Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Zoledronate, Dexamethasone, and Low-Dose Thalidomide: A Phase II Trial.

Background: This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide with dexamethasone and zoledronate (TDZ) in newly diagnosed multiple myeloma (MM) in an inner-city population in which AIDS is the third-leading cause of death. Although the incidence of MM is increased in HIV+ patients, guidelines for treatment of MM in this population are not yet known. The TDZ regimen was intended to be non-myelotoxic and compatible with HAART. Because zoledronate mitigates tumor growth and angiogenesis as well as bone resorption, it was expected to boost the therapeutic effect of thalidomide and dexamethasone.

Method:Of 45 consecutive enrollees, 38 (27F/11M; median age = 60.4 years) were evaluable. All patients had skeletal involvement of varying severity; baseline levels of *2-microglobulin (4.3 mg/dL; SE = 0.68) and serum albumin (3.3 mg/dL; S.E.= 0.38) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P < .001), with marginally higher *2-microglobulin levels (P = .076). Seven of the HIV+ patients were on HAART at the time of treatment. The TDZ regimen, given for 24 months or until progression, consisted of: thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Response was stratified by reduction of M protein levels: > 75% (very good partial response [VPR]), > 50–75% (partial response [PR]), or 25–50% (minor response [MR]).

Results: Age-adjusted one-year survival was 74.4%, and is identical to NCI SEER data (73.7%). Mean duration of TDZ treatment was 21.4 months (range = 13–24). VPR was achieved in 32% (n = 12), PR in 39% (n = 15), and MR in 18% (n = 7). Three patients had stable disease, and one progressed. Median time to maximum response was 3.0 months. Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was not adversely affected by monthly treatment with zoledronate (P > .2 for both). Despite prophylactic ASA, thromboembolism occurred in 6 patients (16%), all of whom were successfully treated with full anticoagulation. Other toxicities ≥ Grade 2, were not observed. Skeletal events occurred in 8% of patients; osteonecrosis of the jaw was not encountered. Death occurred in 10 patients, 9 of whom were evaluable; 6 deaths were due to progression or complications of MM, and 4 were from unrelated causes. Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue).

Conclusion: Thalidomide administered at less than half the standard sage in combination with zoledronate and dexamethasone provided safe and effective long-term treatment of MM both in HIV− and HIV+ patients. The modest frequency of toxicity and skeletal events under this regimen indicates improvement in quality of life as well as survival.