Buadi, Francis K.

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 Purpose: Rearrangements involving the MYC protooncogene are common in newly diagnosed multiple myeloma, but their prognostic significance is still unclear. The purpose of this study was to assess the impact of MYC rearrangement on clinical characteristics, treatment response, and survival in patients with newly diagnosed multiple myeloma. Experimental Design: This is a retrospective study including 1,342 patients seen in Mayo Clinic in Rochester, MN, from January 2006 to January 2018, who had cytogenetic testing by FISH at diagnosis, including MYC testing using the break apart FISH probe (8q24.1). Results: A rearrangement involving MYC was found in 8% of patients and was associated with elevated β2-microglobulin, ≥50% bone marrow plasma cells, IgA multiple myeloma, and the cooccurrence of trisomies. There were no differences in overall response rates between patients with and without MYC rearrangement when induction chemotherapy was proteasome inhibitor (PI)-based, immunomodulatory drug (IMiD)-based or PI + IMiD-based. Overall survival was shorter in patients with MYC rearrangement compared with patients without MYC rearrangement (5.3 vs. 8.0 years, P < 0.001). MYC rearrangement was associated with increased risk of death on multivariate analysis when high-risk cytogenetic abnormalities, ISS stage III, and ≥70 years of age were included (risk ratio: 1.5; P = 0.007). Conclusions: MYC rearrangement is associated with high disease burden and is an independent adverse prognostic factor in patients with newly diagnosed multiple myeloma.

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.

e19513 Background: The outcome of patients with MM relapsing after ASCT used early in the disease course or after failure of initial therapy, is not well defined. We undertook this study to understand treatment approaches for patients relapsing after single ASCT. Methods: Patients relapsing after single ASCT were identified from a prospectively maintained database and relevant clinical data were extracted from medical records. Relapse and treatment responses were according to IMWG Uniform Response Criteria. Patients relapsing between Jan 2000 and 2008 were included in order to capture a recent cohort contemporaneous to availability of novel drugs. Results: We studied 487 patients who had relapsed following a single ASCT, of whom 351 (72%) had an early SCT (≤ 12 mos from diagnosis). The median estimated follow up for all patients was 27 mos, 50 mos and 69 mos from relapse, SCT and diagnosis respectively. The median overall survival (OS) from the time of relapse was 30 mos for the early SCT group and 21 months for the late SCT group. The median time to relapse following transplant was 15 mos (3–119) among early SCT group and 12 mos (3–76) among the late SCT group. Longer time to relapse as well as longer time from relapse to initiation of therapy were independent predictors of better outcome. Among the early group, nearly a third of the patients achieved a PR or better to first salvage therapy (Table), with another third achieving stable disease and 25% of patients did not have response data. The median progression free survival for the first salvage regimen was 8 mos; 18 mos for those with PR or better and 5 mos for those with SD as the best response. Data on the regimen 2, 3, 4, 5, and 6 were available for 211, 133, 84, 53 and 28 patients respectively. As expected, the response rates and the response duration decreased with increasing number of relapses. Conclusions: Patients relapsing after ASCT can obtain prolonged response duration with the currently available treatments. Those with a durable response to transplant and those not requiring initiation of therapy for long periods after disease relapse have favorable disease biology and have prolonged survival after relapse. The natural history of the disease provides a valuable benchmark for evaluation of newer treatment approaches. No significant financial relationships to disclose.

Abstract A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)–, immunomodulatory drug (iMiD)–, or PI plus IMiD–based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.

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.

AbstractTransplant‐associated thrombotic microangiopathy (TA‐TMA) has a wide range of presentations after hematopoietic stem‐cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA‐TMA. Among the 1451 HSCT recipients, early TA‐TMA occurred in 45 (3.1%) patients at a median of 27 (3‐91) days, and late TA‐TMA in 39 (2.7%) patients at a median of 303 (122‐2595) days. Patients with early TA‐TMA were more likely to have high blood calcineurin‐inhibitor levels (P < .001) and acute graph‐vs‐host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00‐1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98‐6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16‐0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03‐0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02‐0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.

e20520 Background: Cytogenetic abnormalities detected by FISH are found in the majority of multiple myeloma (MM) patients. Although their prognostic value has been studied extensively, less is known about their association with disease characteristics and treatment response. Methods: To address these questions, we designed a retrospective study including 2031 Mayo Clinic patients diagnosed with MM from 2004 to 2018. We compared baseline characteristics and treatment outcomes between primary cytogenetic groups: t(11;14), t(4;14), t(14;16), (14;20), t(6;14), unknown IgH translocation/del and trisomy (without IgH translocation). These included 373, 177, 78, 20, 18, 228 and 791 patients respectively. Kruskal-Wallis and Fisher’s exact tests were used for categorical and continuous variables respectively. Time to next treatment (TTNT) was estimated using Kaplan-Meier method and compared using Log-Rank test. Results: t(4;14), t(14;16), t(6;14) and t(14;20) groups were associated with hemoglobin < 10 g/dL, beta2microglobulin > 5.5 µg/ml, ISS stage 3 and ≥50% bone marrow plasma cells. The latter 3 groups were also associated with renal dysfunction (Cr ≥2 mg/dL) and higher urinary monoclonal protein. t(4;14) was associated with IgA isotype, serum monoclonal protein ≥1g/dL and plasma cell labeling index ≥1%. Light chain myeloma was more prevalent in patients with t(11;14). Overall response rate (ORR) to proteasome inhibitor (PI) induction was higher for those with IgH translocations (any) compared to trisomies (85% vs 77% P = 0.02), while ORR was higher for those with trisomies with immunomodulatory drug (IMiD) induction (90% vs 78% P < 0.01). The rate of ≥ very good partial response was higher for patients with high risk IgH translocations [t(4;14), t(14;16) or t(14;20)] compared to standard risk with PI-IMiD combination treatment (88% vs 65% P < 0.01). Otherwise, response rates did not differ between these 2 groups. TTNT was longer in patients with trisomies compared to those with IgH translocation with IMiD or PI-IMiD treatments (32.2 vs 19 and 44 vs 27.4 months, respectively P < 0.01). For all cytogenetic groups, better treatment responses and longer TTNT were seen with PI-IMiD combinations compared to other treatments. Conclusions: t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high risk disease characteristics. Patients with IgH translocations may have better response to PI induction compared to those with trisomies, while those with trisomies may have better response to IMiD treatment, with best outcomes for both seen with PI-IMiD combinations.

e20515 Background: IgA monoclonal proteins (MCPs), unlike IgG MCPs, often migrate in the beta region on serum protein electrophoresis (SPEP) which can lead to underestimation of their size due to the co-migration with physiologic proteins. In IgA multiple myeloma (MM), the utility of quantitative IgA levels in assessing disease response in comparison to SPEP is not well studied. Methods: We retrospectively analyzed 304 IgA MM patients, diagnosed between 2004 and 2018, with available serial MCP and quantitative IgA levels. Kaplan Meier analysis was used to estimate the median progression free survival (mPFS) using the IMWG criteria and our study definition of IgA progression (2 consecutive IgA values that are > 25% above the nadir IgA value and above upper limit of normal (ULN) of 356 mg/dL, and a detectable IgA MCP on serum immunofixation). The mPFS was defined as the time from treatment initiation until disease progression or death. Results: IgA MCP migrated in the beta region in 134 (44%) patients, and in the gamma region in 150 (56%) patients. At diagnosis the median MCP was 3 (IQR 1.9-4) g/dL and the median IgA was 3240 (IQR 2008-4420) mg/dL. The median time from treatment initiation to MCP nadir was 80 (IQR 42-144) days and median time to IgA nadir was 154 (IQR 90-238) days. At MCP nadir 40% of patients had an IgA above the ULN. All complete responders (n = 104) had normal IgA levels, with a median IgA of 54 (IQR 27-88) g/dL. A ≥90% decrease in IgA between treatment initiation and IgA nadir, compared to a < 90% decrease, was associated with a longer mPFS (34 vs. 20 months, p = 0.006) and overall survival (97 vs. 33 months, p = 0.003). Patients with serial MCP and IgA levels available prior to progression (n = 195) were used to compare the mPFS using the IMWG and IgA progression criteria. The mPFS using the IgA criteria was 32 (95% CI 29-39) months, versus 39 (95% CI 33-45) months using IMWG criteria. Overall, 92 (47%) patients progressed by both IMWG and IgA criteria. At the time of progression using the IgA criteria compared to at IMWG progression, the median hemoglobin was higher (13.3 vs. 11.6 g/dL, respectively, p < 0.001) and fewer patients had new symptomatic bone lesions (2% vs. 33%, respectively, p < 0.001). Conclusions: In IgA MM patients, monitoring quantitative IgA levels predicts disease response and allows for earlier detection of disease progression, prior to the development of end organ damage.