Multiple Myeloma: A Practical Guide to Current Management

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Multiple Myeloma: A Practical Guide to Current Management 6 The most commonly cited reason for not using thalidomide in combination with dexamethasone for frontline therapy is risk of deep vein thrombosis (DVT), which is significantly higher with the combination than with thalidomide alone. DVT was seen in both the initial Mayo Clinic trial of combination thalidomide/dexamethasone therapy (19%) and in the M.D. Anderson trial (15%). These toxicities have prompted recommendations that DVT prophylaxis with either therapeutic doses of warfarin, a low molecular weight heparin, or aspirin be considered when using this combination. The role of thalidomide in newly diagnosed patients was discussed in the context of the results of Eastern Cooperative Oncology Group (ECOG) Study E1A00 [Rajkumar 2004]. In this study, 207 patients were randomly assigned to receive dexamethasone with or without the addition of thalidomide. Thalidomide was administered orally at 200 mg/day. Dexamethasone 40 mg daily was administered on days 1 to 4, 9 to 12, and 17 to 20 of a 30-day cycle. Responses were assessed after four cycles of treatment. In the intent-to-treat patients, best responses were defined as 50% reduction in serum and urine M protein as measured by SPEP (serum protein electrophoresis) and UPEP (urine protein electrophoresis), respectively, and 90% reduction in urine M protein as measured by UPEP, if only urinary protein was evaluable for response. The efficacy and safety data for the study Table 1: Eastern Cooperative Oncology Group Study E1A00: Efficacy and Safety Efficacy are summarized in Table 1. Patients treated with dexamethasone alone showed response rates of 41%, compared to 63% for those treated with thalidomide/ dexamethasone. In addition, DVT was seen in only 3% of patients receiving dexamethasone, compared to18% in patients receiving thalidomide/dexamethasone. The study concluded that although response rates with thalidomide/ dexamethasone are superior to response rates with dexamethasone alone, additional significant toxicity is seen in patients receiving thalidomide/dexamethasone. Some participants were of the opinion that there is still a need for intense induction therapy with VAD (or similar regimen) in patients who are candidates for stem cell transplantation, particularly patients with hypercalcemia and renal insufficiency, who require very rapid disease control. Patients administered VAD typically receive vincristine 0.4 mg, doxorubicin 9 mg/m 2 (by continuous infusion every four hours for four days), and dexamethasone 40 mg (orally on days 1 to 4, 9 to 12, and 17 to 20), administered every 30 days. However, VAD is cumbersome to administer, with the need for central venous access, and has the potential to cause doxorubicin-associated cardiotoxicity as well as neurotoxicity secondary to vincristine. In addition, reported response rates of 55% are similar to response rates of 41% seen in ECOG E1A00 patients administered dexamethasone alone. Thalidomide/Dexamethasone Dexamethasone Patients 103 107 Best response within 4 cycles 73% 50% p=0.002 Progressed at 4 months 3% 5% Safety Patients 102 101 Deep vein thrombosis (grade ≥ 3) 18% 3% Grade 4 or higher toxicity 34% 17% Grade ≥ 3 non-heme toxicity 68% 43% Deaths 7% 11% *Allowing for using serum M protein levels (or Q1 levels, in 2 patients) in patients in whom measurable urine M protein was unavailable at follow up.
Multiple Myeloma: A Practical Guide to Current Management Although no randomized trials exist, one recent retrospective study attempted to put the question of VAD versus the combination of thalidomide and dexamethasone to the test. The two regimens were analyzed as induction therapy prior to autologous peripheral blood stem cell transplantation [Cavo 2005]. The study was a case-control analysis of 200 patients who entered two consecutive studies from 1996 to 2004 and received thalidomide and dexamethasone (n=100) or VAD (n=100) for four cycles. Patients receiving thalidomide were given initial oral doses of 100 mg/day. After 14 days, the thalidomide dose was escalated to 200 mg/day. Patients were matched for age, clinical stage of disease, and serum β 2 -microglobulin. Significantly higher response rates were reported for STARTING DOSAGE IN COMBINATION THERAPY What is the starting dosage of thalidomide recommended in combination therapy? When using thalidomide in combination therapy, several roundtable participants recommend the use of 50 mg thalidomide per day as the starting dose while others begin at 100 mg per day. Patients can be dose-escalated every one to two weeks. Starting doses of 200 mg are generally recommended for high-risk patients where the need for cytoreduction is urgent. Clinical experience suggests that this approach allows for maximum tolerability. In elderly patients and patients with poor performance status, it is particularly important to start with thalidomide at a dose of 50 or 100 mg. Clinicians who start at thalidomide doses of 50 mg and 100 mg will typically dose-escalate to doses of 200 to 400 mg per day based on tolerance. The most common target dose level is 200 mg. Does a lower starting dose of thalidomide adversely impact response rate? The consensus of this panel of experts was that it does not. It was felt that finding a tolerable maximum dose and patients receiving thalidomide and dexamethasone (76% versus 52% for VAD; p200 mg/day recommended with aggressive disease and high tumor burden and risk factors Special populations (e.g., the elderly, 50 mg/day starting dose. poor performance status) Escalate by 50mg/day q 2 weeks 7
Page 1 and 2: Multiple Myeloma: A Practical Guide
Page 3 and 4: Introductory Letter Multiple Myelom
Page 5 and 6: Monograph Overview Target Audience:
Page 7 and 8: Faculty Disclosures Dr. Ivan Borrel
Page 9: Multiple Myeloma: A Practical Guide
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