Muchtar, E

Abstract Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high‐dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty‐five patients required ostomies with all surviving surgery. Twenty‐four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8–59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti‐myeloma treatment appears to be safe.

Abstract 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.

AbstractResponse assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.

AbstractWe evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10−5; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD‐negative rate after one‐line of therapy was 71% (20/28). And, MRD negative rates were higher with stem‐cell transplant as first‐line therapy (86%, 18/21) vs chemotherapy alone as first‐line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD‐negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow‐up of 14 months, the estimated 1‐year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk‐adapted trials may help optimize treatment in AL amyloidosis.

Key PointsPatients with an abnormal sFLC ratio because of LC suppression have outcomes similar to those with a normal ratio. sFLC ratio has prognostic value in patients achieving CR who have an absence of clonal BMPCs assessed by MFC.

AbstractOur prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R‐ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009 to 2017. Those patients that had ≥5 cPCs/μL and either R‐ISS stage I or stage II disease were re‐classified as R‐ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥5 cPCs/μL at diagnosis was as follows: R‐ISS I (N = 110) ‐ 40 months and not reached; R‐ISS II (N = 69) ‐ 30 and 72 months; R‐ISS IIB (N = 96) ‐ 21 and 45 months and R‐ISS III (N = 281) ‐ 20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R‐ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.

AbstractHistological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high‐grade lymphoma, with median time‐to‐transformation of 4.5 (range 0‐21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non‐transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1‐23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time‐to‐transformation (HR 7.9 [95%CI: 2.3‐27; P = .001]), with a 5‐year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8‐6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time‐to‐transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.