Metformin, one of most widely prescribed oral hypoglycemic agents, has recently received increased attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. Several potential mechanisms have been suggested for the ability of metformin to suppress cancer growth in vitro and vivo: (1) activation of LKB1/AMPK pathway, (2) induction of cell cycle arrest and/or apoptosis, (3) inhibition of protein synthesis, (4) reduction in circulating insulin levels, (5) inhibition of the unfolded protein response (UPR), (6) activation of the immune system, and (7) eradication of cancer stem cells. There is also a growing number of evidence, mostly in the form of retrospective clinical studies that suggest that metformin may be associated with a decreased risk of developing cancer and with a better response to chemotherapy. There are currently several ongoing randomized clinical trials that incorporate metformin as an adjuvant to classic chemotherapy and aim to evaluate its potential benefits in this setting. This review highlights basic aspects of the molecular biology of metformin and summarizes new advances in basic science as well as intriguing results from recent clinical studies.

Key Points Significant improvement in outcome is a reality for newly diagnosed AL amyloidosis in the past decade. Six-month mortality among transplant ineligible patients has declined since 2005.

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45–72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63–3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11–2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55–2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

A B S T R A C T PurposeThere 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 MethodsWe 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 (Յ 10% BMPCs) and AL plasma cell MM (AL-PCMM; Ͼ 10% BMPCs). ResultsAmong 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 Ͻ .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. ConclusionPatients 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.

Objectives Lung cancer is strongly associated with venous thromboembolism (VTE), but primary prevention against VTE is not a validated management strategy. Risk assessment models will be necessary for efficient implementation of preventative strategies. Materials and methods Utilizing a prospectively collected lung cancer database, we aimed to validate the Khorana Risk Score (KRS) in the prediction of VTE among patients with lung cancer. VTE events were retrospectively identified by reviewers unaware of the clinical prediction score calculation. The association between KRS and the risk of VTE was examined using cumulative incidence function with competing risks models. Mortality prediction was evaluated as secondary outcome. Results We included 719 patients in our review. The patients were predominantly older males with NSCLC and 40% had metastatic disease at inception. The median follow up was 15.2 months. There were 83 VTEs (11.5%) and 568 (78.8%) patients died. A high KRS (Cumulative Incidence 12.4%, 95% Confidence Interval 6.4-20.5%) was not associated with VTE compared to an intermediate score (Cumulative Incidence 12.1%, 95% Confidence Interval 9.5-15.0%)) in both univariate and multivariable analyses. However, a high KRS was a predictor of mortality (HR 1.7 95% CI 1.4 - 2.2). Conclusions Among patients with lung cancer the KRS did not stratify the patients at the highest risk of VTE. Improved risk stratification methods are needed for this group of patients prior to implementing a primary prevention strategy.

Key Points Mass spectrometry is a high-throughput, low-resource technique that can identify immunoglobulin variable region gene from tissue specimens. IGVL gene usage is restricted and different between systemic and localized AL and only partially explains organ tropism in this disease.

The significance of interphase fluorescence in situ hybridization (iFISH) by regimen type was assessed in 692 immunoglobulin light-chain (AL) amyloidosis patients with iFISH at diagnosis. First-line treatment was categorized as stem cell transplant and three non-transplant regimens. The most common abnormality was t(11;14) (49% of patients) followed by monosomy 13/del(13q) (36%) and trisomies (26%). A lower rate of very good partial response (VGPR) or better was observed in patients with t(11;14) treated with bortezomib-based (52% vs 77%; P=0.004) and IMiD-based regimens (13% vs 54%; P=0.04) compared with those lacking t(11;14). This corresponded to an inferior overall survival (OS) in t(11;14)-positive bortezomib-treated (median 15 vs 27 months; P=0.05) and IMiD-treated patients (median 12 vs 32 months; P=0.05). The inferior OS associated with t(11;14) bortezomib-treated patients was restricted to patients with favorable disease. Trisomies were associated with a shorter OS (median 29 vs 69 months; P=0.001), reaching statistical significance only for melphalan (median 15 vs 32 months; P=0.02). Multivariate analysis confirmed an independent survival impact for trisomies in the entire cohort and for t(11;14) among bortezomib-treated patients. iFISH is prognostic in untreated AL amyloidosis and may influence treatment selection. Patients with t(11;14) should be considered for ASCT or standard-dose melphalan at diagnosis because the survival disadvantage may be abrogated.

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