Lin, Yi

Purpose There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM. Patients and Methods We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL-CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (≤ 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs). Results Among the 1,255 patients, 100 (8%) had AL-CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain. Conclusion Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM.

Abstract Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

Key Points A continued monoclonal protein response after ASCT in the absence of further therapy is prognostic in MM patients.

Key PointsRadiation is appropriate primary therapy in approximately 25% of cases. Radiation provides long-term remissions in more than 50% of patients.

To clarify the presentation and course of patients with chronic lymphocytic leukemia (CLL) and amyloidosis. Mayo databases were interrogated for patients who carried a diagnosis of amyloidosis and CLL evaluated at Mayo Clinic, Rochester from January 1974 to October 2012. Charts were abstracted and data analyzed. Of the 33 patients identified, 20 (61%) were diagnosed with AL and 13 (39%) with non‐AL. Only four patients had immunoglobulin light chain amyloidosis (AL) that could be solely attributed to the CLL clone; another six had both a plasma cell clone and a CLL clone that shared the same light chain. Median overall survival was 15.6 months for patients with AL and 58.1 months for patients with non‐AL. For patients with AL management involved chemotherapy targeted toward monoclonal plasma cells, lymphocytes or both, and for patients with non‐AL no specific amyloid treatment was administered. AL is a rare complication of CLL, but in this elderly population of patients non‐AL is nearly as common. Distinguishing between these two groups is essential since patients with non‐AL amyloidosis have better outcomes and they do not require cytotoxic chemotherapy to treat their amyloidosis. Am. J. Hematol. 88:375–378, 2013. © 2013 Wiley Periodicals, Inc.

Mesenchymal stem cells (MSCs) represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair byin vitroand animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT), multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD) and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting.

AbstractImmunosuppression is a known risk factor for B-cell non-Hodgkin lymphoma (NHL), yet mechanisms of tumor-associated immunosuppression remain to be fully characterized. We examined the immunophenotype of 40 NHL patients and 27 age-matched healthy volunteers to better understand systemic immune suppression. NHL peripheral blood mononuclear cells had significantly decreased interferon-γ production and proliferation. This suppression was not the result of regulatory T cells, interleukin-6 or interleukin-10, as these factors were not different between NHL and healthy volunteers (controls). We were able to restore T-cell proliferation by removing NHL monocytes, suggesting that these monocytes are suppressive. This suppression was mediated in part through arginine metabolism as exogenous arginine supplementation partially overcame monocytes' suppression of T-cell proliferation in vitro and NHL patients had elevated arginase I in their plasma. NHL monocytes had impaired STAT1 phosphorylation and interferon-α production to CpG stimulation and a dendritic cell differentiation deficiency. Further studies demonstrated that monocytes from NHL patients had decreased HLA-DR and Tumor necrosis factor-α receptor II (CD120b) expression compared with controls (CD14+HLA-DRlow/−CD120blow). Patients with increased ratios of CD14+HLA-DRlow/− monocytes had more aggressive disease and suppressed immune functions. In summary, we report that CD14+HLA-DRlow/− monocytes are a major and multifactorial contributor to systemic immunosuppression in NHL.

Abstract Purpose: Preexisting antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its antitumor potency. In contrast to “naked” viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles-immune mice might be superior if MV-infected mesenchymal stem cell (MSC) carriers are used. Experimental Design: Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles, and tumor infiltration capability of MSC were determined. Measles-naïve or immune tumor–bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared. Results: MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody, at levels that completely inactivated naked virus. Athymic mice bearing i.p. human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles-immune human serum were treated with saline, naked MV, or MV-infected MSC. Bioluminescent and fluorescent imaging data indicated that i.p. administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma, and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles-immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC. Conclusions: MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients. (Clin Cancer Res 2009;15(23):7246–55)