Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains.

Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ⩾5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non-evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels.

Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.

Natural history of t(11;14) multiple myeloma.

Translocation (11;14) on interphase fluorescent in situ hybridization in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 patients with no chromosomal translocation. The median progression-free survival for the three groups were 23.0 (95% confidence interval (CI), 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months, respectively (P<0.01). The median overall survival (OS) for t(11;14), non-(11;14) translocation and no-translocation groups were 74.4 (95% CI, 64.8-89.3), 49.8 (95% CI, 40.0-60.6) and 103.6 (95% CI, 85.2-112.3) months, respectively (P<0.01). Excluding those with 17p abnormality, the median OS in the three groups were 81.7 (95% CI, 67.0-90.7), 58.2 (95% CI, 47.0-76.4) and 108.3 (95% CI, 92.4-140.1) months, respectively (P<0.01). The above relationship held true in patients with age <65 years, international staging system (ISS) I/II stage or those who received novel agent-based induction. Advanced age (hazard ratio (HR): 1.98), 17p abnormality (HR: 2.2) and ISS III stage (HR: 1.59) at diagnosis predicted reduced OS in patients with t(11;14). These results suggest that outcomes of t(11;14) MM are inferior to other standard risk patients.

Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma.

Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors.

Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma.

Little is known about the impact of multiple myeloma (MM) treatment on uninvolved immunoglobulins (Ig). We identified 448 patients who received high-dose dexamethasone (HD-DEX), lenalidomide and dexamethasone (RD), bortezomib and dexamethasone (VD), bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD) for newly diagnosed MM at our institution between 2000 and 2013, and who had available data on absolute lymphocyte count (ALC) and quantitative uninvolved Ig at baseline and at the end of four cycles of therapy. Changes in ALC and uninvolved Ig were significantly different across treatments, with VCD and HD-DEX producing reductions in uninvolved Ig, and RD, VD and VRD leading to increases in uninvolved Ig. In addition, treatment with RD, VD and VRD was independently associated with higher odds of achieving a ⩾25% increase in or normalization of the primary uninvolved Ig on multivariate analysis. Although achievement of a humoral response in the primary uninvolved Ig was associated with a higher odds of achieving VGPR or better after four cycles of therapy, it was not associated with improved overall survival. These data highlight the different mechanisms of action of MM drugs and point toward a possible role for the use of VCD in treating antibody-mediated autoimmune disease.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis.

BACKGROUND: Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited. OBJECTIVE: To assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors. METHODS: 1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid-stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L-1 ; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log-rank test and a multivariate analysis. RESULTS: Patients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety-three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4-year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis. CONCLUSION: A significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted.

Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma.

We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III (P<0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III (P<0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.

Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression.

The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ⩾150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ⩾150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.

Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival.

Immunoparesis is an adverse prognostic marker in plasma cell proliferative disorders. Its impact in AL amyloidosis has not been explored in depth. Newly diagnosed AL amyloidosis patients (n=998) were evaluated for immunoparesis by two methods. The first method was qualitative, considering the number of suppressed uninvolved immunoglobulins below the lower limit of normal (LLN) (none, partial, all). The second method was quantitative, assessing the average relative difference (ARD) of the uninvolved immunoglobulins from the LLN. Patients with suppression of all the uninvolved immunoglobulins were less likely to achieve very good partial response (VGPR) or better to first-line treatment (44%) compared with patients with partial suppression (68%) or preserved uninvolved immunoglobulins (64%; P<0.0001). In addition, patients with suppression of all the uninvolved immunoglobulins had a shorter survival compared with the respective comparators (median 18 vs 54 vs 52 months; P<0.0001). In the quantitative method, patients with a negative ARD were less likely to achieve VGPR or better (48%) and had a shorter survival (median 24 months) compared with patients with a positive ARD (69%, 57 months, respectively; P<0.0001). In a multivariate analysis for survival, both assessment methods retained an independent impact. Significant immunoparesis has a negative impact on response and survival in newly diagnosed AL amyloidosis.

Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.

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.

Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma.

We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30-8.77), P=0.013), eMP (OR=8.20 (3.19-21.05), P<0.001) and eHb (OR=5.86 (2.12-16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0-3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors.

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents.

Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.

Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma.

Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09-0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37-6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73-6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification.

Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma.

Early high-dose therapy (HDT), consisting of high-dose melphalan and autologous stem cell transplantation following doublet or triplet novel agent induction, is a preferred management strategy for transplant-eligible myeloma patients. We set out to examine the utility of the current fluorescence in situ hybridization (FISH)-based risk stratification in a homogenously treated population of transplant-eligible myeloma patients receiving novel induction regimens and early HDT with or without posttransplant maintenance therapy. FISH was available in 409 patients at the time of diagnosis for patients receiving HDT within 12 months of diagnosis. We present comprehensive outcomes for chromosome 14 translocations and 17p abnormalities that both support and refute current risk stratification models. In contrast to its current classification as a marker of 'standard risk' (SR), t(11;14) was associated with inferior overall survival (OS) when compared with the classical SR cohort. The use of novel agent maintenance therapy (bortezomib or lenalidomide) following early HDT ameliorates the negative prognostic value of high-risk (HR) cytogenetic markers. HR patients who received maintenance following early HDT had similar OS compared with the SR cohort at 5 years.

Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment.

Although clinical improvement is almost universal with therapy in patients with POEMS (an acronym for polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and a variety of skin changes) syndrome, outcomes and management of patients who relapse or progress (R/P) after first-line treatment have not been described. We retrospectively identified 262 patients with POEMS syndrome treated at the Mayo Clinic from 1974 to 2014 and who had follow-up information. The 5-year progression-free survival (PFS) and overall survival (OS) was 58% and 78%, respectively. Median time to R/P was 42 months. Seventy-nine patients (30%) had an R/P, with 52 (19%) experiencing a symptomatic R/P. Eighteen patients relapsed with symptoms or signs that were not documented at diagnosis. Median times to vascular endothelial growth factor, hematologic, radiographic and clinical R/P were 35 months (range, 4-327 months), 72 months (range, 4-327 months), 51 months (range, 4-327 months) and 48 months (range, 6-311 months), respectively. On multivariate analyses, low albumin at diagnosis and failure to achieve a complete hematologic response to first-line therapy were independent risk factors for PFS. Thirty patients had documentation of a second R/P at a median of 26 months from diagnosis of the first R/P. An early R/P was a risk factor for death, but most patients with an R/P had salvageable disease. A majority of patients are still without R/P at 5 years from diagnosis.

Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death.

Importance of interphase fluorescent in situ hybridization (FISH) with cytoplasmic staining of immunoglobulin FISH (cIg-FISH) on bone marrow is not well understood in light chain amyloidosis (AL). This is in contrast with multiple myeloma where prognostic and treatment related decisions are dependent on cytogenetic testing. This retrospective study reviewed 401 AL patients with cIg-FISH testing performed at our institution between 2004 and 2012. Eighty-one percent of patients had an abnormal cIg-FISH. Common abnormalities involved translocations of chromosome 14q32 (52%), specifically: t(11;14) (43%), t(14;16) (3%) and t(4;14) (2%). Other common abnormalities include monosomy 13/deletion 13q (30%), trisomies 9 (20%), 15 (14%), 11 (10%) and 3 (10%). Median overall survival for this cohort of patients is 3.5 years. When plasma cell burden was greater than 10% trisomies predicted for worse survival (44 vs 19 months), and when it was ⩽10% t(11;14) predicted for worse survival (53 months vs not reached). Abnormal cIg-FISH was significantly associated with advanced cardiac involvement, and remained a prognostic factor on multivariate analysis. This large AL cohort demonstrates that abnormal FISH at diagnosis is prognostic for survival and advanced cardiac disease. Particularly, trisomies and t(11;14) affect survival when degree of plasma cell burden is considered.

Utility of serum free light chain measurements in multiple myeloma patients not achieving complete response to therapy.

Normalization of the serum-free light-chain ratio (FLCr) with the absence of bone marrow monoclonal plasma cells following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma (MM), and is associated with improved overall survival (OS). However, its value in patients achieving

Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma.

Renal impairment (RI) is seen in over a quarter of patients with newly diagnosed multiple myeloma (NDMM). It is not clear if reversal of RI improves the outcome to that expected for NDMM patients without RI. We evaluated 1135 consecutive patients with NDMM seen at the Mayo Clinic between January 2003 and December 2012. RI was defined as having a creatinine clearance (CrCl) <40ml/min. The median overall survival (OS) for patients with RI at diagnosis receiving and not receiving novel agent induction therapy was not reached vs 46 months (P<0.001). The median OS for patients with CrCl ⩾40 ml/min at diagnosis, CrCl <40 ml/min at diagnosis but improved to ⩾40 ml/min and CrCl <40 ml/min at diagnosis and remained <40 ml/min, were 112, 56 and 33 months, respectively (P<0.001). The complete renal response rate for patients with RI at diagnosis receiving novel agent induction therapy compared to the rest was 40 vs 16% (P<0.001). In conclusion, patients with reversal of RI have improved outcomes, but it remains inferior to patients with normal renal function at diagnosis. These results have implications for identifying early treatment strategies for patients at risk of developing renal insufficiency.

High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis.

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.