Leung, Nelson

8034 Background: Minimal residual disease (MRD) assessment in multiple myeloma (MM) has improved our ability to assess disease activity, resulting in more advanced prognostication. While MRD assessment remains confined to the bone marrow (BM) plasma cell population, serum studies including immunofixation (IFE) are required to complete response evaluation. The significance of those who are MRDneg yet have detectable monoclonal protein through IFE remains unclear. Methods: We retrospectively studied 256 MM patients who had MRD assessment via the Euroflow multiparametric flow cytometry on the BM with concomitant serum IFE testing. Patients who were MRDneg were included in the study. Outcomes included probability of disease progression (PD) at 1 year. The Cox-proportional hazards model was used to compare probability of PD among different groups. Time to progression (TTP) was calculated as the difference from date of MFC analysis to PD in months. Results: Among the entire cohort, 178 (70%) patients were MRDneg and median follow-up from MRD assessment was 6.3 months. Among these patients, 74 (42%) had a positive IFE at the time of MRD analysis. Within the MRDneg/IFEpos group, 31 (42%) patients remained IFEpos after a median follow up of 5.5 mo from initial MRD/IFE testing while 34 patients eventually became IFEneg after a median of 2.8 mo with no subsequent IFE available in 9 patients. The 1 year probability of PD in the MRDneg/IFEneg group was 20% compared to 41% in the MRDneg/IFEpos group (P < 0.01, Wilcoxon test). When comparing subsequent IFE status in those who were MRDneg/IFEpos, those who remained IFEpos had a trend towards shorter TTP compared to patients who later became IFEneg. Conclusions: Persistent monoclonal protein in the face of MRD negativity predicts for a shorter TTP. This likely reflects persistent disease that was not sampled on the BM aspirate in many of these patients compared to those who eventually become IFEneg with a trend towards longer TTP owing to the prolonged half-life and therefore clearance of M protein. This supports the current strategy of assessing for MRD at the time of suspected complete response to reduce the chance of positive MRD tests and thus avoidance of multiple BM exams.

8031 Background: Our prior studies identified the prognostic significance of ≥400 cPCs/150,000 analyzed events quantified by MFC in NDMM. We evaluated if a similar quantification of cPCs using MFC can add prognostic value to the current R-ISS classification of NDMM pts. Methods: We evaluated all NDMM pts seen at the Mayo Clinic, Rochester from 2009-2017 who had their peripheral blood samples evaluated by 6-color MFC prior to therapy. The cPCs detected were reported as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 566 consecutive pts with NDMM with a median age of 66 years (27-95). The distribution of the R-ISS classification of this cohort is as follows: Stage 1- 128 (23%) pts, Stage 2- 369 (65%) pts and Stage 3- 69 (12%) pts. The median number of cPCs was 59 (0-46,412) / 150,000 events. The median time-to-next-treatment (TTNT) and overall survival (OS) for pts with ≥400 cPCs (n = 140, 25%) was 19 months and 46 months compared with 34 months and 77 months for those with < 400 cPCs respectively (n = 426, 75%) (p < 0.001 for both). The median TTNT and OS for pts based on their R-ISS classification as well as with and without the presence of ≥400 cPCs by MFC was as follows in the following Table. Conclusions: Quantifying ≥400 cPCs/150,000 analyzed events by MFC can potentially upstage the R-ISS classification of a subset of NDMM pts with stage I and II disease and identify those pts with a worse than expected survival outcome.[Table: see text]

8019 Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF > 200 pg/ml, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]

7559 Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 & 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]

7509 Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 & 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, & 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]

8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (>= 1 g/dL), dFLC (>=10 mg/dl) or 24 hour urinary M protein excretion (UrM; >=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P<0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]

8516 Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.

Abstract Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Abstract Background Fibrillary glomerulonephritis (FGN) is a rare type of glomerulonephritis with poor prognosis, with no known effective therapies available for treatment. The objective of the study was to evaluate the efficacy and safety of rituximab in treatment of patients with FGN and to investigate the effect of rituximab on DNAJB9 levels. Methods This was a pilot prospective clinical trial in which patients with idiopathic FGN were treated with two courses of rituximab (1 g each) 2 weeks apart at the beginning and then again at 6 months. Primary outcome was defined as preservation of kidney function at 12 months with stable or increased creatinine clearance. Secondary outcome was defined as achieving complete remission (CR) defined as proteinuria &lt;300 mg/24 h or partial remission (PR) with proteinuria &lt;3 g/24 h and at least 50% reduction in the proteinuria. DNAJB9 levels were also measured in the serum at baseline, 6 and 12 months. Results The creatinine clearance did not change significantly during this time, from 47.7 mL/min/1.73 m2 at baseline to 43.7 mL/min/1.73 m2 during follow-up (P = 0.15). Proteinuria declined from 4.43 (1.6–5.53) g/24 h at baseline to 1.9 (0.46–5.26) g/24 h at 12 months but did not reach significance (P = 0.06). None of the patients reached CR, and 3 of the 11 achieved PR. There was no change in the DNAJB9 levels following treatment with rituximab. The most common adverse event was nasal congestion, fatigue and muscle cramps. Conclusions Treatment of patients with two courses of rituximab over a span of 6 months was associated with stabilization of renal function but did not result in a significant change in proteinuria and with no change in the DNAJB9 levels.

AbstractThe diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.