Rajkumar, S. Vincent

Objectives To define whether the high sensitivity cardiac troponin T (hs-cTnT) assay in patients with immunoglobulin light chain amyloidosis (AL) improves risk prediction. Background Cardiac involvement is the major cause of death in patients with AL amyloidosis. Risk stratification is facilitated by cardiac biomarkers such as cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods Stored serum from patients with newly diagnosed AL was used to measure hs-cTnT, cTnT, and NT-proBNP. Survival modelling was performed. Results The direct numeric result from hs-cTnT measurement cannot merely be substituted for a cTnT measurement in the Mayo AL staging system. The performance of the receiver operator curve derived an hs-cTnT cut-point of 54 ng/L which improves on the value of 35 ng/L validated with the prior iteration of the assay. An alternate staging option using hs-cTnT alone—using the two thresholds 14 ng/L and 54 ng/L—performs as well as either the original Mayo AL staging system or other systems incorporating hs-cTnT. On multivariate analysis, an hs-cTnT alone staging system was independent of period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models were explored, but none performed better than the original system or the new hs-cTnT system. Thus, hs-cTnT can be used alone for the staging of disease prognosis. Conclusions A survival model based on hs-cTnT improves the prognostic staging of patients with AL amyloidosis, relegating NT-proBNP to a measure of cardiac response.

There are no systematic data regarding nonmaintained induction for those patients with multiple myeloma (MM) who do not receive consolidative autologous stem cell transplantation. Of 173 patients with newly diagnosed MM treated with lenalidomide and dexamethasone (LenDex) as primary therapy, 31 patients had their lenalidomide discontinued for reasons other than progression or alternate therapy. Median progression free survival (PFS) from the time of discontinuing lenalidomide was longer in patients who received lenalidomide ≥1 year (39 vs. 13 months, P < 0.05); there was no difference in PFS for those treated for 1–2 years as compared to ≥2 years. Among those taking lenalidomide for ≥1 year PFS was superior in patients who were in very good partial response (VGPR) or better as compared to those with partial response (48.4 versus 14.8 months, P < 0.05). All patients who progressed and were rechallenged with LenDex responded. These analyses illustrate that discontinuation of lenalidomide after 1 year among those patients achieving a ≥VGPR can result in long‐term disease control. Am. J. Hematol. 89:302–305, 2014. © 2013 Wiley Periodicals, Inc.

Purpose To study the impact of achieving stringent complete response (sCR), an increasingly attainable goal, after autologous stem-cell transplantation (ASCT) in patients with multiple myeloma (MM). Patients and Methods Maximal response rates were determined in 445 consecutive patients who underwent ASCT within 12 months of diagnosis of MM. The patients achieving varying degrees of complete response (CR) are the focus of our study. Results One hundred and nine patients (25%) achieved sCR after ASCT. The median overall survival (OS) rate from the time of transplantation for patients attaining sCR was not reached (NR), in contrast to those patients achieving conventional complete response (CR; n = 37; OS, 81 months) or near CR (nCR; n = 91; OS, 60 months; P < .001). Five-year OS rates were 80%, 53%, and 47% for sCR, CR, and nCR, respectively. The median time to progression (TTP) from ASCT of patients achieving sCR was significantly longer (50 months) than TTP of patients achieving CR or nCR (20 months and 19 months, respectively). On multivariable analysis, post-ASCT response of sCR was an independent prognostic factor for survival (hazard ratio, 0.44; 95% CI, 0.25 to 0.80; versus CR; P = .008), in addition to proliferation rate, pre-ASCT cytogenetics, and performance status. OS rates of patients attaining sCR continued to remain superior at 2-year landmark (median, NR v 70 months for conventional CR group; P = .007). Conclusion Improved long-term outcome is seen after ASCT with achievement of sCR when compared with lesser degrees of responses. Myeloma trials reporting the response rates should identify patients achieving sCR and CR separately, owing to markedly disparate outcomes of the two categories.

Key PointsMGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to matched controls.

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.

BACKGROUNDTwo randomized trials have demonstrated improved progression‐free survival (PFS) with lenalidomide maintenance after autologous transplantation for multiple myeloma (MM). Overall survival (OS) results are conflicting, and quality‐of‐life (QOL) data are lacking. The authors conducted a systematic survey of patients with MM regarding what constitutes a meaningful benefit that would make burdens of maintenance treatments (toxicity and cost) acceptable.METHODSA self‐administered survey was mailed to 1159 consecutive, living patients who were evaluated at Mayo Clinic. The survey provided background information on the standard of care for MM and data on maintenance. Patients were asked to estimate the magnitude of OS benefit that would be acceptable for various degrees of toxicity and cost.RESULTSOf 1159 surveys sent, 886 patients (83.2%) responded, and 736 patients returned a completed survey (66% raw response rate). The most worrisome potential toxicity was identified as peripheral neuropathy by 27% of patients, cytopenias by 24%, deep vein thrombosis by 20%, fatigue by 15%, nausea by 8%, and diarrhea/constipation by 7%. If treatment was free, had no toxicity, and the OS benefit was ≤1 year, then 49% of patients indicated that they would choose maintenance; with moderate toxicity, this proportion decreased to 42%. Adding a treatment cost of $25 per month decreased the proportion that would choose maintenance to 39% of patients.CONCLUSIONSThe current results indicated that willingness to receive maintenance treatment declined when actual benefits were provided in concrete numeric terms compared with a general statement of PFS benefit. The authors also observed that the magnitude of benefit required to consider maintenance was affected by cost and toxicity. Cancer 2013;119:4308–4315. © 2013 American Cancer Society.

AbstractThe introduction of novel immunomodulatory drugs (IMiDs) has dramatically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib‐based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). We examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its downstream target interferon regulatory factor‐4 (IRF4), which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that lenalidomide response did not correlate with specific cytogenetic translocations. There were distinct groups of lenalidomide‐responsive and non‐responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC‐1 (IC50 = 2.6 μm vs. 0.005 μm, P < 0.0001), but did not have an effect on the IC50 of the non‐responsive DP‐6 HMCL (P > 0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN and IRF4 expression. Our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. While CRBN and IRF4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment.