Greipp, Patricia T.

8603 Background: Steroids, primarily dexamethasone (Dex), remains an integral part of the therapy for myeloma. Prior to the advent of novel agents, Dex as a single agent was demonstrated to produce overall response rates of around 50%. The toxicity associated with pulsed high dose Dex has led to this approach being abandoned. This study investigates whether responsiveness to Dex correlates with biological qualities of the plasma cell clone that predicts outcome. Methods: We identified from our prospectively maintained database, patients with newly diagnosed myeloma, who were seen at Mayo Clinic within 30 days of diagnosis and were treated with single agent Dex. The M-protein measurements and responses were assessed using the IMWG criteria. Results: 182 patients seen between March 1998 and June 2007, initially treated with single agent Dex for at least 4 weeks, were included in the analysis. The median age at diagnosis was 63 (range; 39–81) and 59% were male. The actuarial median survival for the entire group was 55 months. The median duration of Dex therapy was 15 weeks (range; 4–193). Ninety one (50%) had a partial response or better and 11 (6%) were not evaluable, with the remaining patients (44%) having less than PR or progression. 10 patients (5%) achieved a VGPR or CR. The median overall survival from diagnosis for the 91 responders was 75 months compared to 71 months for the remaining patients; p = 0.6. There was no correlation between baseline disease characteristics and Dex responsiveness. One hundred thirty (70%) patients proceeded to an autologous SCT after a median of 15 weeks (range 1–46 months) of Dex. While the median overall survival was longer among the group of patients who underwent SCT, among either group, there were no survival benefit between those with a PR or better to Dex compared to the rest. Conclusions: Among this group of patients with newly diagnosed myeloma treated with single agent Dex, failure to respond to Dex induction therapy did not impact overall survival. Failure to respond to single agent steroid does not have an adverse impact on outcome in newly diagnosed myeloma. [Table: see text]

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.

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.

7523 Background: tALL is a recently appreciated but poorly defined clinical entity. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and we report a comparative analysis of characteristics, cytogenetics and outcomes for this subset among a modern unselected ALL cohort from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all patients (pts) diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) between 2008-2018. Comparisons of characteristics between tALL and dnALL were made using a Wilcoxon rank sum test (continuous variables) and Fisher’s exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 431 ALL pts were identified during the study period, including n = 69 (16%) classified as tALL. Median follow-up from diagnosis was 2.3 years (range 0-18 years). The most common prior malignancies among tALL pts were Breast (24.6%), Lymphoma (15.9%), Myeloid (15.9%), GU/GYN (14.5%) and Myeloma (11.6%). In comparison to dnALL, pts with tALL were significantly older (63.2 vs 45.2 years, P < 0.001), more often female (65.2% vs 39.8%, P < 0.001), less frequently Hispanic (3.5% vs 13.1%, P = 0.042); more often of B-lineage (92.8% vs 81.8%, P = 0.022). On review of cytogenetics, tALL pts more often had hypodiploidy/near triploidy (Ho/Tr) (21.7% vs 4.1%, P < 0.001), more often had monosomal (MDS-like) (33.3% vs 12.4%, P = 0.0047) and complex karyotype (38% vs 17.3%, P = 0.0069). Importantly, incidence of BCR/ABL-positive (Ph+) ALL was not significantly different. Latency period between exposure to prior cancer therapy and development of tALL was significantly longer for Ph+ compared to Ph-negative ALL (median 9 vs. 4 years, P = 0.007). Patients with tALL had a 3-year OS after diagnosis of 37% [vs 59.7% for dnALL (HR death 1.86, 95% CI 1.31-2.65, P < 0.001)]. However, the two groups did not differ significantly regarding occurrence of AlloHCT (HR = 0.91, 95% CI 0.63-1.31, P = 0.61) or post-AlloHCT survival (HR = 1.29, 95% CI 0.75-2.23, P = 0.35). Conclusions: Therapy-related ALL represents an important & unique clinical entity with poor prognosis & adverse cytogenetic features. Ph+ tALL has a longer latency and similar frequency in both tALL and dnALL. AlloHCT appears to be an appropriate treatment strategy, possibly abrogating the poor prognosis of tALL.

AbstractMetaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy involving complex cytogenetic dysregulation of genes and heterogeneous expression of multiple B cell and plasma cell (PC) surface antigens. 60% of MM patients have cytogenetic translocations of the IGH locus. In 16% of myeloma patients, the partner oncogene is cyclin D1 on 11q13 causing t(11;14)(q13;q32) (Fonseca et al. Blood. 2002). This translocation is more common in patients with a lymphoplasmacytic morphology and confers a more favorable prognosis (Fonseca et al. Blood. 2003). A subset of MM patients (20%) harbor a clonotypic population of CD20+ bone marrow plasma cells (BMPC). These patients have a shortened survival time (SanMiguel et al. Br J Haematol. 1991). There is a strong association with CD20+ surface expression and t(11;14)(Robillard et al. Blood. 2003) and CD20+ PC has been suggested to be clonogenic and important in the pathogenesis of MM. A small Phase II study showed only a modest response to the humanized anti-CD20 monoclonal antibody rituximab in MM patients with CD20+PC (1 PR and 5SD) (Treon et al. J. Immunother. 2002). We report a response to treatment with rituximab in a MM patient with CD20+ BMPC and t(11;14)(q13;q32) by FISH. Case: The patient is a 68 year old male with a 1.5 year history of MM. Initial diagnosis of ISS stage I disease was made after a three year history of IgA kappa monoclonal gammopathy of undetermined significance (MGUS). At diagnosis of MM, he had symptomatic anemia Hgb10.5g/dL, rising serum IgA of 3950 mg/dL, serum m-spike of 4.1 g/dL (IgA kappa), PCLI (plasma cell labeling index) of 1%, and a small monoclonal IgA kappa with kappa fragment in the urine. BM showed 44% monoclonal kappa plasma cells with 90% CD20+,clonal PC on flow cytometry. Karyotype was normal; 46, XY, but FISH showed evidence of an IGH translocation t(11;14)(q13;q32) in 60% of PC. Immunohistochemical staining was positive for cyclin D1. Given the marked elevation of CD20+ PC and early stage of disease, initial treatment was employed with four weekly cycles of rituximab (375mg/m2). IgA fell from 4750 mg/dL to a nadir of 2990 mg/dL, (m-spike; 4.5g/dL to 3.2 g/dL) five weeks after completion of treatment. The monoclonal protein (MP) in the urine disappeared. Hgb improved to 12.5g, with erythropoietin. Three months later, IgA rose to 3260mg/dL (m-spike 3.2 g/dL) and urinary MP returned. The patient remained asymptomatic. A second course of weekly rituximab was started. IgA level and serum m-spike remained fairly stable over the next 7 months. All treatment was tolerated well except for initial transient rigors, fever, and nausea. Despite bi-monthly maintenance rituximab, the patient devloped a rising IgA of 4940 mg/dL, m-spike of 4.7, falling Hgb and a rising PCLI of 1.5%, 15 months after his original diagnosis of MM. Of particular concern is the development of new, unfavorable, cytogenetic aberrations by FISH with BMPC now showing deletion 13 in 93% and mutation of p53 (17p13) in 98%.100% show fusion of CCND1 and IGH and PC now only partially express CD20. Conclusion: This report suggests that MM patients with CD20+ BMPC and t(11;14)(q13;q32) may represent a target population for anti-CD20 therapy. Our report supports the concept proposed that targeting this clonotypic subset of B cells possibly interrupts a critical oncogenic pathway that is important in the pathogenesis of the clonogenic development of MM.

AbstractInfant leukemias are a rare group of neoplasms that are clinically and biologically distinct from their pediatric and adult counterparts. Unlike leukemia in older children where survival rates are generally favorable, infants with leukemia have a 5‐year event‐free survival rate of <50%. The majority of infant leukemias are characterized by KMT2A (MLL) rearrangements (~70 to 80% in acute lymphoblastic leukemia), which appear to be drivers of early leukemogenesis. In this report, we describe three cases: a 9‐month‐old female infant with B‐acute lymphoblastic leukemia (B‐ALL), an 8‐month‐old female presenting with B/myeloid mixed phenotype acute leukemia (MPAL), and a 16‐month‐old male with B‐ALL. The first case had a normal karyotype and B‐ALL FISH results consistent with an atypical KMT2A rearrangement. The second case had trisomy 10 as the sole chromosomal abnormality and a normal KMT2A FISH result. Case 3 had trisomy 8 and a t(11;15)(q23;q21), an atypical KMT2A rearrangement by FISH studies, and a focal deletion of 15q with a breakpoint within the USP8 gene by chromosomal microarray. Mate pair sequencing was performed on all three cases and identified a KMT2A‐USP2 rearrangement (cases 1 and 2) or a KMT2A‐USP8 rearrangement (case 3). These recently characterized KMT2A fusions have been described exclusively in infant and pediatric leukemia cases where the incidence varies vary according to leukemia subtype, are considered high‐risk, with a high incidence of central nervous system involvement, poor response to initial prednisone treatment, and poor event free survival. Additionally, approximately half of cases are unable to be resolved using standard cytogenetic approaches and are likely under recognized. Therefore, targeted molecular approaches are suggested in genetically unresolved infant leukemia cases to characterize these prognostically relevant clones.

e18549 Background: Many vitamin deficiencies can cause anemia. It is prudent prior to diagnosing a myeloid neoplasm, to check for vitamin deficiencies and correct them. Myelodysplastic syndromes with ring sideroblasts (MDS-RS) are associated with anemia. Pyridoxine (Vit B6) replacement may improve anemia found in sideroblastic anemia. The study was to determine how frequently Vit B6 was assessed, replaced and impact replacement had on outcomes in MDS-RS. Methods: Study subjects were from the Mayo Clinic Myelodysplastic syndrome (MDS) database which contains 1315 patients (pts). Appropriate IRB approval was obtained. Diagnosis of MDS and its sub-classification was done according to World Health Organization 2016 criteria. A response was any improvement in hemoglobin. Overall survival (OS) estimates were calculated using Kaplan-Meier curves and univariate and multivariate analysis was done using JMP software version 13. Results: Among 1315 pts with MDS, 161 pts had a diagnosis of MDS-RS. Median age was 73, and 55 (34%) pts were females. Thirty-nine (36%) pts had very low, 53 (50%) low, 9 (8%) intermediate, 3 (3%) high, and 2 (1%) had very high revised international prognostic score. The median white blood cell count was 5.4 x109, platelet count was 255 x109, and hemoglobin was 9.9 gm/dL. Five pts (3%) had a Vit B6 levels done; out of whom, 4 (80%) were not Vit B6 deficient. Among 42 (26%) pts who had Vit B6 replacement, 21 (50%) had no response, 4 (10%) had a response and 17 (40%) had unknown response. 103 (64%) of the pts were transfusion independent (TI). Overall survival in pts who are transfusion dependent was 68 months compared to 85 in pts who are TI (Wilcoxon P =.03). There was an improvement in OS in the group that had Vit B6 replacement compared to the group with no Vit B6 replacement (92 months vs 68 months, Wilcoxon P =.07). Response to Vit B6 replacement did not show OS benefit. Acute Leukemia transformation in Vit B6 replacement was 2% and 6% in pts. who did not have Vit B6 replacement (P= .4). Conclusions: Vit B6 was not checked often in MDS-RS pts. There was a borderline improvement in OS in Vit B6 replacement group (p= .07). Response did not affect OS. A larger prospective study is needed to study Vit B6 role in MDS-RS.

17516 Background: The p53 tumor suppressor is commonly inactivated by mutations. Even in tumors without mutations, there are defects in the response to p53 activation. In MM, the prognostic significance of p53 mutation is unknown, while there has been no systematic study of p53 function. We seek to address these issues in this study. Methods: p53 mutation was studied by conformation sensitive gel electrophoresis with primers encompassing exons 1 to 10 followed by sequencing of DNA fragments with altered electrophoretic pattern in newly diagnosed MM patients entered into ECOG E9486 trial where patients were randomized to receive variations of melphalan-based conventional chemotherapy (VBMCP). Fisher’s exact tests were used to compare variables between patients. Kaplan-Meier survival curves were compared using the log-rank test. To investigate p53 function, we analyzed the expression of p53, and 3 of its transcriptional targets, APAF1, p21 and MDM2, in a separate cohort of 15 normal plasma cells (PC), 14 MGUS, 13 smoldering myeloma (SMM) and 101 MM (73 new and 28 relapsed) from the Mayo Clinic who had gene expression profiling performed on the Affymetrix U133A chip (Santa Clara, Ca). Results: Two hundred and sixty-eight patients had enough materials for study and were included in the analysis. The prevalence of p53 mutation was 3% (n = 9). Five of the 9 patients (56%, p = 0.001) with mutations also had p53 deletion (studied by fluorescent in-situ hybridization) resulting in bi-allelic loss of p53. Soft tissue plasmacytomas (37% v 7%, p = 0.018), and among the common translocations, t(4;14) and t(14;16) (50% v 18%) were more common in patients with p53 mutations. Despite similar response to treatment, those with p53 mutation had very short OS (16.7 v 41.4 months, p < 0.001). There was induction of p53 expression in MGUS and SMM with concurrent induction of APAF1, p21 and MDM2 whereas loss of this pattern was frequent in MM (45% in new MM and 60% in relapse MM compared to 15% in MGUS/SMM (p = 0.03)). Conclusions: p53 mutations are relatively rare in newly diagnosed MM patients but portend a short survival. However, functional abnormalities of p53 are prevalent and may be important in progression from MGUS/SMM to MM. [Table: see text]