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

Background: Although the incidence of multiple myeloma (MM) is increased in HIV+ patients, optimal treatment of MM in the HIV setting remains unknown. This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide in combination with dexamethasone and zoledronate (TDZ) in newly diagnosed MM in an inner-city population, in which the HIV infection rate is high. The TDZ regimen was thus intended to be non-myelotoxic and compatible with HAART. Because it mitigates tumor growth and angiogenesis as well as bone resorption, zoledronate was expected to boost the therapeutic effects of thalidomide and dexamethasone.

Methods: Of 45 consecutive enrollees, 38 (22F/16M; median age = 61 years) were evaluable. All patients had bone disease, and baseline levels of β₂-microglobulin (4.9 mg/dL; SE = 0.76) and serum albumin (3.3 mg/dL; SE = 0.11) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P <.001) and had higher β₂-microglobulin levels (P =.003), and 6 were receiving HAART. The TDZ regimen 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. Patients were treated for 24 months or until disease progression. Response was stratified by reduction of M protein levels: > 90% (near-complete response [N-CR]), > 50–90% (partial response [PR]), or 25–50% (minor response [MR]).

Results: Mean duration of TDZ treatment was 18 months (range = 3–24). Age-adjusted one-year survival was 74.4%, and was identical to SEER data (73.7%). N-CR was achieved in 30% (n = 11, [7 HIV−/4 HIV+]) and PR in 68% (n = 26, [22 HIV−/3 HIV+] of evaluable patients. One patient did not respond. Median time to maximum response was 4.5 months in HIV− patients and 2.5 months in HIV+ patients (P <.05). 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 unaffected by TDZ. Even with prophylactic ASA, thromboembolism occurred in 6 patients (13%), necessitating additional anticoagulation with warfarin. No other significant toxicity was observed. Of the 10 patients who died, 9 were HIV− and 1 was HIV+; deaths were due to progression of MM (n = 3), complications of MM (n = 3), and causes unrelated to MM (n = 4). Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue).

Conclusions: Thalidomide administered at less than half the standard dosage and in combination with zoledronate and dexamethasone is a safe and effective treatment in the long-term management of MM both in HIV− and HIV+ patients. The potential synergy of thalidomide and zoledronate in the treatment of MM should be evaluated in a larger randomized study. In addition, the faster response to TDZ in HIV+ MM patients on HAART suggests a cooperative interaction between the two regimens that should be further evaluated.