Purpose: Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. Experimental Design: Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1week off) along with rituximab (375 mg/m 2 /wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. Results: Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (<50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. Conclusion: Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.Waldenstrom's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells along with demonstration of an IgM monoclonal gammopathy (1). This condition is considered to be lymphoplasmacytic lymphoma as defined by the REAL and WHO classification systems (2, 3). Despite advances in therapy, WM remains incurable. As such, novel therapeutic agents are needed for the treatment of WM.One class of therapeutics that has been successfully used in patients with WM are monoclonal antibodies. Both rituximab and alemtuzumab have been evaluated in WM as single agents with major response rates of 30% to 40%, whereas the combination of rituximab with chemotherapy has resulted in response rates of 70% to 90% (4). With the attainment of higher response rates with chemo-antibody therapy, considerably more short-term and long-term toxicities have been reported (4, 5). In an effort to augment monoclonal antibody responses in WM patients while averting short-term and longterm chemotherapy-induced toxicities, we have sought the development of immunomodulatory agents for combination with rituximab. Thalidomide and its more potent immunomodulatory derivative lenalidomide augment antibodydependent cell-mediated cytotoxicity (5). Moreover, these agents also lead to expansion of natural killer cells, which serve as important effector cells for rituximab activity in patients with indolent non-Hodgkin's lymphoma (6 -9). As a follow-up to these findings, we recently performed a clinical trial exploring the ...

The effect of moderate elevation in extracellular potassium concentration (up to 12 mm) on contraction of cat ventricular muscle was examined. Isometric force development was recorded from eight excised trabeculae and from six coronary-perfused in situ papillary muscle preparations. Contraction in the steady state was variably affected, sometimes decreasing monotonically, sometimes remaining unchanged, with increasing potassium level. In 11 of these 14 preparations, the steady state was preceded by a transient period in which the contraction was augmented. In addition, eight excised trabeculae were used in an experimental arrangement designed to distinguish between inotropic effects caused by potassium-induced alterations in the action potential and other, more direct, effects of this ion on contraction. The negative inotropic effect is attributable to a potassium-induced reduction in the amplitude and/or duration of the action potential plateau. The positive inotropic effect was found in experimental arrangements where effects of the potassium-rich medium on action potential time-course were effectively "buffered." The positive inotropic effect thus depends on the presence of the elevated potassium concentration and can occur independently of effects on the action potential time-course.

Myelomatous meningitis is a rare occurrence in multiple myeloma. We report 2 cases of documented IgD myeloma with cytologic evidence of meningeal involvement in 1 and detailed paraprotein analysis in both. The occurrence of meningeal involvement in this rare form of plasma cell neoplasm may be more common than previously thought.