but it is a benefit to therapy in battling these devastating disease states. At this time, I would not recommend adding lenalidomide to a formulary. I would add thalidomide to a formulary before lenalidomide because it is more cost effective, and in the clinical trials, it was used as a prior therapy to lenalidomide. If patient would fail thalidomide, I would then recommend trying lenalidomide for treatment therapy.
REFERENCES:
1. Anderson KC, et al. Lenalidomide in Multiple Myeloma. Expert Rev. Anticancer Ther 2006; 6(8): 1165-1173.
2. Anderson KC, et al. Therapeutic Use of Immunomodulatory Drugs in the Treatment of Multiple Myeloma. Expert Rev. Anticancer Ther 2006; 6(9): 1239-1247.
3. Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, CO USA. Available at: http://0-www.thomsonhc.com.library.uchsc.edu:80 (cited:11/13/06).
4. Mosby’s Drug Consult 2006 [book on CD-Rom]. Jackson: Teton Data Systems; 2006. Based on : Dashley K, editor. Mosby’s Drug Consult. St. Louis: Mosby’s, Inc.; 2006. STAT!Ref Electronic Medical Library.
5. Myeloma Treatments. Multiple Myeloma Research Foundation. Available at: http://www.multiplemyeloma.org/treatments/3.04.html. Date accessed: November 14, 2006.
6. Revlimid® [Package Insert]. Summit, NJ: Celgene Corporation; 2006.
7. Sherritze, Sonja. Lenalidomide (Revlimid®). P&T Product Profiler Aug 2006; 31(8):1-21.
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An editorial about using aspirin for clot prevention with lenalidomide
Dr. Jack Hirsh, a co-chair of the prestigious American College of Chest Physicians Consensus Conference of Antithrombotic Therapy, has written an editorial about using aspirin for clot prevention with lenalidomide. He points out that both thalidomide and lenalidomide are associated with a high risk of clots in the veins particularly when used with high doses of dexamethasone. He points out that many practitioners feel that aspirin is effective in preventing these clots, particularly with lenalidomide. If this is correct it would be im