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Management of Thalidomide Toxicity in Multiple Myeloma

Thalidomide is active in patients with relapsed and refractory multiple myeloma. Although it is generally well tolerated at daily doses up to 400 mg, thalidomide may cause a number of different adverse effects, including sedation, constipation, rash, peripheral neuropathy, and others. By starting thalidomide at a low dose (50 mg once daily at 1 to 2 hours before bedtime) and then gradually escalating the dose in 50-mg increments each week, it is possible to minimize many of these adverse effects. In addition, other strategies may be implemented to prevent or effectively manage some adverse effects, such as using a mild laxative to manage constipation and correcting any vitamin B12 and folate deficiencies to reduce neuropathic symptoms. Nurses must be proactive in recognizing the adverse effects associated with thalidomide and then take appropriate steps to manage them in order for patients to realize the full benefits of this agent.

In order to prevent potential birth defects and ensure the safe use of thalidomide, the System for Thalidomide Education and Prescribing Information (STEPS®) has been implemented in conjunction with the Food and Drug Administration (FDA) and several advocacy groups. Zeldis 1999 The critical period of thalidomide-induced teratogenicity is thought to occur between 34 and 50 days after the last menstrual cycle. Lenz 1962 Accordingly, thalidomide should never be used by pregnant women or those considering pregnancy. Women of childbearing potential may be treated with thalidomide providing they abstain from sexual intercourse or use 2 methods of birth control, 1 of which should be an effective barrier method. The STEPS® program includes pregnancy testing and contraception for female patients and contraceptive counseling for both male and female patients. It requires that all patients provide informed consent before qualifying for thalidomide therapy and complete telephone surveys every 28 days during treatment. Physicians, physician assistants, and advanced registered nurse practitioners must also register with the STEPS® program, indicating that they will comply with these requirements, before they can prescribe thalidomide. The registration process involves a telephone survey and a written registration form that can be faxed to the manufacturer (Celgene Corporation). Zeldis 1999 Thalidomide is available in 50-mg white, hard-gelatin capsules imprinted with the word “Celgene.” Thalidomide is supplied in boxes of 6 prescription packs of 14 capsules each for a total of 84 capsules per box. Thalidomide PI Prescriptions are written for a 28-day supply without any refills.

Management of Adverse effects

In general, adverse effects are usually mild to moderate in severity and related to the thalidomide start, and cumulative dose.

Sedation

Thalidomide frequently causes drowsiness and somnolence, particularly at doses of 200 mg or higher. Patients with poor performance status of 3 or 4 tend to be more susceptible to this adverse effect according to the use of thalidomide at the Cleveland Clinic( http://www.clevelandclinic.org/myeloma ) with multiple myeloma patients. Signs and symptoms associated with sedation include dizziness, weakness, fatigue, unsteadiness, confusion, blurred vision, and memory loss. Sedation can be minimized by gradually increasing the thalidomide dose by 50 mg per week in those with performance status of 2 or worse and by 50 to 100 mg per week in those with performance status of 0 or 1. The sedative effects usually decline over time, and most patients become tolerant after continued treatment for several weeks. The sedative effects should be allowed to diminish before escalating the dose to the next level.

Thalidomide administration is not recommended during the daytime because of its sedative properties. Instead, it should be given in the evening 1 or 2 hours before retiring. This dosing strategy is generally effective in minimizing drowsiness and lethargy in the morning. However, if the patient is increasingly lethargic in the early morning hours, thalidomide should be taken earlier in the evening. If this change fails, dosing adjustments may be necessary, such as a dose reduction followed by a more gradual dose escalation every 2 weeks. Patients should be warned about the risks of driving or operating heavy machinery while receiving thalidomide. To help reduce dizziness, patients should increase fluid intake to 8 to 10 glasses per day, and they should be advised to change positions slowly. Hussein 2000 For example, patients should sit upright for several minutes before standing from a recumbent position. Hussein 2000 Finally, it is important to ensure that patients avoid other medications that can worsen the sedative effects of thalidomide, including alcohol, sedatives, tranquilizers, and antidepressants.

Constipation

With the appropriate use of bowel regimens at the initiation of thalidomide therapy in myeloma patients at the Cleveland Clinic , the occurrence of constipation occurs is virtually not present. This complication can be incapacitating without the appropriate care, because many patients are also receiving narcotics. Together, thalidomide and narcotics decrease bowel motility. Prevention is the key to constipation management. Patients should be advised to increase their intake of fluid and dietary fiber. Stool softeners/laxatives, such as Senokot-S, psyllium, milk of magnesium, or docusate sodium, may also be started at the beginning of thalidomide therapy in order to achieve regular bowel movements. Exercise may reduce constipation and should be encouraged as tolerated. More aggressive therapy, including use of suppositories and enemas, may be considered providing the patient is adequately hydrated. In severe cases, intermittent dosing or a dose reduction may be necessary until the constipation has resolved.

Rash

Two different types of rashes may occur in patients during thalidomide therapy. The more common rash, which usually occurs within the first 2-6 weeks of treatment, is typically non-pruritic, erythematous, and macular, generally starting on the trunk and then spreading to the back and proximal extremities. Hasslet 1997 In the absence of systemic signs and symptoms, this rash should be managed symptomatically by using soothing creams, and if necessary antihistamines, or topical corticosteroids. A significant proportion of multiple myeloma patients treated at the Cleveland Clinic develops a mild asymptomatic rash that does not require any specific therapy other than monitoring. This form of rash often resolves with continued therapy.

The presence of pruritic rash, fever, eosinophilia, or reduced blood pressure may indicate a potentially serious reaction to thalidomide. Thalidomide PI Such patients should be monitored carefully, and thalidomide should be discontinued until a full clinical evaluation has been completed. Those patients should not be re-challenged with thalidomide, as the risk of severe allergic reaction in the form of Stevens Johnson is highly. Thalidomide should not be resumed if the rash is exfoliative, purpuric, or bullous, or if Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN) is suspected. Stevens-Johnson syndrome generally presents with sore throat, malaise, fever, and erosions of mucous membranes followed several days later by the development of small blisters on purpuric lesions and subsequently by the detachment of the outer epidermal layer. Stern 2001 Up to 10% of the body surface area may detach. TEN is the most serious skin reaction; it usually develops acutely with lesions similar to those seen in Stevens-Johnson syndrome, resulting in epidermal detachment of more than 30% of the body surface. Stern 2001

Peripheral Neuropathy

Peripheral neuropathy is a common and potentially severe adverse effect of thalidomide therapy occurring in as many as 80% of the patients. Thalidomide PI The incidence of neuropathy appears to be related to the dose and the duration of therapy. Zomas 2000. This toxicity presents initially as numbness, tingling, pain, or burning of the toes and feet and subsequently of the fingers and hands. It may be described as a sensation of “pins and needles.” These symptoms usually improve after the thalidomide is discontinued; however in occasional cases the symptoms and signs are not reversible. The relationship between the cumulative thalidomide dose and neuropathy is unclear.

Peripheral neuropathy is usually reversible upon discontinuation of thalidomide, but the symptoms may resolve slowly in some patients or not at all in others.Wulff 1985, Tseng 1996 Younger patients tend to recover more quickly and completely than those over 60 years of age. Patients who were treated previously with chemotherapy, particularly with drugs that may cause neuropathy on their own, such as vincristine, are at increased risk of neuropathy during thalidomide therapy. Approximately 40% of myeloma patients have vitamin B12 and folate deficiency.Beckmann 1995 By monitoring and correcting these deficiencies, it is often possible to minimize or eliminate neuropathic symptoms. (Beckmann 1995) Neuropathy may be increased in patients with peripheral nerve problems, such as amyloid nerve damage or diabetes mellitus.

Patients should be monitored monthly for signs of peripheral neuropathy during the first 3 months of therapy and periodically thereafter. Thalidomide PI Reducing the dose or temporarily discontinuing treatment will alleviate neuropathic symptoms in the majority of cases within 2 to 3 weeks. Treatment may be restarted only if symptoms have resolved. Avoiding cramped positions and pressure points may also be helpful. Another option is to give patients a trial of low-dose gabapentin (Neurontin®) starting at 300 mg t.i.d. and potentially escalating it to a total daily dose of 3600 mg.

Musculoskeletal Effects

Based on the Cleveland Clinic experience of patients with multiple myeloma taking thalidomide, achiness and muscle weakness is one of the most frustrating adverse effects of thalidomide, usually occurring after patients have received therapy for several weeks. These symptoms can be minimized or eliminated by increasing fluid intake and performing a regular exercise routine. In patients with increased cramping in their extremities, the administration of glucosamine sulfate 500 mg t.i.d. may help to relieve pain.

Neutropenia

A reduction in white blood cell counts may occur in some patients receiving thalidomide. According to product labeling, thalidomide therapy should not be initiated in patients who have an absolute neutrophil count (ANC) <750/mm3, and it should be interrupted if clinically appropriate in patients with persistent reductions in ANC below this level. Thalidomide PI accordingly, laboratory testing should be conducted on a regular basis. In the experience of the Cleveland Clinic myeloma group, the occurrence of neutropenia has not resulted in an increased incidence of infection, and consequently the thalidomide dose has not had to be changed or interrupted. In clinical studies conducted there, the dose of thalidomide is not adjusted based on the hematologic status.

Deep Vein Thrombosis

Deep vein thrombosis may occur rarely with single-agent thalidomide. In the study of 169 patients with multiple myeloma, the incidence of deep vein thrombosis was 1%.Barlogie 2001 However, the risk of deep vein thrombosis is much higher if patients are treated with thalidomide in combination with chemotherapy. In a randomized controlled trial of patients with newly diagnosed multiple myeloma, deep vein thrombosis occurred in 28% of patients receiving thalidomide in combination with a multidrug chemotherapy regimen but in only 4% of those receiving chemotherapy alone. Zangari 2001 By introducing anticoagulation therapy with low-molecular weight heparin followed by warfarin (to achieve an international normalized ratio of 2.5 to 3), it is possible to continue thalidomide therapy in a majority of patients. During thalidomide treatment, nurses should evaluate whether signs and symptoms of deep vein thrombosis are present, including swelling or inflammation in the lower extremities, leg cramping or pain, abnormal breath sounds, or chest pain. Available unpublished data from this institution shows that non of 100 relapsed refractory patients treated with Thalidomide in combination with different chemotherapy regimen have developed deep venous thrombosis, moreover non of the newly diagnosed patients that have received thalidomide with non Adriamycin containing chemotherapy.

Miscellaneous Adverse effects

Patients may also experience several nonspecific adverse effects, including mood changes, confusion, “buzzing in the ears,” dry mouth, headache, dry skin, itching, brittle nails, thyroid problems, changes in heart rate, hypotension, and peripheral edema. When an adverse effect becomes problematic, then thalidomide should be withheld and the adverse effect investigated further. Some of these effects can be prevented or minimized by simple precautions. For example, patients with multiple myeloma should be kept well hydrated in order to prevent any hypotensive effects. Concomitant use of antihypertensive agents may contribute to or exacerbate these hypotensive symptoms, and accordingly, a reduction in the dose of the concomitant medication may be appropriate. Peripheral edema, which is generally mild and short lived, should be treated by intermittently elevating the extremities, resting supine for several hours each day, and using elastic stockings before rising from bed in the morning. In more severe cases, diuretics may be helpful or the dose of thalidomide may be reduced or withheld.

Thalidomide Dose

The dose, schedule, and duration of thalidomide treatment have varied considerably in clinical trials of patients with multiple myeloma. At the Cleveland Clinic, thalidomide is started at a dose of 50 mg, which is given in the evening about 1 to 2 hours before retiring. The dose is escalated in 50-mg increments each week until a maximum of 400 mg daily has been achieved. When patients experience an increased amount of adverse effects, thalidomide is lowered to the previous dose and then increased more slowly. In the experience of the Cleveland Clinic, this dosing strategy is associated with fewer adverse effects than regimens in which the starting dose is higher or dose escalations are made in larger increments. Usually when thalidomide is prescribed, Senakot-S is also prescribed to help maintain a good bowel regimen. Patients are encouraged to increase fluid intake and to eat a well-balanced meal.

 

 

Conclusion

On the basis of clinical trials as well as experience at many medical centers, thalidomide can benefit patients with relapsed and refractory multiple myeloma. A low starting dose and slow escalation of thalidomide results in a better tolerance to the therapy, and allow patients to receive a fair trial of the drug. As additional clinical trials are conducted, the role of thalidomide alone and in combination with other drugs will become more clearly defined. Patients receiving thalidomide may experience a variety of different adverse effects, and if managed inappropriately, these can limit the delivery of optimal dosages of the drug. Compared to the adverse effects of standard therapies, however, the toxicities associated with thalidomide are mild and very manageable. Accordingly, nurses must be proactive in recognizing adverse effects and taking appropriate steps to manage them.    

 

 

References:

 

  1. Barlogie, B., Desikan, R., Eddlemon, P., Spencer, T., Zeldis, J., Munshi, N., Badros, A., Zangari, M., Anaissie, E., Epstein, J., Shaughnessy, J., Ayers, D., Spoon, D., & Tricot, G. (2001a). Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood, 98, 492-494.
  1. Barlogie, B., Zangari, M., Spencer, T., Fassas, A., Anaissie, E., Badros, A., Cromer, J., & Tricot, G. (2001b). Thalidomide in the management of multiple myeloma. Seminars in Hematology, 38, 250-259.
  1. Beckmann MJ, Hussein MA, Lichtin A, Jacobson DW, Manteuffel L and Green R. (1995). Low Serum Vitamin B12 in Patients with Plasma Cell Myeloma Is Associated with Plasma Cell Myelomawith True Functional Cobalamin Deficiency. American Journal of Clinical Pathology, 140:350.
  1. Hasslett, P.A., Tramontana J., Burroughs M., Hempstead, M., & Kaplan G. (1997). Adverse reactions to thalidomide in patients infected with human immunodeficiency virus. Clinical Infectious Diseases, 24, 1223-1227.
  1. Hussein, M.A. (2000). Research on thalidomide in solid tumors, hematolgic malignancies, and supportive care: introduction. Oncology, 14(suppl 12), 9-15.
  1. Hussein, M.A. (2001). Patient management issues with thalidomide and myeloma. Presented at: VIIIth International Myeloma Workshop; Banff, Alberta, Canada; May 4-8, 2001.
  1. Lenz, V.W., Knapp, K. (1962). Die thalidomide embryopathic. Deutsche Medizinische Wochenschrift, 87, 1232-1242.
  1. Stern, R.S., Chosidow, O.M., & Wintroub, B.U. (2001). Cutaneous drug reactions. In E. Braunwald, A.S. Fauci, D.l. Kasper, S.L. Hauser, D.L. Longo, & J.L. Jameson (Eds.), Harrison’s Principles of Internal Medicine, 15th ed. (pp. 336-342). New York: McGraw-Hill.
  1. Thalomid® Capsules (thalidomide) product insert. Celgene Corporation, Warren, NJ; November, 2001.
  2. Wulff, C.H., Høyer, H., Asboe-Hansen, G., & Brodthagen, H. (1985). Development of polyneuropathy during thalidomide therapy. British Journal of Dermatology, 112, 475-480.
  1. Zangari, M., Anaissie, E., Badros, A., Desikan, R., Gopal, A.V., Morris, C., Toor, A., Siegel, E., Fink, L., & Tricot, G. (2001). Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood, 98, 1614-1615.
  1. Zeldis, J.B., Williams, B.A., Thomas, S.D., & Elsayed, M.E. (1999). S.T.E.P.S.™: a comprehensive program for controlling and monitoring access to thalidomide. Clinical Therapeutics, 21, 319-330.
  1. Zomas A, Anagnostostopoulos N, Dimopoulos MA. (2000). Successful treatment of multiple myeloma relapsing after high-dose therapy and autologous transplantation with thalidomide as a single agent. Bone Marrow Transplant 25:1319-1320.

 

 

 
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