Citations

Purpose: To describe ophthalmic manifestations of systemic amyloidosis, a group of devastating conditions. Methods: A retrospective chart review including patients who had ocular examinations at Mayo Clinic between January 1, 1985, and April 1, 2014, and a diagnosis of light-chain (AL), secondary (AA), or nontransthyretin familial amyloidosis was undertaken. Sixty-eight patients with AL amyloidosis, eight patients with AA amyloidosis, and five patients with nontransthyretin familial amyloidosis were included. Results: Of 68 patients, 8 patients (14 eyes) with AL amyloidosis had ocular involvement secondary to conjunctiva, temporal artery, extraocular muscle, trabecular meshwork, and cranial nerve deposition. One of the five patients with nontransthyretin familial amyloidosis had gelsolin-related corneal dystrophy. No patients with AA amyloidosis (n = 8) had ophthalmic manifestations. Conclusion: Systemic amyloidosis can lead to ocular morbidity. Patients with AL amyloidosis had involvement of the temporal artery, conjunctiva, extraocular muscles, trabecular meshwork, and cranial nerves. Those with gelsolin nontransthyretin familial amyloidosis were susceptible to corneal dystrophy. Patients with AA amyloidosis did not manifest ophthalmic involvement. Finally, if ocular amyloidosis is detected, patients should be referred for systemic workup.

AbstractAchievement of a normal FLC ratio (FLCr) following treatment indicates hematologic response and suggests better outcomes in light chain amyloidosis (AL). We examined if elevated involved free light chain (hiFLC) impacts outcomes in patients achieving normal FLCr. We retrospectively analyzed 345 AL patients who were diagnosed within a 10‐year period (2006‐2015) and had 2 consecutive normal FLCr values after 1st line treatment. Among these, patients with hiFLC at 1st reading of normal FLCr (hiFLC1; n = 166; 48.1%) were compared to those who did not (n = 179; 51.9%). Patients with AL who have hiFLC1 after initial therapy had higher rates of multi‐organ involvement (63.3 vs 46.4%; P = .002) and patients in advanced Mayo stage (42.9 vs 32.2%; P = .04) at diagnosis. The median progression free survival [PFS; 38.2 (95%CI; 26.4, 55.4) vs 67.1 (95%CI; 55.8, 88) months; P = .0002] and overall survival [OS; 94.4 (95%CI; 78, 107.1) vs not reached (NR, 95%CI; 116.1, NR) months; P < .0001] were lower in those who had hiFLC1. A more stringent comparison for patients with 2 consecutive hiFLC (hIFLC2; n = 111; 32.2%) versus not (n = 2234; 67.8%) showed consistent results [PFS; 27.1 (95%CI; 23, 53.8) vs 63.3 (95%CI; 55.4, 77) months; P < .0001 and OS; 78 (95% CI; 54.6, 98.8) vs NR (95%CI; NR, NR); P < .0001]. This poor prognostic impact of hiFLC on survival was independent of serum creatinine, Mayo stage, negative immunofixation status and inclusion of transplant in initial therapy on multivariate analysis. Hence, persistent elevation of iFLC predicts poor prognosis even among patients achieving normal ratio after initial therapy in AL.

Key Points Organ progression at second-line therapy predicated inferior survival. Patients relapsing from >VGPR had a longer time to develop organ progression.

AbstractOutside of clinical trials, experience with daratumumab‐based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43‐93) years. High‐risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1‐14) and time to first DCT from diagnosis was 4.3 years (range, 0.4‐13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty‐two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and “other” DCTs, respectively. Overall response rate was 47%. Median follow‐up was 5.5 months (95% CI, 4.2‐6.1). Median progression‐free survival (PFS) was 5.5 months (95% CI, 4.2‐7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta‐refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1‐2.4] vs 3.1 [95% CI, 2.1‐NR] vs 5.9 [95% CI, 5.0‐NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1‐6.0] vs 8.2 [95% CI, 4.6‐NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7‐5.9] vs NR [95% CI, NR‐NR]; P = .002). Non‐hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.

SummaryThe management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression‐free survival (PFS) and time‐to‐next‐therapy (TTNT) were 32 (95% confidence interval [CI]: 15–51) and 50 (95% CI: 35–60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23–not reached [NR]) and NR (95% CI: 37–NR), respectively. Twenty‐five (86%) of 29 genotyped patients harbored MYD88L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well‐tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed‐duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Introduction The role of cardiac implantable electronic device (CIED) therapy in patients with ATTR-wt (senile) amyloid is not very well defined. It is unknown whether there is mortality benefit or harm with the implantation of CIEDs. Methods We performed a retrospective analysis of a prospectively collected registry of patients with biopsy proven ATTR-wt amyloid with cardiac involvement. These patients were followed up at Mayo Clinic, Rochester, Minnesota between Jan 1, 1985 to Sep 30, 2015. The follow-up of these patients was done via personal communication (written or verbal) and entered into the database. During analysis these patients were subdivided on the basis of the presence or absence of a CIED, cardiac involvement or not, and all-cause mortality analysed. The implantation of a CIED was analysed as a time-dependent covariate in the survival of these patients and Kaplan-Meier (K-M) survival plots created. Comparison between groups with CIED and those without CIED was made. In addition, CIEDs were subdivided into permanent pacemakers (PPM), defibrillators (ICDs) and cardiac resynchronization devices (CRT-P/D). Mortality among the patients with each device subtype was estimated and compared to overall mortality. Results 409 patients with ATTR-wt and cardiac involvement were reviewed with CIEDs implanted in 101 (25%) patients. The median follow-up (25th, 75th centile) was 2.4 (1.1, 4.3) years. Utilisation of ICDs in this population was higher than the general community in Olmsted county. There was no association in the overall survival or evidence of harm with CIED utilisation in patients with ATTR amyloidosis and cardiac involvement. Conclusions CIEDs utilisation remains high in ATTR-wt with cardiac involvement. Due diligence is needed in selecting the optimal patient for benefit prior to the implantation of CIEDs in this cohort. Further research is required to pool multi-centre amyloid registry data and determine if there is mortality benefit.

SummaryThe significance of serum lactate dehydrogenase (LDH) in light chain (AL) amyloidosis has not been previously explored. We studied 1019 newly diagnosed patients and correlated the elevation of LDH above the upper limit of normal (ULN) with disease characteristics and outcome. Four hundred and nine patients had an LDH above ULN, representing 40% of the study population. Patients with an elevated LDH were older, were less likely to be male and had more extensive organ involvement compared to patients with a normal LDH. Patients with high LDH had greater cardiac and renal dysfunction. Elevated LDH was an independent prognostic marker for overall survival and for death within 6 months of diagnosis, but this was restricted to patients not eligible for stem cell transplant. Serum LDH may act as a marker for organ damage and should be explored as a potential marker for tissue healing and organ recovery.