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Thalidomide: Clinical Outcomes
By Brian G.M. Durie, MD, Cedars-Sinai Comprehensive Cancer Ctr.


Dr. Kenneth Anderson of the Dana-Farber Cancer Center, Boston, who chaired the session, gave a brief overview of potential biologic effects of thalidomide and the new analogues such as the immunomodulatory drug IMiD 501. IMiD 501 is currently being evaluated in a Phase I trial at Dana-Farber and in Little Rock. Thus far, IMiD 501 has been generally well tolerated without evidence of neuropathy. The appropriate dosage for Phase II trials is not yet established.


The keynote speaker was Dr. Bart Barlogie of the Arkansas Cancer Research Center. Results with "total therapy" (including double stem cell transplantation) indicate a 50% complete remission rate in patients with very good prognosis; such patients can live for 10 years or more. Conversely, patients with chromosome 13 deletion, even with total therapy, had a very poor prognosis. A focal point of the presentation was the role of thalidomide, first as an agent for relapse therapy and then incorporated into the new "Total Therapy II" protocol. Follow-up of 169 patients with relapsing disease treated with thalidomide as a single agent showed evidence of response in one third of patients treated with a q2wk dose-escalation schedule with 200 mg/day as the starting dosage. Toxicity was significant with dosages of at least 400 mg/day. Overall survival was 60% at 2 years from the start of thalidomide therapy, with 20% of patients still in remission at 2 years. Patients with good prognostic factors did the best, including low serum b2 microglobulin, LI% (labeling index) and CRP (C-reactive protein) as well as no major chromosome abnormalities.

Based on these data, thalidomide was incorporated into "Total Therapy II" at 400 mg daily. Results of this trial are not yet available. Anticipated accrual is 600 patients. Thalidomide is now stopped during stem cell mobilization/harvesting because of impaired collection of peripheral blood stem cells. Higher likelihood of deep venous thrombosis and blood test evidence of low thyroid function occurred with thalidomide treatment. Results of this trial, as well as of the ongoing IMiD 501 trial, are now awaited with interest.

Five other investigators discussed the role of thalidomide, both alone and in combination. Dr. Brian Durie from Cedars-Sinai Cancer Center focused on the use of low-dose thalidomide, ie, dosages from 50 mg (one capsule) to 400 mg daily. This study, started in 1998, provided long-term follow-up and reflected significant clinical benefit with dosages of 50 to 200 mg daily. Three (33%) of the responders required only 50 mg/day. Overall, 78% of the responses occurred with 200 mg/day or less of thalidomide. Although fewer patients in this series (25% versus 75%) had received prior stem cell transplants, response rates and survival were remarkably similar to those at Little Rock: 44% response rate overall and 25% with at least 50% regression; 64% of patients were alive at 2 years, with 22% still in remission. A major difference was the much lower toxicity with the low-dose schedule. Nonetheless, ongoing peripheral neuropathy was a significant concern, especially with therapy for more than 1 year. Thalidomide combined with pulse dexamethasone (40 mg daily for 4 days twice per month), with or without added Biaxin (clarithromycin 500 mg twice daily), was used to treat failing or relapsing patients. Thalidomide plus dexamethasone produced responses in three of seven patients (43%), with less than a 50% response with thalidomide alone. The three-drug combination BLT-D (Biaxin, low-dose thalidomide, dexamethasone) produced benefits in 4 of 10 patients (40%) who were failing with the two-drug combination, confirming added benefit with Biaxin in this setting. Further studies with low doses of thalidomide alone and in combination were recommended.

With these encouraging results in relapsing patients, there was considerable interest in the efficacy of thalidomide as part of primary therapy for previously untreated disease. Data from M.D. Anderson Cancer Center were presented by Dr. Donna Weber and from the Mayo Clinic by Dr. Vincent Rajkumar. Both groups studied thalidomide plus dexamethasone. The M.D. Anderson study evaluated thalidomide 400 mg combined with dexamethasone using intensive 4-day-on/4-day-off pulses. Eleven of 16 patients (69%) with symptomatic (active), previously untreated myeloma responded. Follow-up is still short. Patients with "asymptomatic disease" (a subgroup of patients with early disease, identified by the MD Anderson team) were also treated with thalidomide alone; 10 of 28 (36%) had an initial response duration of more than 1 year. Toxicity in both groups was significant, with neurologic toxicity occurring in approximately 60% including unsteadiness/lightheadedness, tremors, psychosis, and peripheral neuropathy. The rapid responses in these studies indicated a direct cytoreductive effect of thalidomide rather than an antiangiogenic mechanism. This aspect was commented on by several speakers as well as in posters presented at the meeting.

The Mayo Clinic study included 26 patients with active, previously untreated myeloma. Twenty of them (77%) responded to thalidomide with a dose-escalating schedule (200-800 mg/day) combined with dexamethasone using the same intensive 4-day-on/4-day-off protocol as used by the M.D. Anderson group. Toxicity was again significant and included life-threatening skin rashes in three patients. Following this, the thalidomide dosage was kept at 200 mg/day without dose escalation. Other toxicities included syncope, sedation, constipation, arrhythmia, and myalgia. In the M.D. Anderson group, patients with smoldering myeloma were treated with thalidomide alone (200–800 mg/day), and six patients (38%) responded (c.f. 36% Houston). Although angiogenesis was evaluated serially, the direct relationship to thalidomide response was unclear.

Perhaps the most consistent observation was the overall efficacy of thalidomide. When it is used as monotherapy, responses occur in 25% to 40% of patients both at relapse and with previously untreated disease. As first pointed out in the low-dose study from Cedars-Sinai Cancer Center, patients with kappa light chain subtype disease are more likely to respond. The M.D. Anderson data and large studies from Greece (Dimopoulos) and Italy (Boccadoro) show the same trend.

Twenty abstracts in the poster session dealt with thalidomide treatment. Results were presented from around the world, including Europe (United Kingdom, Italy, France, Germany, Poland) and Asia (India, Australia), as well as from the United States. Efficacy and toxicities were remarkably similar between groups. Combination with steroids clearly enhances short-term efficacy. Other combinations may also have merit, including with high-dose Cytoxan and in DT-PACE. Results with TAD were presented, in which thalidomide (T) replaces vincristine (V) in the VAD regimen. At Memorial Sloan–Kettering Cancer Center, early results show significant efficacy. Coumadin was added as an anticoagulant to prevent deep venous thrombosis. Further follow-up is required.

Perhaps the greatest interest concerned the BLT-D protocol presented as a poster by Dr. Morton Coleman of Cornell. Based on prior evidence of efficacy with Biaxin 500 mg PO BID, (twice daily) Biaxin was added to low-dose thalidomide (50 mg daily) plus dexamethasone at a starting dosage of 40 mg once weekly.

Enteric-coated aspirin (81 mg/day) was added as a preventive for clotting complications. The 55 patients were a mixed population in terms of both diagnosis (6 Waldenstrom’s, 49 myeloma) and disease status (9 untreated, 46 previously treated with a variety of regimens). A very high response rate was observed (80% to 90% depending on population). The data indicate that BLT-D is superior to LT-D, but an ongoing randomized trial will be necessary to fully assess the impact of the added Biaxin. It should be noted, however, that evaluation of Biaxin, both in vitro in myeloma cultures and added to therapy for failing patients as part of the thalidomide/dexamethasone trial at Cedars-Sinai Cancer Center, supports the notion that Biaxin provides additional benefit. Although this is in part because of synergy with steroids, the definite mechanism of benefit awaits full explanation.

Dr. Mohamed Hussein from the Cleveland Clinic reviewed thalidomide toxicities and outlined plans for ongoing monitoring and management. Continuing thalidomide treatment in the face of progressive peripheral neuropathy (especially numbness and difficulty with fine movements such as buttoning clothing) is an important dilemma. How safe is it to stop thalidomide? Clearly, some patients taking thalidomide alone can stop the drug once remission is achieved and maintain remission for more than 6 months. However, others have early evidence of increasing myeloma protein levels. Further studies are required to assess stopping versus low-dose maintenance of some sort (eg, 50 mg 2 or 3 times per week).

The greatest anticipation focuses on the early IMiD trials. What toxicities will there be? What level of benefit will be achieved? How soon will broader Phase II trials begin? Thalidomide and its analogues represent a rich area for clinical research and major new treatment advances to improve outcomes for patients with myeloma and related disease.

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