Tandon, Nidhi

AbstractTrisomies of odd numbered chromosomes are seen in nearly half of patients with multiple myeloma (MM) and typically correlate with a hyperdiploid state and better overall survival (OS). We compared DNA ploidy of monoclonal plasma cells (as a surrogate for the presence of trisomies) assessed simultaneously by PCPRO (plasma cell proliferative index), a novel method that estimates DNA index by multi‐parametric flow cytometry to fluorescence in situ hybridization (FISH) in 1703 patients with plasma cell disorders. The distribution of ploidy was hyperdiploid: 759 (45%), diploid 765 (45%), hypodiploid: 71 (4%), tetraploid/near‐tetraploid: 108 (6%). FISH identified trisomies in 82% (621/756) of patients with hyperdiploidy by PCPRO and no trisomy by FISH was observed in 88% (730/834) of patients without hyperdiploidy. 95% (795/834) of patients without hyperdiploidy on PCPRO had one or less trisomy by FISH. Sensitivity and specificity of PCPRO for detecting hyperdiploidy was 86% (621/725) and 84% (730/865), respectively. Sensitivity increased to 94% (579/618) for patients with more than one trisomy. Newly diagnosed MM patients with hyperdiploidy on PCPRO (147/275) had better OS compared to nonhyperdiploid patients (median not reached vs 59 months, P = 0.008) and better progression free survival (median: 33 vs 23 months, P = 0.03). Within the hyperdiploidy group, patients with high‐hyperdiploidy (DNA index: 1.19‐1.50) versus those with low‐hyperdiploidy (DNA index: 1.05‐1.18) had superior OS (3 year OS of 88% vs 68% P = 0.03). Ploidy assessment by flow cytometry can provide rapid, valuable prognostic information and also reduces the number of copy number FISH probes required and hence the cost of FISH.

8049 Background: Complete response in AL is defined as normal FLC ratio with negative serum and urine immunofixation. It is not clear if high involved serum FLC (hIFLC) in a patient with normal ratio may contribute to ongoing amyloid formation and hence affect outcomes. Methods: Data of 1308 patients (pts) with systemic AL seen within 90 days of diagnosis, at Mayo Clinic between 2006-2015, was analyzed retrospectively. Among these, 369 pts had 2 consecutive normal FLC ratio values after 1st line treatment and form the study population. Log rank test was used to estimate survival differences. Results: Among these 369 pts, pts with hIFLC at 1streading of normal FLC ratio (hIFLC1; n=170; 46.1%) were compared to those who did not (n=199; 53.9%). At diagnosis, the median age [61.5 vs 60.8 years (y); p=0.2], proportion of males (62.4 vs 58.3%; p=0.4), percentage of pts with renal involvement (73.5 vs 64.8%; p=0.07), in mayo stage I / II / III / IV (32.9% / 23%/ 27.3% / 16.8% vs 43.6 %/ 22.9% / 18.1% / 15.4%; p=0.1), with bone marrow plasma cells >10% (24.2 vs 30%; p=0.2) and with presence of t(11; 14)(48.4 vs 60; p=0.08) was similar, while cardiac (67.5 vs 53.3%; p=0.006) and hepatic (18.2 vs 9.1%; p=0.01) involvement was higher in hIFLC1 group. The median follow-up from diagnosis was 6.1 y (95% CI; 5.6, 6.8). The median progression free survival (PFS) in pts who had hIFLC1 was lower than for those who did not; 2.6 y (95% CI; 1.9, 4.5) vs 5.2 y (95% CI; 4.6, 6.4), p<0.0001, as was the median overall survival [OS; 6.7 y (95% CI; 4.5, 8.3) vs not reached (NR), p<0.0001]. We performed a more stringent comparison for pts with 2 consecutive hIFLC values (hIFLC2; n=112; 30.4%) versus not (n=257; 69.6%). The median PFS (3.2 y; 95%CI; 2.2, 4.5 vs 5.6 y; 95% CI; 4.7, 7.1; p<0.0001) and OS (7.8 y; 95% CI; 6.4, NR vs NR; 95%CI; 9.5, NR; p<0.0001) were significantly reduced in pts with hIFLC2 versus not as well. A multivariate analysis confirmed an impact of hIFLC1 and hIFLC2 on PFS/OS independent of serum creatinine. Conclusions: In pts with systemic AL, persistent elevation of the involved FLC predicts for poor prognosis (independent of serum creatinine) even among those who achieved normal FLC ratio after 1st line treatment.

8048 Background: Organ response (OR) in AL is often delayed and difficult to predict early. Methods: We retrospectively analyzed 1308 patients (pts) with newly diagnosed AL from 2006 – 2015 to determine factors which could predict for OR. Results: Median age was 64 years (yr) and Mayo Stage was: 1 (22%); 2 (23%); 3 (25%); 4 (31%). Organ involvement was: cardiac (74%, n=932); renal (59%, n=738), liver (16%, n=205); gut (24%, n=310) and autonomic (12%, n=152). 59% (n=765) had > 1 organ involved, including 43% (n=567) with > 1 critical organ (heart, kidney, liver) involved. Treatment was: ASCT based (28%, n=330, N=1186), bortezomib based (24%, n=281), alkylator based (33%, n=392), others (5%, n=54) and none (10%). In evaluable pts, VGPR or better rates were: 53% at 6 months (m) (N=625), 72% at 12 m (N=465) and 57% overall (N=688). Table 1 lists OR at various time points. Complete OR in all involved critical organs was seen in: 51% (n=308, N=600), partial response (at least 1 OR when >1 organ involved) in 12% (n=73) and none in 37% (n=219). Complete OR was associated with better overall survival (OS) than partial or no OR (median OS: not reached vs 42 m vs 29 m; P <0.0001). In multivariate model the following variables at baseline or 1 yr mark were predictive of complete OR: lower Mayo Stage (p=0.01), fewer critical organs involved (p=0.007), higher baseline GFR (p=0.03), female sex (Complete OR 60% vs 47%; p=0.04) and VGPR at 1 yr (Complete OR 70% vs. 36%; p <0.0001). Other factors included in the model were age (p=0.9), bilirubin (p=0.1) and transplant (p=0.2). All aforementioned factors were significant in univariate analysis. Conclusions: Achievement of response in all involved critical organs is associated with better survival in AL pts than partial or no OR. Various baseline factors and VGPR at 1 yr can predict for achieving complete OR, with 70% pts who achieve VGPR at 1 yr having a complete OR. [Table: see text]

8047 Background: Presence of CPCs by six color MFC is associated with worse outcomes in multiple myeloma (MM). Using a slide based immunofluorescence assay, CPCs are associated with worse prognosis in AL, but outcomes with MFC are not known. Methods: We retrospectively analyzed 154 patients (pts) from Jan 2008 – Dec 2015 with AL who had CPCs analyzed by MFC at diagnosis. Results: CPCs were present in 42% pts (n = 64, median = 88 per 150,000 events, range 6-17844). Table 1 lists baseline characteristics, treatment and response. In univariate analysis, bone marrow (BM) plasma cells > 15% (p<0.0001), dFLC > 60 mg/dL (p=0.02) and presence of active MM (p=0.0004) were associated with detectable CPCs. In multivariate (MV) model, only BM plasma cells > 15% predicted for presence of CPCs (p=0.02). There was no difference in hematologic or organ response in the 2 groups. Median follow up was 43 months (m). Pts with detectable CPCs had worse survival than those without detectable CPCs (90 m vs. 98 m, p=0.0004). In MV analysis model with Mayo Stage and detectable CPCs, presence of CPCs at diagnosis was independently associated with poor survival (CPCs p= 0.02, Mayo Stage p < 0.0001). Conclusions: Presence of detectable CPCs is an independent adverse prognostic factor for survival in AL. Comparatively fewer pts with detectable CPCs underwent early ASCT, which may reflect a more aggressive disease presentation. [Table: see text]

Abstract Introduction: Hyperdiploidy on FISH portends a good prognosis in myeloma. We compared hyperdiploidy determined by MFC to that by conventional FISH. Methods: We studied 1711 patients with plasma cell disorders who had simultaneous FISH and DNA index testing. Monotypic plasma cells in bone marrow are identified by MFC with antibodies to CD19, CD38, CD45, CD138, kappa and lambda; followed by staining by DAPI. DNA index is determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. Plasma cells with DNA content index of &lt;0.95 are hypodiploid and G0/G1 DNA content index of &gt;1.05 are considered hyperdiploid. Results: Distribution DNA index and FISH results are described in Table 1. Sensitivity and specificity of DNA index by hyperdiploidy was 86% and 83%. Cohen's Kappa coefficient for concordance was 0.69. Sensitivity increased to 94% for those with 2 or more trisomies and 97% for 3 or more trisomies. Of the 104 patients with trisomy and non-hyperdiploid DNA index, 62% patients had monosomy (mono) or deletion (del) 13q. Overall, DNA index was lower in patients with mono 13/del 13q (1.01; 0.97-1.11) compared to those without (1.07; 1.0-1.19), p&lt;0.001. After excluding patients with mono 13/del 13q, sensitivity and specificity of hyperdiploidy by DNA index were 92% and 82%, kappa = 0.73. Hyperdiploidy was seen in 55% of 272 patients with newly diagnosed myeloma. Sensitivity and specificity were 88% and 93%, kappa = 0.78. After median follow-up of 2.3 yrs, those with hyperdiploid DNA index had better progression free survival at 2,3 and 5 years, 62%, 45% and 21% compared to 50%, 33% and 13% in non-hyperdiploid group, p=0.05. Median overall survival (OS) was not reached; estimated 2, 3 and 5 year OS was 83%, 76% and 63% vs. 76%, 64% and 44%, respectively; p=0.08. Conclusions: DNA index by MFC is a rapid method to determine hyperdiploidy, with potential for replacing trisomy testing by FISH, especially when coupled with monosomy FISH probes. Hyperdiploid N=768 n/N (%)Diploid N=762 n/N (%)Hypodiploid N=78 n/N (%)P1P2Any trisomy 619/765 (81)96/758(13)8/76 (11)&lt;0.001&lt;0.001One chromosome42587733191429-111362Others12204Two chromosomes8525-Three or more chromosomes492131Any translocation124/744 (17)566/748 (76)53/74 (72)&lt;0.001&lt;0.001t(4;14)106313t(11;14)2240127t(14;16)5325t(14;20)38-t(6;14)8104Unknown partner76524Trisomy + Translocation95/743 (13)60/744 (8)6/74 (8)0.0090.002Monosomy 13/17 or deletion 13q/17p252/759 (33)295/744 (40)54/74 (73)&lt;0.0010.0001Monosomy 13/Deletion 13q208/717 (29)282/718 (39)20/70 (29)Monosomy 17/Deletion 17p70/749 (9)50/735 (7)20/72 (28)P1= three groups; P2= hyperdiploid vs. non-hyperdiploid Citation Format: Surbhi Sidana, Nidhi Tandon, Dragan Jevremovic, Rhett P. Ketterling, Angela Dispenzieri, Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, William Morice, Curtis A. Hanson, Michael Timm, Patricia Greipp, Linda B. Baughn, David Dingli, Suzanne R. Hayman, Wilson I. Gonsalves, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A. Lust, S.Vincent Rajkumar, Shaji K. Kumar. Hyperdiploidy in plasma cell disorders using multi-parametric flow cytometry (MFC) vs. FISH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 655.

Autologous stem-cell transplantation (ASCT) remains an integral part of treatment for previously untreated, and may have value in the treatment of relapsed patients with, multiple myeloma (MM). The addition of novel agents like immunomodulators and proteasome inhibitors as induction therapy before and as consolidation/maintenance therapy after ASCT has led to an improvement in complete response (CR) rates, progression-free survival (PFS) and overall survival (OS). With advances in supportive care, older patients and patients with renal insufficiency are now able to safely undergo the procedure. The data concerning the timing of ASCT (early in the disease course or at first relapse), single versus tandem (double) ASCT and the role and duration of consolidation and maintenance therapy post ASCT remain conflicting. This review aims to discuss the evolution of stem-cell transplant over the past 3 decades and its current role in the context of newer, safer and more effective therapeutic agents.