No abstract

Major histocompatibility complex (MHC) class I-related chain A gene (MICA) sequence-based genotyping (SBT) was attempted on a peripheral blood sample collected from a patient evaluated for hematopoietic stem cell retransplant. The electropherogram pattern of MICA SBT indicated the possibility of carrying more than two MICA alleles. Subsequent cloning and sequencing of the polymerase chain reaction products revealed the presence of three distinct MICA alleles: MICA*008:01/:04 (A5.1), MICA*007:01(A4), and MICA*002:01 (A9) in the genotype of this patient. The origin of the third extra MICA allele could not be determined and would require MICA genotyping information from other family members, which is unavailable.

7616 Background: Temsirolimus (TEM) is a novel inhibitor of mTOR, a critical molecule in the PI3K/Akt pathway, which is known to play an important role in transducing mitogenic signals induced by the action of cytokines on MM cells. Methods: We performed a phase II trial to investigate the clinical activity and toxicity of TEM in relapsed/refractory MM patients. Patients had Salmon-Durie stage I-IIIA, failed at least one prior therapy, were ≥18 years, had ANC ≥1.2x109/l, platelets ≥75x109/l, serum Cr ≤1.5 mg/dl, fasting cholesterol ≤350 mg/dl, triglycerides ≤400 mg/dl, and ECOG performance status 0–2. TEM was dosed at 25 mg IV on days 1, 8, 15 and 22 of each 28-day cycle. Treatment was continued until progression. Results: 14 patients are evaluable for response and toxicity. Median age was 62.5 (range, 41–75) years; 8 patients were male. 12 patients had stage IIIA and 1 patient had stage IIA and IA each, respectively. Median β2-mg was 3.3 (range, 2.5–7.9) and CRP was 2.2 (range, 0.5–139). Patients had failed a median of 2 (range, 1–5) prior regimens, and 6 had failed autologous stem cell transplant. Overall, 6 (43%) of 14 patients responded, with 5 achieving minor (26–49% decrease in M-protein) responses, and 1 a partial (>50% decrease in M-protein) response using Bladé criteria. 11 patients progressed on treatment. Overall, median time-to-progression was 4.6 months from start of treatment. Grade 3/4 toxicity included neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), nausea (n=1), stomatitis (n=1) and diarrhea (n=1). Response was associated with a maximal reduction in phosphorylated p70S6K (p-p70S6K) and 4EBP1 (p-4EBP1) in peripheral blood mononuclear cells at 48 hours after TEM dosing. The median proportion of p-p70S6K relative to baseline following treatment was 0.38 (range, 0.26–0.84) in responding patients versus 1.65 (range, 0.74–1.66) in non-responders (P=0.0001). Similarly, the median proportion of p-4EBP1 following treatment in responders was 0.49 (range, 0.12–1.25) versus 1.12 (range, 0.73–2.09) in non-responders (P=0.025). Correlation with blood levels of TEM is ongoing. Conclusions: TEM has anti-myeloma activity, and further investigation of TEM as a single agent and in combination therapy is warranted. No significant financial relationships to disclose.