The adverse effects of thalidomide in relapsed and refractory patients of multiple myeloma

J. K. Grover1,+, G. Uppal1 and V. Raina2

1 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi; 2 Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

Received 25 October 2001; revised 21 February 2002; accepted 27 March 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Thalidomide has shown efficacy in relapsed or refractory patients of multiple myeloma (MM). We present the adverse effect profile of thalidomide in 23 relapsed or refractory MM patients treated with this drug over a period of 15 months. Constipation (100% incidence) and sedation (87%) were the most common adverse effects. Neuropathy had low incidence and was late in onset (>12 months). Tolerance developed to sedation, constipation and skin lesions. All the adverse drug reactions were tolerable and did not warrant decrease or termination of therapy, except for peripheral neuropathy. Contrary to Western reports, peripheral neuropathy in Indian patients developed at a cumulative dose of 200 g or more after 10 months or more of therapy. Therapy was discontinued in one patient due to marked elevation of liver enzyme that was later attributed to acute hepatitis C infection. Only one patient dropped out of the trial for unknown reasons. Overall, thalidomide was found to be a relatively safe drug that can be used over a prolonged period of time.

Key words: adverse reaction, dose–duration relationship, multiple myeloma, thalidomide


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Multiple myeloma (MM) accounts for approximately one-tenth of all hematological malignancies, and its incidence is increasing [1]. The current treatment regimens provide only temporary remission, lasting on average ~60.5 months [2]. It has become imperative to look for effective therapies in refractory and relapsed cases. Thalidomide has shown encouraging results in relapsed or refractory MM patients [36].

The worldwide withdrawal of thalidomide in the early 1960s was based on its unwanted teratogenic effects and not because of ineffectiveness; this study was undertaken to assess the safety of high doses (800 mg/day) of thalidomide given over a long period (>15 months) in Indian patients with refractory or relapsed MM.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Twenty three patients of both sexes (16 male, seven female) with ages ranging between 35 and 72 years suffering from primary refractory disease (non-responders to chemotherapy, n = 5), relapsed disease (initially responders but subsequently with progressive MM, n = 13), or patients with incomplete or minimal response to primary chemotherapy (n = 5) but not suffering from any other malignancy or other life-threatening condition were selected from the outpatient department of the Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. The patient profile is given in Table 1. Patients with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >100 IU were excluded. A pregnancy test was carried out in all females before the start of therapy, and these patients were advised to use double contraceptive measures during the trial. An open trial consent (according to WHO guidelines and the Grunenthal Laboratory) was obtained from the patients before initiating therapy. Patients were started on thalidomide 200 mg/day, followed by an increase of 200 mg fortnightly to a maximum tolerated dose of 800 mg/day. During the course of therapy, intensive adverse drug reaction (ADR) monitoring was carried out using voluntary filling of the performa by the patient every 15 days, listing all possible adverse effects from the checklist. In addition, a history was obtained along with clinical, biochemical and hematological evaluation of the patient. Renal and liver function tests were performed fortnightly during the course of therapy.


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Table 1. Profile of patients included in the trial (n = 23)
 
In event of an ADR, these patients were evaluated by specialists in specific fields to assess the cause–effect relationship of the adverse effect. Patients have been evaluated for 15 months to date.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
The efficacy of thalidomide in terms of ‘m’ proteins is given in Table 2. Type A reactions were reported in 100% of patients; however, type B reactions were reported in only 22%.


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Table 2. Efficacy of thalidomide as assessed on the basis of ‘m’ proteins
 
Table 3 shows the relationship of ADRs with dose and duration of thalidomide, respectively. Constipation was reported in 100% of patients; in 78.26% it occurred at a dose of 200 mg/day within 2–4 days of initiation of therapy. It was more marked in the elderly, and less severe and more tolerable in active and mobile patients. Increase in dose did not increase the severity of constipation. In 21 patients, laxatives were required; two patients were managed by a high-fiber diet.


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Table 3. Relationship of ADRs with dose and duration of therapy (n = 23)
 
Sedation, an early ADR, occurred in 87% of patients and persisted throughout therapy, but with reduced severity. In 78% of cases, sedation occurred at a dose of 200 mg/day within the first 15 days of therapy. Patients reported mild early-morning drowsiness that did not interfere with routine activities. Paradoxically, two patients reported delayed onset of sleep with a latent period of 2 h.

Ankle edema was noted in 70% of patients. In 50% of these it occurred at a dose of 200 mg/day, 14 days after initiation of therapy. Some of these patients suffered multiple episodes of peripheral edema that was responsive to diuretic therapy, and reduction or discontinuation of thalidomide was not required. One patient, a non-responder to thalidomide, had marked generalized edema that was non-responsive to diuretic therapy. Renal, cardiac or hepatic causes were ruled out.

Dry skin and dry mouth were problematic in 65% of patients. The severity was dose- and duration-dependent (Table 3). Pruritus was reported in 22% of patients and occurred only at a dose of >=400 mg/day.

No significant neutropenia was seen, and total leukocyte count (TLC) ranged between 2500 and 6000/mm3 in all the patients throughout the course of therapy. Thirteen episodes of inter-current infections, chiefly involving the respiratory tract, were reported, and during these the TLC remained the same or higher than the range given above. Maximum episodes occurred at a dose of 800 mg/day after 2 months of therapy. All patients were treated symptomatically. Two patients died due to septicemia secondary to pneumonia. The third patient had septicemia secondary to infection of an in situ Hickman’s catheter. Removal of the catheter and antibiotics led to recovery.

Generalized weakness/fatigue was reported with an incidence of 52%, but did not significantly alter the daily routine of the patients. In all but one patient, this occurred 1.5 months after initiation of therapy at a dose of 600 mg/day. The severity of fatigue was dose- and duration-dependent. Headache with no dose–duration correlation was noted in 30% of patients.

Despite the fact that thalidomide was launched as a drug for morning sickness, nausea and vomiting occurred in 26% of patients. In four patients it was reported at a dose of 200 mg/day within the first 15 days of therapy.

Skin eruptions of a vesicular type occurred at a dose of 400 mg/day or more after >1 month of therapy, but before the end of 8 weeks, in 22% of patients. The vesicles were distributed in the anterior part of the chest, forelimbs, hands and the beard area, and were 5 x 5 mm in size, painless, and associated with itching, and subsided spontaneously without thalidomide interruption. In the first patient with vesicles, thalidomide was discontinued and the lesions disappeared within 15 days. Upon re-challenge, a fresh crop of vesicles surfaced but subsided spontaneously even though thalidomide was continued. In 17% of patients, skin rash occurred at a dose of 800 mg/day after >2 months of therapy. The rash was in the form of erythematous macules, 2 x 3 mm in size on the abdomen and limbs, and associated with itching. Subsequent dermatological examination ruled out other skin conditions. The rash subsided without treatment after ~15 days. Discontinuation of treatment was not required.

Heart-burn was reported by 21.73% (n = 5) and tremors by 13% of patients; neither had a correlation to dose or duration of thalidomide.

At the end of 10 months of therapy, one patient reported weakness of the lower limbs manifested as difficulty in climbing the stairs. Similarly, two patients at the end of 1 year had similar complaints. Nerve conduction studies were done and all three patients reported peripheral motor and sensory neuropathy. All these patients had received a total dose of >200 g and were receiving 800 mg/day at the time of diagnosis of neuropathy. These patients showed more sensory loss than motor loss; lower limb involvement was greater than upper limb. Hence, the incidence of peripheral neuropathy is 13%.

Blood urea ranged between 14 and 43 mg/dl, and creatinine between 0.1 and 1.6 mg/dl in all patients, except one who developed acute renal failure, for whom these values ranged between 20 and 89 mg/dl, and 0.9 and 4.5 mg/dl, respectively. AST and ALT ranged between 17 and 50 IU, and 14 and 96 IU, respectively in all patients except one, who had acute hepatitis C; thalidomide was discontinued in this patient.

Hypertensive and diabetic patients did not require change in drug or the dosage of treatment. None of these patients reported any symptom related to thyroid dysfunction.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Thalidomide was banned in 1961 due to teratogenecity and fell into disrepute, but has recently been reintroduced in clinical trials with MM. Many studies have shown 30% to 40% efficacy in this condition [35]. However, due to the past history of thalidomide and its potential to cause serious irreversible peripheral sensory neuropathy, doubts have been raised regarding the safety of this drug. The present study was carried out to assess the safety profile of thalidomide in refractory or relapsed MM patients when a high dose of the drug was given for a longer duration (12–14 months; see Table 4). Hence, this study is first to be undertaken in which high dose thalidomide has been used for such a long duration.


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Table 4. Patient profile with respect to dose and duration (n = 23)
 
Earlier studies reported dose-dependent constipation as the most common (25–100% incidence) adverse effect [35], but did not comment on the severity–duration relationship. In this study, constipation has no dose dependence; instead patients developed tolerance to this effect with increase in duration of therapy.

Incidence of sedation (87%) is similar to that reported earlier (range 25–100%) [35], with no dose–duration relationship. With increased dose, patients developed tolerance, although mild daytime somnolence persisted. Although earlier studies reported that patients were unable to lead active daily lives [4, 5], in the present study, despite the high dose and longer duration of therapy, patients led active lives and most of them continued with their professional work, e.g. a surgeon receiving thalidomide was able to operate.

Ankle edema with no dose–duration relationship was a significant side effect (incidence 70%), which is in variance with earlier studies (incidence 6–22%) [3, 4]. There were multiple episodes of peripheral edema (pitting type). This high incidence demonstrates Indian predisposition to stasis of blood in extremities when on thalidomide, although no cases of deep vein thrombosis were reported.

Dose-dependent dryness of skin and mouth (incidence 65%), which was not reported in earlier studies, was treated with emollients. It is possible that tolerance developed to this, as there was reduction in severity of dryness.

Multiple episodes of inter-current infections reported may be related to the immunomodulator effects of thalidomide. Severity of generalized weakness or fatigue increased in a linear manner, with dose as well as duration of therapy.

Thalidomide resulted in nausea and vomiting, which was more apparent when therapy was initiated. Skin rash showed a dose-dependent relationship. It was apparent only at dose of 400 mg/day or more. However, no treatment or dose reduction was required, as the rash subsided without treatment, and did not warrant discontinuation of thalidomide.

Peripheral neuropathy, a serious and dose-limiting side effect of thalidomide, has been conspicuous by its low incidence and it’s late onset in Indian patients [3, 4]. Also noteworthy is the fact that one patient with diagnosed sensory and motor peripheral neuropathy before starting thalidomide did not show any worsening of his condition despite being on high-dose therapy for 9 months.


    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
Almost all the adverse effects of thalidomide developed within the first month of therapy, and mostly at a dose of 400 mg/day or less, except for peripheral neuropathy, which occurred after >=10 months. All the side effects were mild to moderate in intensity and did not warrant withdrawal. Tolerance developed to skin lesions, sedation and constipation. The side effects did not warrant a decrease in dose or stopping of therapy, except in peripheral neuropathy. Overall, thalidomide is a very safe drug and relatively high doses can be given for a long duration without any significant side effects.


    Acknowledgements
 
We acknowledge the contribution of Dr S. K. Acharya, Dr R. Guleria and Dr B. K. Khaitan, (All India Institute of Medical Sciences, India) for their help in evaluation of adverse effects related to liver, respiration and skin. We are grateful to Dr Vikrant Vats and Satpal Yadav for the help provided. We also acknowledge the help of Grunenthal GMBH, International Product Care, Germany, for providing thalidomide for the trial.


    Footnotes
 
+ Correspondence to: Dr J. K. Grover, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. Tel: +91-11-6594897; Fax: +91-11-6862663/6521041; E-mail: jkgrover{at}hotmail.com Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 
1. Silverberg E. Cancer Statistics 1985. CA Report 35: 19.

2. Fermand JP. High dose therapy and autologous bone stem cell transplantation vs conventional treatment in multiple myeloma. Results of a randomized trial in 191 patients 55 to 65 years of age. Presented at the Eighth International Multiple Myeloma Workshop, Stockholm, Sweden, September 1999.

3. Singhal S, Mehta J, Desikan R et al. Anti tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 344: 1565–1571.

4. Rajkumar SV, Despenzieri A, Fonseca R et al. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 2001; 15: 1274–1276.[ISI][Medline]

5. Rajkumar SV, Fonseca R, Dispenzieri A et al. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000; 75: 897–901.[ISI][Medline]

6. Julieusson G, Celsing F, Turesson I et al. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 2000; 109: 89–96.[ISI][Medline]