Understanding Thalidomide Therapy in Myeloma

Founded in 1990, the International Myeloma Foundation (IMF) is the first and largest organization focusing specifically on myeloma. The IMF’s reach extends to more than 525,000 members in 140 countries. The IMF is dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure through our four founding principles: Research, Education, Support, and Advocacy.

RESEARCH

The IMF is dedicated to finding a cure for myeloma, and we have a range of initiatives to make this happen. The International Myeloma Working Group, which emerged from the IMF’s Scientific Advisory Board established in 1995, is the most prestigious organization with more than 300 myeloma researchers conducting collaborative research to improve outcomes for patients while providing critically appraised consensus guidelines that are followed around the world. Our Black Swan Research Initiative® is bridging the gap from long-term remission to cure. Our annual Brian D. Novis Research Grant Program is supporting the most promising projects by junior and senior investigators. Our Nurse Leadership Board, comprised of nurses from leading myeloma treatment centers, develops recommendations for the nursing care of myeloma patients.

EDUCATION

The IMF’s webinars, seminars, and workshops provide up-to-date information presented by leading myeloma scientists and clinicians directly to patients and their families. We have a library of more than 100 publications for patients, care partners, and healthcare professionals. IMF publications are always free-of-charge, and available in English and select other languages.

SUPPORT The IMF InfoLine responds to your myeloma-related questions and concerns via phone and email, providing the most accurate information in a caring and compassionate manner. We also sustain a network of myeloma support groups, training hundreds of dedicated patients, care partners, and nurses who volunteer to lead these groups in their communities.

ADVOCACY We empower thousands of individuals who make a positive impact each year on issues critical to the myeloma community. In the U.S., we lead coalitions to represent the interests of the myeloma community at both federal and state levels. Outside the U.S., the IMF’s Global Myeloma Action Network works to help patients gain access to treatment.

Learn more about the ways the IMF is helping to improve the quality of life of myeloma patients while working toward prevention and a cure. Call us at 1.818.487.7455 or 1.800.452.CURE, or visit myeloma.org .

You are not alone

The International Myeloma Foundation (IMF) is here to help you. The IMF is committed to providing information and support for patients with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family members.

We achieve this through a broad range of resources available on our website myeloma.org, and through numerous programs and services such as seminars, webinars, workshops, and the IMF InfoLine, which consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

What you will learn from this booklet

Myeloma is a cancer that is not known to most patients at the time of diagnosis. To play an active role in your own medical care and to make good decisions about your care with your doctor, it is important and helpful to learn about myeloma, as well as its treatment options and supportive care measures.

The IMF’s Understanding-series publications address treatments for myeloma, supportive care measures, and the tests that are used to diagnose, monitor, and assess disease status throughout its course.

This booklet discusses thalidomide, an oral drug that was first used for the treatment of patients with myeloma in 1997. Thalidomide was the first immunomodulatory agent approved for myeloma.

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

To learn about myeloma in later disease settings, read the IMF’s publication Concise Review of Relapsed and Refractory Myeloma.

Words in bold+blue type are explained in the “Terms and definitions” section at the end of this booklet. A more comprehensive glossary can be found in the IMF’s publication Understanding Myeloma Vocabulary located online at glossary.myeloma.org.

If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources. All IMF publications are free-of-charge and can be downloaded or requested in printed format at publications.myeloma.org.

The emergence of thalidomide in myeloma

From 1957 to 1966, thalidomide was manufactured by a German company and was prescribed to pregnant women outside the U.S. to combat symptoms of morning sickness. When taken during the first trimester of pregnancy, thalidomide prevented the proper growth of the fetus. Only half of the affected children survived, and those who did had severe birth defects.

The risk to fetal development is why it is so important to prevent women who may be pregnant from being exposed to immunomodulatory agents.

Thalidomide was first approved by the U.S. Food and Drug Administration (FDA) in the 1960s for the treatment of erythema nodosum leprosum (ENL), an inflammatory condition seen in some patients with lepromatous leprosy.

Using thalidomide to treat myeloma is an idea that emerged in the 1990s. In 1997, Dr. Bart Barlogie conducted a small clinical trial for patients with advanced myeloma. In 2006, thalidomide was approved by the FDA for the treatment of patients with newly diagnosed myeloma in combination with the steroid dexamethasone. Thalidomide is active against myeloma and can produce lasting response in patients with different stages of myeloma, including newly diagnosed disease, myeloma that has not responded to other treatments, and myeloma that has relapsed.

Current use of thalidomide in myeloma

Currently, thalidomide is used infrequently in the U.S., but it is still sometimes used during late stage of disease, in cases of renal failure, or when the patient has low blood counts. Thalidomide is sometimes used in induction therapy and consolidation therapy.

Thalidomide continues to be used more often abroad. In the U.S., the FDA approval of thalidomide launched the era of “novel therapies” in myeloma, giving rise to a next generation of immune modulators with increased efficacy and reduced side effects, the drugs Revlimid® (lenalidomide) and Pomalyst® (pomalidomide).

However, Revlimid can cause low blood counts. For patients with low blood counts, thalidomide may be an alternative because it has a more minor impact on the bone marrow ’s ability to make new blood cells. Moreover, thalidomide may be a more affordable option for patients whose insurers cover the cost of Revlimid inadequately or not at all.

How thalidomide works

Thalidomide is an oral, small-molecule immunomodulatory agent that has both anti-inflammatory and anti-cancer activities. Immunomodulatory agents can modify, enhance, or suppress the functioning of the immune system.

Immunomodulatory agents inhibit inflammation by altering the levels of growth factors called cytokines and interleukins. Immunomodulatory agents kill cancer cells by enhancing the activation of specialized T cells (T lymphocytes) called natural killer (NK) cells and by inhibiting the growth of blood vessels upon which cancer cells depend for sustenance and growth.

Response to thalidomide therapy takes time. In myeloma, improvement is typically seen after about 3 months of treatment; however, improvement has also occurred as early as 2 weeks and as late as 8 months after initiating treatment. Once a response is achieved, your doctor will determine if ongoing maintenance therapy is appropriate.

Thalidomide is not chemotherapy. Immunomodulatory agents work very differently from chemotherapy agents, which kill cells that are dividing rapidly, including cancer cells as well as normal cells like hair cells and the cells of the mucosa lining the mouth and digestive tract.

How thalidomide is taken

Thalidomide is taken by mouth. Since you do not need to be at the doctor’s office or in a clinic or hospital to receive thalidomide, it is your responsibility to take thalidomide as directed by your doctor. It is crucial that you read and understand the information in this booklet and in any other materials your doctor provides. Therefore, before you begin taking thalidomide, we recommend that you also read a related IMF tip card, Adherence to Oral Cancer Therapy.

Dose and schedule of thalidomide

Your dose of thalidomide will be determined by your doctor based on a number of factors, including whether thalidomide is being given alone or in combination with other drugs as well as how thalidomide is tolerated by your body. To ensure that the most effective dose is given as safely as possible, your dose may be gradually increased over time. The dose may be modified only under the direction of your doctor.

Over the years, with the data gathered from clinical trials, doctors have learned to tailor the dose and schedule of thalidomide + dexamethasone [Td] combination therapy to improve patients’ quality of life. When quality of life improves, patients can adhere better to a treatment protocol, and in turn respond better to the treatment.

A study of low-dose versus high-dose thalidomide for advanced myeloma was published in 2012 in the European Journal of Hematology by Intergroupe Francophone du Myélome (IFM), the French myeloma research group. The study concluded that “low-dose thalidomide 100 mg/day has significant

activity in advanced myeloma with an improved safety profile.” Thalidomide is rarely prescribed at doses greater than 100 mg/day.

Dexamethasone appears to increase or “boost” the ability of other agents to destroy myeloma cells, thereby improving response to treatment. However, dexamethasone is associated with many short-term and long-term side effects. Many factors are taken into consideration by your myeloma doctor when determining your dose of dexamethasone, including age and fitness.

The use of low-dose dexamethasone has been well established. Dexamethasone is usually prescribed at a dose of 20 mg to 40 mg once-weekly. For patients who cannot tolerate these doses, dexamethasone has proven to be effective at doses as low as 4 mg once-weekly. For more information about dexamethasone, read the IMF’s publication Understanding Dexamethasone in the Treatment of Myeloma.

Thalidomide in the maintenance setting

Thalidomide has been tested extensively in the maintenance setting. In the British MRC IX study in 2012, thalidomide was demonstrated to improve progression-free survival (PFS), but not overall survival (OS) in newly diagnosed patients who had received a wide variety of prior therapies. In that study, maintenance thalidomide was given at 50 mg/day, increasing to 100 mg/day after 4 weeks, if tolerated, and continuing until progression. Thalidomide at the low 50–100 mg/day dose level remains an option for maintenance therapy.

In 2017, a study published in the journal Leukemia compared maintenance therapy with thalidomide + Velcade to either thalidomide alone or recombinant interferon alpha-2b alone in newly diagnosed myeloma patients after their induction therapy. Recombinant interferon alpha-2b is an antiviral and anticancer drug with immune-modulating effects. After a median follow-up of 58.6 months, median PFS was significantly longer with thalidomide + Velcade than with either of the other two therapies alone. There was no significant difference in overall survival between the three maintenance therapy arms.

Thalidomide in clinical trials

A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat cancer and to answer scientific questions.

Thalidomide continues to be studied in clinical trials. For up-to-date information, contact the IMF InfoLine or visit clinicaltrials.gov. For a broader discussion about clinical trials, read the IMF’s publication Understanding Clinical Trials in Myeloma.

Possible side effects of thalidomide

The REMS program

Thalidomide can cause severe birth defects or the death of a developing fetus. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Thalidomide may be detected in male sperm; therefore, both males and females of reproductive potential must follow strict rules for birth control while taking thalidomide.

In the U.S., the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program is a mandatory safety measure for medications with serious safety concerns. The aim of the REMS program is to help ensure that the benefits of the medication outweigh its risks. To minimize the risk of exposure for an unborn child, the thalidomide REMS program includes the following requirements:

¡ Male and female patients must provide informed consent , complete confidential enrollment, and complete follow-up surveys throughout treatment with thalidomide.

¡ Females of reproductive potential must have pregnancy tests every week during the first month of thalidomide therapy. Afterwards, females with regular menstrual cycles must have pregnancy tests monthly, and females with irregular menstrual cycles must have pregnancy tests every 2 weeks. Females must receive contraceptive counseling and use 2 methods of birth control 4 weeks before, during, and at least 4 weeks after completing thalidomide therapy.

¡ Males with female partners of reproductive potential must use a latex condom during and until at least 4 weeks after completing thalidomide therapy.

Drowsiness

Thalidomide often causes drowsiness, a feeling of being sleepy and lethargic. Talk to your doctor about methods that may help relieve drowsiness, such as taking thalidomide at bedtime, avoiding alcohol, avoiding other drugs that may contribute to feelings of drowsiness, and taking medication prescribed by your doctor to alleviate drowsiness.

Drowsiness may impair your mental and physical abilities, and may be problematic or dangerous in certain situations. For example, you may need help from your care partners with tasks such as driving a car.

Peripheral neuropathy

Peripheral neuropathy (PN) is a serious condition that affects nerves in the hands, feet, lower legs, and/or arms. Patients may experience PN from the effects of the myeloma itself and/or from treatments for myeloma such as thalidomide. Symptoms may include a feeling of numbness, tingling, burning, and/or pain.

Alert your doctor as soon as you begin experiencing any symptoms of PN. Typically, PN from thalidomide occurs after a long period of taking this drug, but it can occur sooner. Ask your doctor about walking and other forms of exercise. Avoid tight shoes and socks with elastic. Your doctor may reduce your dose of thalidomide or prescribe additional medications. If your PN is severe, thalidomide therapy may need to be discontinued.

Dizziness

Dizziness may occur during treatment with thalidomide. Sitting up and waiting a few minutes before standing or getting out of bed may help reduce dizziness. Report any occurrences of dizziness to your doctor.

Constipation

The medical definition of constipation is 3 or fewer bowel movements within 1 week. The stool may be hard, dry, and difficult to pass. You may also experience stomach cramps or bloating. Constipation may occur during treatment with thalidomide, but it is rarely severe. Prevention is the key to management.

Discuss with your doctor strategies that may help alleviate constipation, such as how much fluid you should drink daily, if consuming dietary fiber is appropriate, and which form of exercise may be helpful. Do not take stool softeners or laxatives without first asking your doctor. If your constipation is severe, your doctor may lower your dose of thalidomide or it may be temporarily discontinued.

Rash

A rash may develop while taking thalidomide. A mild rash is red or discolored skin, with or without raised bumps, which usually begins on the body and spreads to the arms and legs. Ask your doctor if taking antihistamines or topical steroids is appropriate for your rash. Using oatmeal soap and calendula or cocoa butter cream may help with dry skin.

Some rashes are a potentially serious reaction to thalidomide. Rare reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Symptoms of Stevens-Johnson syndrome include persistent fever, rash, blisters, or red splotches on the skin and blisters in the mouth, eyes, ears, nose, and genital area. TEN is characterized by blistering and peeling of large sections of skin. Contact your doctor immediately if a fever or a drop in blood pressure occur.

Leukopenia

Your doctor will monitor your blood counts for leukopenia, which is a decrease in white blood cells (WBC). If your WBC count becomes too low, your dose of thalidomide may be lowered or interrupted.

Other side effects

Other side effects have been reported, although infrequently. Promptly report to your doctor all the side effects you experience while receiving treatment for myeloma. In addition, any changes in your overall health or well-being should also be reported to your doctor.

In closing

This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF intends only to provide you with information that will guide you in discussions with your healthcare team. To help ensure effective treatment with good quality of life, you must play an active role in your own medical care.

We encourage you to visit myeloma.org for more information about myeloma and to contact the IMF InfoLine with your myeloma-related questions and concerns. The IMF InfoLine consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

Terms and definitions

The following selected terms are used in this booklet, while a more complete compendium of myeloma-related terms can be found in the IMF’s publication Understanding Myeloma Vocabulary located online at glossary.myeloma.org.

Bone marrow: The soft, spongy tissue in the center of bones that produces white blood cells, red blood cells, and platelets. When myeloma is growing, myeloma cells build up in the bone marrow.

Cancer: A term for diseases in which malignant cells divide without control. Cancer cells can invade nearby tissues and spread through the bloodstream and lymphatic system to other parts of the body.

Cell: The basic unit of any living organism. Millions of microscopic cells comprise each organ and tissue in the body.

Consolidation therapy: Treatment that may be given to deepen the patient’s response after an autologous stem cell transplant (ASCT). Usually, consolidation therapy is the same regimen used for induction therapy.

Cytokine: A protein that circulates in the bloodstream, usually in response to infection. Cytokines can stimulate or inhibit the growth or activity in other cells.

Efficacy: Ability of treatment to produce a beneficial effect.

Frontline therapy: A general term for the initial treatment used in an effort to achieve response in a newly diagnosed myeloma patient. See “Induction therapy ” and “ Response or remission.”

Growth factors: Drugs that stimulate blood stem cells to both grow and be released into the bloodstream.

Immune system: A complex network of cells, tissues, organs, and the substances they make. The immune system helps the body defend itself by destroying infected and diseased cells and removing cellular debris, while protecting healthy cells.

Induction therapy: The initial treatment given to a patient in preparation for an autologous stem cell transplant (ASCT). See “ Frontline therapy ” and “ Line of therapy.”

Informed consent: The process that requires a doctor to give a patient enough information about a procedure, strategy, or clinical trial – including the issues of risks, benefits, alternatives, and potential costs – for the patient to make an informed decision about whether or not to consent.

Interferon: A naturally produced hormone (cytokine) released by the body in response to infection or disease that stimulates the growth of certain disease-fighting blood cells in the immune system. Interferon can be artificially produced by genetic engineering techniques and used as a form of immunotherapy.

Interleukin: A naturally produced chemical released by the body, or a substance used in biological therapy. Interleukins stimulate the growth and activities of certain kinds of white blood cells. Interleukin-2 (IL-2) is a type of biological response modifier that stimulates the growth of certain blood cells in the immune system that can fight some types of cancer. Interleukin-6 (IL-6) is a cytokine that is a potent stimulus to osteoclast and plasma cell growth.

Line of therapy: A term used to calculate the number of therapies a patient has received. A line of therapy is 1 or more complete cycles of a regimen that can consist of a single agent, a combination of several drugs, or a planned sequential therapy of various regimens. Also see “ Induction therapy.”

Maintenance therapy: Drug or drugs given to patients to prolong remission.

Multiple myeloma: A cancer of the bone marrow plasma cells, white blood cells that make antibodies. Cancerous plasma cells are called myeloma cells.

Natural killer (NK) cell: NK cells are a type of white blood cell responsible for tumor surveillance. NK cells are able to recognize cells that have been transformed by tumors and can induce a strong response against tumors through the release of cytokines. NK cells can do this without the need of a “trigger” antigen on the tumor, which can result in a faster defensive response. In patients with active myeloma, NK cells are reduced both in number and in function.

Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer.

Overall survival (OS): The median number of individuals in a group who are alive after a particular duration of time. OS is often used as a measure of treatment efficacy in clinical trials. The lengthening duration of OS in myeloma trials makes it a difficult endpoint to use, leading to the effort to validate minimal residual disease (MRD) status as a new endpoint.

Progression-free survival (PFS): The length of time during and after the treatment of myeloma that a patient lives with the disease but the myeloma does not get worse. In a clinical trial, PFS is one way to measure how well the treatment is working. See “ Progressive disease.”

Progressive disease: Myeloma that is becoming worse or relapsing, as documented by tests. Defined as an increase of ≥ 25% from the lowest confirmed response value in the myeloma protein level and/or new evidence of disease.

Relapse: The reappearance of signs and symptoms of myeloma after a period of improvement. Patients with relapsed disease have been treated, then developed signs and symptoms of myeloma at least 60 days after treatment ended. Most clinical trials for advanced myeloma are for patients with relapsed and/or refractory disease.

Response or remission: Interchangeable terms to describe the complete or partial disappearance of the signs and symptoms of cancer.

• Stringent complete response (sCR) – sCR is CR (as defined below) plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

• Complete response (CR) – For myeloma, CR is negative immunofixation on serum (blood) and urine, and disappearance of any soft tissue plasmacytomas, and ≤ 5% plasma cells in bone marrow. CR is not the same as a cure.

• Very good partial response (VGPR) – VGPR is less than CR. VGPR is serum M-protein and urine M-protein detectable by immunofixation

but not on electrophoresis, or 90% or greater reduction in serum M-protein, plus urine M-protein less than 100 mg per 24 hours.

• Partial response (PR) – PR is a level of response in which there is at least a 50% reduction in M-protein, and reduction in 24-hour urinary M-protein by at least 90% (or to less than 200 mg per 24 hours).

Side effect: An unwanted or unexpected effect caused by a drug. Also known as adverse reaction or adverse event (AE).

Stage: The extent of myeloma in the body.

Steroid: A type of hormone. Steroidal hormones are produced by the body. Synthetic analogues (equivalents) of some steroids can be manufactured in a laboratory. Dexamethasone, prednisone, and methylprednisolone are synthetic steroids that have multiple effects and are used for many conditions, including myeloma.

T cell (T lymphocyte): A type of white blood cell that originates in the bone marrow but matures in the thymus, a gland beneath the breastbone (sternum). T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on the cell surface. T cells can recognize and bind to specific antigens, thereby triggering an immune response.

White blood cells (WBC): General term for a variety of leukocytes responsible for fighting invading germs, infections, and allergy-causing agents. These cells begin their development in bone marrow and then travel to other parts of the body. Specific white blood cells include neutrophils, basophils, eosinophils, lymphocytes, and monocytes.

INTERACTIVE RESOURCES AT A GLANCE

Use the hyperlinks and web addresses included in this publication for quick access to resources from the IMF.

Contact the IMF InfoLine with your myeloma-related questions and concerns infoline.myeloma.org

about FDA-approved therapies for myeloma medications.myeloma.org

Diversity and inclusion are integral aspects of the myeloma community diversity.myeloma.org

IMF booklets, tip cards, guides, and periodicals –subscribe to stay in the know! publications.myeloma.org

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