"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.

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.

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.

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.

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.

Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.

Autologous stem cell transplantation (ASCT) is an important treatment modality in light chain (AL) amyloidosis. Use of reduced-dose melphalan conditioning is common, given the associated organ and functional decline. The impact of full-intensity melphalan conditioning (n=314) was compared to reduced-dose conditioning (n=143). Patients in the full-intensity group were younger, with better performance status, fewer involved organs, lower tumor burden and lower Mayo stage. Full-dose conditioning was associated with higher rate of very good partial response or better (79% vs 62%; P<0.001), complete response rate (53% vs 37%; P=0.003) and organ response rate (74% vs 59%; P=0.002) as compared to reduced-dose conditioning. PFS was superior in the full-intensity group compared to the reduced-dose group (4-year PFS 55% vs 31%; P<0.001) as well as a longer overall survival (OS) 4-year OS (86% vs 54%; P<0.001). In addition, the OS and PFS were significantly lower in the reduced-dose group compared to the full-intensity group in Mayo stage III/IV as well as stage I/II. A multivariate analysis confirmed an independent impact for conditioning dose on PFS/OS. This study calls for re-assessment of the use of reduced-dose conditioning in ASCT for AL amyloidosis.

The impact of induction regimen on transplant outcome in newly diagnosed multiple myeloma in the era of novel agents.

We compared overall survival (OS) of 1017 patients with newly diagnosed multiple myeloma (MM) who were treated with different novel agent-based induction regimens and who underwent early autologous stem cell transplant (ASCT). Subgroups were defined by type of induction therapy: cyclophosphamide-bortezomib-dexamethasone (CyBorD; n=193), bortezomib-dexamethasone (Vd; n=64), lenalidomide-dexamethasone (Rd; n=251), bortezomib-lenalidomide-dexamethasone (VRd; n=126), thalidomide-dexamethasone (Td; n=155) and vincristine-doxorubicin-dexamethasone or dexamethasone alone (VAD/Dex; n=228). The median follow-up of the surviving patients was 66.7 months. The 5-year OS rates with CyBorD, Vd, Rd, VRd, Td and VAD/Dex were 79.2%, 72.3%, 79.2%, 79.0%, 57.4% and 63.4%, respectively (log-rank, P<0.001). In a multivariate analysis, after controlling for important patient and disease variables, VRd had a superior OS compared with CyBorD (hazard ratio (HR), 0.32; 95% confidence interval (CI), 0.10-0.88; P=0.03) and Vd (HR, 0.16; 95% CI, 0.04-0.52; P=0.002). In conclusion, our study demonstrates that among patients completing induction therapy and continuing to early transplant, VRd induction leads to improved OS compared with CyBorD and Vd regimens.

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.

Risk stratification in myeloma by detection of circulating plasma cells prior to autologous stem cell transplantation in the novel agent era.

The impact of circulating plasma cells (CPCs) prior to autologous stem cell transplantation (ASCT) for multiple myeloma has not been defined in the novel agent era. We evaluated the impact of pre-transplant CPCs, detected by six-color flow cytometry in patients undergoing early ASCT on post-transplant response, progression-free survival (PFS) and overall survival (OS). CPCs were detected in 162 out of 840 (19.3%) patients, with the median number of CPCs being 58 per 150 000 events. Ninety-nine percent of patients had received proteasome inhibitor and/or immunomodulator-based induction. The incidence of post-transplant stringent complete response (sCR) in the subgroups with and without CPCs was 15% and 38%, respectively, (P<0.001). The median PFS in the subgroups with and without CPCs was 15.1 (95% confidence interval (CI), 12.5-17.8) and 29.6 months (95% CI, 26.2-32.8), respectively, and the median OS was 41.0 months (95% CI, 32.6-58.2) and not reached (NR) (95% CI, 99.1-NR), respectively, (P<0.001 for both). On multivariate analysis for OS, factors independently predictive of mortality were the presence of CPCs (hazard ratio (HR) 2.5; 95% CI, 1.8-3.6; P<0.001) and sCR post transplant (HR 0.4; 95% CI, 0.2-0.6; P<0.001). Presence of CPCs prior to transplant has a high prognostic impact and should be prospectively validated in clinical trials.

Autologous stem cell transplant for multiple myeloma patients 70 years or older.

Autologous stem cell transplant (Auto-SCT) is increasingly used in older patients with multiple myeloma (MM), despite lack of phase 3 trials in this age-defined population. For 207 consecutive MM patients who underwent Auto-SCT and were 70 years or older at transplant (study cohort), data were analyzed and compared with a younger cohort (1764 Auto-SCT patients <70 years old). The proportion of Auto-SCT in the older patients increased from 7.8% of all transplants in 1998-2006 to 12.9% in 2007-2015. Sixty percent of patients required stem cell mobilization with chemotherapy or plerixafor. Full-dose melphalan conditioning was given to 55% of the older patients compared with 93% of the younger patients (P<0.001). Older patients were more likely to be hospitalized (64% vs 55%; P=0.01), but hospitalization duration was comparable. For newly diagnosed patients, median PFS was 33.5 months for the older cohort and 33.8 months for the younger cohort (P=0.91), and median overall survival was 6.1 and 7.8 years, respectively (P=0.11). Presumably, a smaller fraction of patients, age 70-76, is selected for Auto-SCT, but the benefits are comparable to those seen for younger patients. Reduced-dose melphalan was given to approximately half the patients to avoid excessive toxicity.

Surgical site infections following craniotomy focusing on possible post-operative acquisition of infection: prospective cohort study.

Neurosurgery is characterized by a prolonged risk period for surgical site infection (SSI), mainly related to the presence of cerebrospinal fluid (CSF) drains. We aimed to examine factors associated with post-neurosurgical SSIs, focusing on post-operative factors. A prospective cohort study was conducted in a single center over a period of 18 months in Israel. Included were adult patients undergoing clean or clean-contaminated craniotomy, including craniotomies with external CSF drainage or shunts. SSIs were defined by the Centers for Disease Control and Prevention (CDC) criteria for healthcare-associated infections. All patients were followed up for 90 days and those with foreign body insertion for 1 year. We compared patients with and without SSI. A multivariable regression analysis for SSI was conducted including uncorrelated variables significantly associated with SSI. A total of 502 patients were included, with 138 (27.5%) undergoing emergent or urgent craniotomy. The overall SSI rate was 5.6% (28 patients), of which 3.2% (16 patients) were intracerebral. Non-elective surgery, external CSF drainage/monitoring devices, re-operation, and post-operative respiratory failure were independently associated with subsequent SSI. External CSF devices was the only significant risk factor for intracerebral SSIs (p < 0.001). Internal shunts or other foreign body insertions were not associated with SSIs. A phenotypically identical isolate to that causing the SSI was isolated from respiratory secretions prior to the SSI in 4/9 patients with microbiologically documented intracerebral SSIs. Patients with SSIs had longer hospital stay, poorer functional capacity on discharge, and higher 90-day mortality. We raise the possibility of post-operative infection acquisition through external CSF devices. Standard operating procedures for their maintenance are necessary.

Benchmarking inappropriate empirical antibiotic treatment.

Inappropriate empirical antibiotic treatment for severe infections is associated with increased mortality. Superfluous treatment is associated with resistance induction. We aimed to define acceptable rates of inappropriate empirical antibiotic treatment. We included all prospective cohort studies published between 1975 and 2009 reporting the proportion of appropriate and inappropriate empirical antibiotic treatment of microbiologically documented infections. Studies were identified in PubMed and in reference lists of included studies. Funnel plots were drawn using the proportion of inappropriate empirical treatment as the effect size. A pooled estimate of inappropriate empirical antibiotic treatment was calculated using a ß-binomial model. Control limits were calculated with the overdispersion factor technique and 20% winsorized data. Heterogeneity was assessed through subgroup analysis for categorical moderators and meta-regression for continuous variables. Eighty-seven studies, comprising 92 study groups, with 27 628 patients met inclusion criteria. The pooled rate of inappropriate empirical antibiotic treatment was 28.6% (95% CI 25.4-31.8). Funnel plot analysis yielded a dispersed graph with only 37 (40%) studies falling within the control limits. Using the overdispersion factor technique with 20% winsorizing, 79 (86%) studies fell within the control limits. None of the clinical or methodological factors could explain the large heterogeneity observed. The funnel plot presented can be used to benchmark rates of inappropriate empirical antibiotic treatment. Based on the control limits found, at least 500 patients should be evaluated before establishing a local rate. Lower and higher than expected rates might indicate overly aggressive treatment or poor performance, respectively.