Citations

Summary In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma‐defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36‐month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%–97.42%), with a trend towards longer OS in the SLiM cohort ( p = 0.065). The 36‐month progression‐free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%–97.87%) and 65.95% in the control group (95% CI 52.31%–76.53%). There was no difference in the PFS between the cohorts ( p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Background: Transthyretin cardiac amyloidosis (ATTR-CA) carries an elevated risk of developing ventricular arrhythmias (VA) but there remains limited evidence supporting the role of catheter ablation in this population. Purpose: To assess the safety and efficacy of catheter ablation for VA in ATTR-CA. Methods: An electronic database was used to identify all patients suspected of having ATTR-CA who underwent catheter ablation for VA at our institution between January 2010 and December 2023. Patients who did not meet the diagnosis of ATTR-CA and had a negative workup who underwent catheter ablation for ventricular tachycardia (VT) or premature ventricular contractions (PVCs) were used to form a control group matched for age, sex and left ventricular ejection fraction at a ratio of 2:1. Results: 20 controls and 10 cases of ATTR-CA were identified. Examining the two groups at baseline (Table 1), the mean age at index ablation was 67.7±7.0 and 68.6±8.1 years (p=0.359), mean follow-up time was 4.1±3.1 and 4.2±2.6 years (p=0.494), and the proportion of males was 100% and 90% respectively. The ATTR-CA group had a significantly higher proportion of chronic kidney disease (90% vs. 50%, p=0.032) and prior stroke or thrombotic events compared to the control group (50% vs. 10%, p=0.026) with similar CHA 2 DS 2 VASc scores (4.2±1.6 vs. 3.8±1.3, p=0.233). Both groups had comparable left ventricular ejection fraction (41.4%±14% vs. 46.9%±15.2%, p=0.173), VT/PVCs at presentation (40%/60% vs. 25%/75%, p=0.77), use of antiarrhythmics (70% vs. 60%, p=0.592), and high proportion of atrial fibrillation/flutter (70% vs. 90%, p=0.168). Procedural (261.2±101.2 vs. 265.7±125.6 mins, p=0.449) and total energy delivery time (1442.9±1509.1 vs. 1744.6±956.2 secs, p=0.296) was not significantly different in the two groups. Both groups had a significant decrease in PVC burden postablation with a reduction from 26.8% to 3.8% (p=0.024) and from 27.1% to 13.6% (p=0.028) in the ATTR-CA and control group respectively. A downward trend was seen in antitachycardia pacing events for VT postablation in the ATTR-CA (14.7±9.8 vs. 5.3±6.7, p =0.184) and control (193±387.6 vs. 0.67±1.2. p=0.139) groups. No major complications occurred after ablation (Table 2). Mean time to recurrence post-index ablation was similar between both groups (1620.4±483.8 vs. 1498.8±291.4 days, p=0.987, Figure 1). Conclusions: Catheter ablation appears to be safe and effective for VT and PVCs in patients with ATTR-CA.

AbstractIntroductionLittle is known regarding the prevalence and prognostic implications of non‐sustained ventricular tachycardia (NSVT) in patients with wild‐type transthyretin cardiac amyloidosis (ATTRwt‐CA). We aimed to investigate the prevalence of NSVT in patients with ATTRwr‐CA, and the association of NSVT with sustained ventricular arrhythmias (VA) and all‐cause mortality.MethodsIn a cohort of ATTRwt‐CA patients from 2011 to 2022 without prior sustained VA, we ascertained the presence and characteristics of NSVT during clinically indicated ambulatory Holter monitoring. Patients were stratified based on the presence of NSVT at baseline. The primary and secondary endpoints of sustained VA and all‐cause mortality, respectively, were assessed during follow‐up.ResultsThe cohort included 217 patients with ATTRwt‐CA (95% males, median age 75 years; median NYHA class 2). Baseline Holter monitoring demonstrated NSVT in 116 (53%) patients. During a median follow‐up of 27 months (IQR 16–45) after the index Holter monitor, 11 (5.1%) patients reached the primary endpoint of sustained VA (incidence 1.8 per 100 person‐years, all monomorphic VT), and 46 (21%) patients died. In univariable Cox proportional hazard model, NYHA class 3 or 4 heart failure (p = .048), the presence of NSVT (p = .04), the duration of longest NSVT run (p = .029), and the percentage of ventricular ectopy (p < .001) were associated with the primary outcome. When adjusting for age and NYHA class 3 or 4 heart failure, the presence of NSVT remained associated with the primary outcome (p = .03). All‐cause mortality was not significantly different between patients with and without NSVT. A cutoff for ventricular ectopy burden of 0.5%, the median for all patients in this study, was associated with increased risk in sustained VA (log‐rank p = .004) and mortality (log‐rank p = .02).ConclusionNSVT is highly prevalent among ATTRwt‐CA patients undergoing clinically indicated Holter monitoring and may confer an increased risk of incident sustained VA.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.

Abstract Background Hypergammaglobulinemia poses a challenge for identifying and quantitating monoclonal proteins (M-protein). The Increased polyclonal immunoglobulin background can lead to imprecise estimation of the M-protein when quantitated by serum protein electrophoresis (SPEP). This is especially true using the perpendicular drop method of peak integration. Hypergammaglobulinemia also makes it difficult to detect small M-proteins on immunofixation electrophoresis. Overestimation of M-protein concentration can lead to unnecessary follow-ups while missing small M-proteins can mask the underlying diagnosis for patients. In this study, we retrospectively evaluated the prevalence and concentration of M-protein within polyclonal hypergamma backgrounds using immunocapture matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX). Methods We retrospectively analyzed 47061 unique patients tested for SPEP and MASS-FIX in 2022 at Mayo Clinic. If a patient underwent multiple tests during this period, only the first result was included in the analysis. Polyclonal hypergammaglobulinemia was defined as a gamma fraction &gt;1.7g/dL by SPEP. MASS-FIX was used to identify and isotype M-proteins. MASS-FIX was then combined with total immunoglobin quantitation (IgG, IgA or IgM) using nephelometry to quantify concentration of the M- protein using mathematical modeling (method currently under validation). Results Of the 47,061 unique patients, 24,796 were normal by SPEP (53%). M-spikes were present in 5,808 cases (12%). Hypogammaglobulinemia (gamma fraction &lt; 0.5g/dL) in 2897 cases (6%). Small non-quantifiable M-proteins by SPEP were present in 8363 cases (18%). [JC2] There were 4222 hypergamma cases in the cohort (9%), without a quantitative M-spike on SPEP. Of these, 16.1% (680/4222) patients had an M-protein by MASS-FIX. When polyclonal hypergamma was the sole SPEP abnormality, 5.5% were MASS-FIX positive. However, when a small abnormality pattern was observed within the polyclonal hypergamma background on SPEP, 50% of patients were MASS-FIX positive. The most common isotype was IgG (27.2%), followed by IgM (10.2%), IgA (8.1%), and biclonal (3.7%), which is similar to overall isotype distribution in other backgrounds. Using quantitative MASS-FIX, we identified that 95% MASS-FIX positive small monoclonal proteins in polyclonal hypergamma are &lt; 1 g/dL, which is the recommended limited of quantitation for M-protein using SPEP in setting of hypergammaglobulinemia. Conclusion Majority of polyclonal hypergammaglobulinemia cases (83.9%) do not have a monoclonal protein. MASS-FIX allows quantitation of small monoclonal proteins below the SPEP limit of quantitation, which can enhance our understanding of conditions which present with small M-proteins in a polyclonal hypergammaglobulinemia background. Small visual abnormalities within polyclonal hypergamma background on SPEP should be followed-up with immunofixation or MASS-FIX to confirm the presence or absence of M- proteins.

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

Abstract Aims We aim to determine if our previously validated, diagnostic artificial intelligence (AI) electrocardiogram (ECG) model is prognostic for survival among patients with cardiac amyloidosis (CA). Methods A total of 2533 patients with CA (1834 with light chain amyloidosis (AL), 530 with wild-type transthyretin amyloid protein (ATTRwt) and 169 with hereditary transthyretin amyloid (ATTRv)] were included. An amyloid AI ECG (A2E) score was calculated for each patient reflecting the likelihood of CA. CA stage was calculated using the European modification of the Mayo 2004 criteria for AL and Mayo stage for transthyretin amyloid (ATTR). Risk of death was modelled using Cox proportional hazards, and Kaplan–Meier was used to estimate survival. Results Median age of the cohort was 67 [inter-quartile ratio (IQR) 59, 74], and 71.6% were male. The median overall survival for the cohort was 35.6 months [95% confidence interval (CI) 32.3, 39.5]. For AL, ATTRwt and ATTRv, respectively, median survival was 22.9 (95% CI 19.2, 28.2), 47.2 (95% CI 43.4, 52.3) and 61.4 (95% CI 48.7, 75.9) months. On univariate analysis, an increasing A2E score was associated with more than a two-fold risk of all-cause death. On multivariable analysis, the A2E score retained its importance with a risk ratio of 2.0 (95% CI 1.58, 2.55) in the AL group and 2.7 (95% CI 1.81, 4.24) in the ATTR group. Conclusions Among patients with AL and ATTR amyloidosis, the A2E model helps to stratify risk of CA and adds another dimension of prognostication.