Systemic amyloidosis from A (AA) to T (ATTR): a review.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

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.

Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis.

Inherited forms of amyloidosis are rare; of these, transthyretin-related (ATTR) is the most common, but non-ATTR has been described as well. We studied a large case series of ATTR and a small series of non-ATTR to better determine the mutation frequencies and geographic distributions of these inherited forms of amyloidosis in the United States. We performed a retrospective cross-sectional study of 284 ATTR and non-ATTR patients seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970 through 29 January 2013. Mutations were identified by DNA sequencing, restriction fragment length polymorphism, or mass spectroscopy. The genetic testing method was unknown for several patients, but a small proportion were identified by family history or by classical clinical presentation associated with a specific mutation. The most common ATTR mutations were Thr60Ala (24%), Val30Met (15%), Val122Ile (10%), and Ser77Tyr (5%). Non-ATTR mutations included gelsolin (n = 3), apolipoprotein A-I (n = 6), apolipoprotein A-II (n = 1), fibrinogen A-α (n = 9), and lysozyme (n = 1). Although rare, ATTR and, to a lesser extent, non-ATTR are prevalent in the United States and should be considered for patients presenting in the appropriate clinical context.

Computed tomography assessment of bone lesions in patients with POEMS syndrome.

OBJECTIVES: To describe the imaging findings on computed tomography (CT) and skeletal survey (SS) in patients with POEMS syndrome. METHODS: We retrospectively reviewed, with institutional review board approval, the dysproteinemia database at our institution for patients with new diagnosis of POEMS syndrome between January 1998 and December 2008. Twenty-four patients were identified with PET/CT or CT and had skeletal survey (SS) available for review. RESULTS: Twenty-four patients were included in the study group with median age of 47 years. All CTs demonstrated at least one sclerotic lesion. The most common pattern was multiple small lesions, with 18 patients (75%) having at least 5 lesions less than 1 cm. The larger lesions had a central lytic component and were FDG avid. SS had a false negative rate of 36% (8 patients). Serial CT after treatment showed a decrease in size and number of sclerotic lesions in 53% of cases (13 patients), the majority showing increased sclerosis. Two patients had complete resolution of sclerotic lesions. CONCLUSIONS: CT identified sclerotic lesions in all study patients with POEMS syndrome, the majority being less than 1 cm in size, which were not identified radiographically. CT may demonstrate increased sclerosis or even resolution of sclerotic lesions corresponding to treatment response. KEY POINTS: • CT has high sensitivity in identifying sclerotic lesions in POEMS syndrome • Most common CT patterns are multiple, less than 1 cm, sclerotic lesions • Larger lesions have lytic centres and sclerotic margins • Skeletal surveys may have a false negative rate of 36% • Treatment response includes increased sclerosis, decrease in size or resolution of lesions.

Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses.

Oncolytic viruses can be neutralized in the bloodstream by antiviral antibodies whose titers increase progressively with each exposure, resulting in faster virus inactivation and further reductions in efficacy with each successive dose. A single dose of cyclophosphamide (CPA) at 370 mg m(-2) was not sufficient to control the primary antiviral immune responses in mice, squirrel monkeys and humans. We therefore tested clinically approved multidose CPA regimens, which are known to kill proliferating lymphocytes, to determine if more intensive CPA therapy can more effectively suppress antiviral antibody responses during virotherapy. In virus-susceptible mice, primary antibody responses to intravenously (i.v.) administered oncolytic measles virus (MV) or vesicular stomatitis virus (VSV) were partially or completely suppressed, respectively, by oral (1 mg × 8 days) or systemic (3 mg × 4 days) CPA regimens initiated 1 day before virus. When MV- or VSV-immune mice were re-challenged with the respective viruses and concurrently treated with four daily systemic doses of CPA, their anamnestic antibody responses were completely suppressed and antiviral antibody titers fell significantly below pre-booster levels. We conclude that the CPA regimen of four daily doses at 370 mg m(-2) should be evaluated clinically with i.v. virotherapy to control the antiviral antibody response and facilitate effective repeat dosing.

Serum BCMA levels predict outcomes in MGUS and smoldering myeloma patients.

Soluble BCMA (sBCMA) levels are elevated in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the association between sBCMA levels and prognosis in MGUS and SMM has not been studied. We retrospectively analyzed sBCMA levels in stored samples from 99 MGUS and 184 SMM patients. Baseline sBCMA levels were significantly higher in MGUS and SMM patients progressing to MM during clinical follow up. When stratified according to the median baseline sBCMA level for each cohort, higher levels were associated with a shorter PFS for MGUS (HR 3.44 comparing sBCMA ≥77 vs <77 ng/mL [95% CI 2.07-5.73, p < 0.001] and SMM (HR 2.0 comparing sBCMA ≥128 vs <128 ng/mL, 95% 1.45-2.76, p < 0.001) patients. The effect of sBCMA on PFS was similar even after adjusting for the baseline MGUS or SMM risk stratification. We evaluated paired serum samples and found that sBCMA increased significantly in MGUS and SMM patients who eventually progressed to MM, whereas among MGUS non-progressors the sBCMA level remained stable. While our results require independent validation, they suggest that sBCMA may be a useful biomarker to identify MGUS and SMM patients at increased risk of progression to MM independent of the established risk models.

"Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

Impact of additional cytoreduction following autologous SCT in multiple myeloma.

Reported results of high-dose therapy (HDT) reflect the combined effect of initial therapy and HDT. The incremental contribution of HDT is often difficult to analyze with varying degrees of response pre-HDT. Here we analyze results of HDT in patients with measurable disease at transplant, defined as a serum or 24 h urine M protein of >1.0 g per 100 ml and >200 mg per day, respectively. Paraprotein responses were calculated using measurements prior to HDT and the lowest subsequent measurement. A total of 431 patients were studied; 264 (61.3%) transplanted within 1-year of diagnosis. An additional reduction in paraprotein by 50% following HDT was seen in 86% patients; with 129 patients (30%) obtaining a 90% reduction. Patients with at least a 90% reduction had longer time to progression with no overall survival advantage and this was independent of other prognostic factors for decreased risk of progression. This study provides an estimate of the degree of tumor reduction provided by HDT, in addition to that provided by the initial therapy. In this group of patients with measurable disease after initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a 90% reduction in another 7%, an outcome associated with better progression-free survival.

Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT.

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma. Previous studies have suggested a lack of impact of the initial therapy on the outcome after ASCT. It is not clear if incorporation of new agents in the initial treatment regimens will have any impact on the outcome after ASCT. We studied 472 patients undergoing ASCT within 12 months of diagnosis to assess the effect of initial therapy on the outcome after ASCT. Patients received initial therapy with vincristine, adriamycin and dexamethasone (VAD), dexamethasone, thalidomide and dexamethasone or lenalidomide and dexamethasone. While patients treated with dexamethasone alone had higher disease burden at ASCT, no differences were observed in the response rates to ASCT, post transplant complications or treatment-related mortality among the groups. The median time to progression after ASCT was 27.1, 24.7, 21.1 months and did not reach the VAD, Dex, Thal-Dex and Len-Dex group, respectively, P=0.11. The median overall survival from ASCT was 62 months for VAD, 69.6 months for Dex and were not reached for Thal-Dex and Len-Dex groups, P=0.2. For patients undergoing early ASCT for myeloma, the nature of initial treatment utilized has no long-term impact on the outcome of ASCT.

Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma.

While initial therapies have become highly effective with introduction of lenalidomide and bortezomib and patients may opt for delayed stem cell transplantation, it is important to collect stem cells for future transplant. Given its increasing use as initial therapy, we examined if lenalidomide had any impact on the ability to collect peripheral blood stem cells (PBSC). We studied the entire cohort of patients with myeloma undergoing PBSC mobilization at our institution during a 5-year period, comparing the results between patients receiving different initial therapies. Among those mobilized with granulocyte-colony stimulating factor (G-CSF) alone, there was a significant decrease in total CD34(+) cells collected (P<0.001), average daily collection (P<0.001), day 1 collection (P<0.001) and increased number of aphereses (P=0.004) in patients treated with lenalidomide compared to those receiving dexamethasone, thalidomide-dexamethasone or VAD. A similar trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration of lenalidomide therapy as well as increasing age (P=0.002). There was no effect on quality of PBSC collected based on similar engraftment across all groups. We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to minimize the risk of mobilization failures.

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy.

Clinical outcomes for multiple myeloma (MM) are highly heterogeneous and it is now clear that pivotal genetic events are the primary harbingers of such variation. These findings have broad implications for counseling, choice of therapy and the design and interpretation of clinical investigation. Indeed, as in acute leukemias and non-hodgkins lymphoma, we believe it is no longer acceptable to consider MM a single disease entity. As such, the accurate diagnosis of MM subtypes and the adoption of common criteria for the identification and stratification of MM patients has become critical. Herein, we provide a consensus high-risk definition and offer practical guidelines for the adoption of routine diagnostic testing. Although acknowledging that more refined classifications will continue to be developed, we propose that the definition of high-risk disease (any of the t(4;14), t(14;16), t(14;20), deletion 17q13, aneuploidy or deletion chromosome 13 by metaphase cytogenetics, or plasma cell labeling index >3.0) be adopted. This classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued. Conversely, the 75% of patients remaining have more favorable outcomes using existing - albeit non-curative - therapeutic options.

Elevated pre-transplant C-reactive protein identifies a high-risk subgroup in multiple myeloma patients undergoing delayed autologous stem cell transplantation.

The significance of elevated C-reactive protein (CRP) prior to autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has not been studied. We analyzed 1111 MM patients who underwent ASCT at Mayo Clinic from 2007 to 2015. A total of 840 patients (76%) received early ASCT (⩽12 months from diagnosis) and 271 patients (24%) received delayed ASCT (>12 months from diagnosis). Elevated CRP (> upper normal limit (8 mg/L)) was seen in 14% and 22% of patients undergoing early and delayed ASCT, respectively (P=0.003). There was no correlation of CRP with pre-transplant response, bone marrow plasma cell percentage or labeling index. Patients with an elevated CRP had a higher likelihood of having circulating plasma cells prior to ASCT (33 vs 19%; P<0.001). In the early ASCT cohort, the median overall survival (OS) in patients with normal and elevated CRP was not reached and 91 months respectively (P=0.011). In the delayed ASCT cohort, the median OS in respective groups were 73 and 30 months respectively (P<0.001), with elevated CRP being an independent prognostic marker on multivariate analysis (hazard ratio 2.0; 95% confidence interval, 1.0-3.8; P=0.045). Elevated pre-transplant CRP identifies a high-risk population especially in patients undergoing delayed ASCT and should be incorporated in the pre-transplant evaluation.

Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation.

Post-transplant maintenance is widely used in multiple myeloma (MM); however, there is a lack of data on real-world outcomes. We have analyzed 577 patients with newly diagnosed MM undergoing early auto-transplantation between 2010 and 2015. A total of 341, 132 and 104 patients received no, lenalidomide (Len) or bortezomib (Bort) maintenance, respectively. Patients receiving Len or Bort maintenance had a higher incidence of high-risk cytogenetics by fluorescence in situ hybridization (31% (Len) vs 58% (Bort) vs 8% (No); P<0.001). Len maintenance led to a superior progression-free survival (PFS) compared with no maintenance (median, 37 vs 28 months, respectively; P=0.002; adjusted hazard ratio 0.48 (95% CI, 0.35-0.66)), including in subgroups with ISS stage III disease (median, 40 vs 24 months; P=0.008) and high-risk cytogenetics (median, 27 vs 16 months; P=0.032). Bort maintenance did not confer PFS benefit for the entire cohort, but improved PFS in the high-risk cytogenetic subgroup (median, 28 vs 16 months; P=0.035). Discontinuation due to toxicity was seen in 17 and 7% of patients receiving Len or Bort maintenance, respectively. Our results indicate that post-transplant maintenance with Len or Bort is well tolerated in clinical practice and improves PFS in high-risk subgroups of MM patients.

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.

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.

Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

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.