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Thalomid
• Newly Diagnosed Patients
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Thalidomide continues to be evaluated in newly diagnosed, treatment-naïve patients in combination with standard chemotherapy, dexamethasone, and numerous other agents. (see the MMRF's Clinical Trials Monitor).
In Combination with Dexamethasone
The unique activity of the thalidomide molecule against plasma cells offers a promising therapy for multiple myeloma, particularly in combination with dexamethasone (thal-dex). Many studies of this combination have shown response rates comparable to those achieved in relapsed/refractory patients.In 2004, thal-dex was included in the clinical practice guidelines issued by the National Comprehensive Cancer Network (NCCN) as suitable firstline therapy for patients who present with advanced (Durie-Salmon Stage II or III) myeloma (NCCN, 2004). In the thalidomide multiple myeloma panel discussion proceedings held in 2003, thal-dex was also deemed appropriate for patients with newly diagnosed myeloma (both transplant-eligible and -ineligible). (Stewart et al, 2003) Thal-dex was found to be appropriate as an induction therapy in a retrospective analysis of 200 patients entered in consecutive trials from 1996 to 2004. In fact, response rates of thal-dex were superior to standard chemotherapy with vincristine-doxorubicin-dexamethasone (VAD) (76% compared with 52%) given 4 months prior to peripheral stem cell collection and autologous transplantation and thal-dex produced a more significant reduction in myeloma cell mass of both IgG and IgA types. (Cavo et al, Blood 2005;1182/blood-2005-02-0522;)
The addition of bortezomib (Velcade) to the combination of thalidomide and dexamethasone for the treatment of newly-diagnosed multiple myeloma has also demonstrated superiority to previous regimens used for these patients. The rate of remission was 55% with the 3-drug combination was double that observed with bortezomib alone (Alexanian R et al, 2005. ASH Abstract #210).
Results of the randomized Phase III study of thal-dex in newly-diagnosed, symptomatic patients conducted by the Eastern Cooperative Oncology Group (ECOG) were reported at the American Society of Hematology (ASH) meeting in December, 2004 (Rajkumar et al. ASH Abstract 205.) In this study, the patients who received 200 mg/day of thalidomide and dexamethasone (n=103) had a response rate of 59% at 4 months compared with a response rate of 42% seen in patients receiving dexamethasone alone (n=104). Corrected response rates were slightly higher (see table below).
Prior to ECOG, two smaller Phase II studies demonstrated significant responses to thal-dex in newly diagnosed patients. Rajkumar et al. showed a greater than 50% reduction in M protein (J Clin Oncol. 2002;20:4319-4323), while Weber et al showed a response rate of 72%, with a CR rate of 16% in these patients (J Clin Oncol. 2003;21(1):16-19).
Phase III ECOG Thal-dex Trial: Response Rates |
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*Response was defined as a ≥50% decrease in serum and urine M protein; a ≥90% decrease was needed if only the urine M protein was measurable. Corrected response was obtained by using serum M protein levels in patients in whom a measurable urine M protein was unavailable at follow-up |
Patients receiving the combination experienced increased side effects compared with dexamethasone alone, as listed in the table below.
Phase III ECOG Thal-dex Trial: Major Grade 3-4 Toxicities |
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Results of studies evaluating the use of thal-dex in newly diagnosed patients are summarized in the table below.
Summary of Recent Combination Thalidomide-Dexamethasone Trials in Newly Diagnosed Myeloma (previously untreated) |
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*Response defined as >50% reduction in M protein and/or reduction in Bence Jones protein by >75%; for all others, response was defined as ≥25% reduction in M protein. ¹After the first 7 patients, the thalidomide dose was kept constant at 200 mg/day. ¹¹Retrospective review comparing overall response rates among patients receiving thal-dex (n=27; 100%), dexamethasone (n=43; 79%), or VAD (n=80; 79%) as induction therapy. ASH = American Society of Hematology meeting ASCO = American Society of Clinical Oncology meeting IMMW = International Multiple Myeloma Workshop DVT = deep vein thrombosis PE = pulmonary embolism |
It is important to recognize that the combination of thalidomide and glucocorticoids has not been adequately explored in terms of doses of each of these agents that may be effective. Several recent anecdotal reports suggest that lower doses of thalidomide (100-200 mg) with less potent steroids (prednisone or methylprednisolone) may be as effective as more toxic higher doses.
In Combination with Chemotherapy
The efficacy of thalidomide in combination with chemotherapy in newly diagnosed, treatment-naïve patients has been demonstrated in numerous studies. The most common drug combinations being evaluated in this patient population include:
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Melphalan, prednisone, and thalidomide
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Doxil® (liposomal doxorubicin, Ortho Biotech), vincristine, dexamethasone, and thalidomide (DVd-T)
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Thalidomide, Adriamycin® (doxorubicin), and dexamethasone (TAD)
Summary of Recent Combination Thalidomide-Chemotherapy Trials in Newly-diagnosed Myeloma (previously untreated) |
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*Denotes complete response †Denotes disappearance of M protein but positive immunofixation ASCO = American Society of Clinical Oncology meeting ASH = American Society of Hematology meeting IMMW = International Multiple Myeloma Workshop |
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As a Component of Total Therapy
The Arkansas Cancer Research Center has developed a regimen for newly diagnosed patients called Total Therapy II. This efficacy of Total Therapy II is being evaluated with and without added thalidomide in a Phase III trial. This regimen consists of four phases of treatment: induction, transplant, post-transplant consolidation, and maintenance. Thalidomide is added during each phase of treatment. (See figure below.)
TOTAL THERAPY II FLOWCHART |
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Complete data are available on 668 patients enrolled; 85% completed first transplant and 67% completed a second. Increases in CR were seen in the THAL arm from 43% to 62%. 5-year overall survival was superior with transplant plus THAL compared to transplant alone: 68% vs. 63%. (Barlogie et al.2005 ASCO abstract LBA6502.)
Original safety data available on 475 of the patients showed that the aggressive Total Therapy II regimen was associated with significant toxicity but low overall treatment-related mortality (2%). (Anaissie et al. Blood. 2003;102(11). Abstract 1657.) Severe Grade 3 or Grade 4 toxicity was seen in 93% of patients and occurred throughout treatment, including hematologic (93%), metabolic (78%), gastrointestinal (60%), infectious (51%), neurologic (43%), and cardiovascular problems (41%). Greater toxicity was seen in the thalidomide arm, including thrombosis/embolism, weakness, neuropathy, dizziness, tremor, fainting, and red cell transfusion requirements. The increased incidence of clotting events attributed to the combination of thalidomide and doxorubicin was reduced with appropriate anticoagulation. (Zangari et al. Blood. 2002;100(11). Abstract 1546.)