Citations

AbstractImmunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.

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.

Abstract BACKGROUND Accurate evaluation of unclassified sequence variants in cancer predisposition genes is essential for clinical management and depends on a multifactorial analysis of clinical, genetic, pathologic, and bioinformatic variables and assays of transcript length and abundance. The integrity of assay data in turn relies on appropriate assay design, interpretation, and reporting. METHODS We conducted a multicenter investigation to compare mRNA splicing assay protocols used by members of the ENIGMA (Evidence-Based Network for the Interpretation of Germline Mutant Alleles) consortium. We compared similarities and differences in results derived from analysis of a panel of breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) gene variants known to alter splicing (BRCA1: c.135-1G&gt;T, c.591C&gt;T, c.594-2A&gt;C, c.671-2A&gt;G, and c.5467+5G&gt;C and BRCA2: c.426-12_8delGTTTT, c.7988A&gt;T, c.8632+1G&gt;A, and c.9501+3A&gt;T). Differences in protocols were then assessed to determine which elements were critical in reliable assay design. RESULTS PCR primer design strategies, PCR conditions, and product detection methods, combined with a prior knowledge of expected alternative transcripts, were the key factors for accurate splicing assay results. For example, because of the position of primers and PCR extension times, several isoforms associated with BRCA1, c.594-2A&gt;C and c.671-2A&gt;G, were not detected by many sites. Variation was most evident for the detection of low-abundance transcripts (e.g., BRCA2 c.8632+1G&gt;A Δ19,20 and BRCA1 c.135-1G&gt;T Δ5q and Δ3). Detection of low-abundance transcripts was sometimes addressed by using more analytically sensitive detection methods (e.g., BRCA2 c.426-12_8delGTTTT ins18bp). CONCLUSIONS We provide recommendations for best practice and raise key issues to consider when designing mRNA assays for evaluation of unclassified sequence variants.

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.

Abstract Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.