Specific Cytogenetic Abnormalities Research Articles

Exploring the Impact of Cytogenetic Abnormalities on Treatment Responses and Survival Outcomes in Multiple Myeloma: A Single-Centre Experience of 13 Years of Follow-Up.

(1) Background: The introduction of novel therapies has led to a considerable evolution in the management of Multiple Myeloma, and chromosomal abnormalities predict the success of treatment. We aimed to characterize cytogenetic abnormalities for risk stratification in the patient population and to evaluate the predictive and prognostic value of the specified abnormalities in distinct treatment modalities. (2) Methods: This study included patients with Multiple Myeloma who applied to the Internal Medicine Clinic of the Cukurova University Faculty of Medicine. Between 2010 and 2023, 98 cases with cytogenetic abnormality data were identified. We analysed the effects of cytogenetic abnormalities on survival and response rates to first chemotherapies. (3) Results: P53 del was the most prevalent abnormality, and t(11;14) was the most common translocation. There was no significant difference in the mean survival and treatment response rates for specific cytogenetic abnormalities. When chemotherapies based on lenalidomide were initiated, patients' life-death statuses differed significantly from those of treatments without lenalidomide. Regardless of the type of chromosomal aberration, lenalidomide-based treatments independently enhanced average survival 14-fold, while there was no significant difference in overall survival among treatments. (4) Conclusions: In individuals with cytogenetic abnormalities, lenalidomide-based treatments should be started regardless of the chemotherapy to be used for the condition.

Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenström Macroglobulinemia: a monocentric experience.

The prognostic and predictive role of specific gene mutations in Waldenström Macroglobulinemia (WM) is well-ascertained whereas the clinical impact of chromosome aberrations is far less known. Recent work has provided initial evidence for an adverse prognostic impact of some aberrations, such as del(6q), while other studies suggest a possible relationship between some clinical features (e.g. advanced age and/or inflammatory status) and specific cytogenetic abnormalities. To add to the still limited knowledge on WM cytogenetics and its clinical implications, we herein report our experience in a cohort of WM patients across 23years. Based on our retrospective study, we found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Our data suggests that the role of the altered karyotype deserves to be further clarified especially in elderly WM patients, in whom cytogenetic abnormalities and disease biology appear to be characterized by a higher degree of complexity.

C-Kit and Flt3 mutation status in acute myeloid leukaemia with cytogenetic correlation and prognosis: A series of 75 cases

Recent WHO classification (5 edition) has included Acute Myeloid Leukaemia (AML) with mutations in NPM1, CEBPA as separate entities along with AML with cytogenetic abnormalities in AML with recurrent genetic abnormalities. Even though C-kit and FLT3 mutations in AML have no diagnostic importance, prognostic significance in different subtypes of AML for the presence of these mutations are not the same.To assess the correlation between French American British (FAB) AML classification, specific cytogenetic abnormalities with C-kit, and FLT3 mutation in AML and to evaluate the prognosis and survival of AML patients with respect to cytogenetic abnormalities and C-kit and FLT3 mutation status. Retrospectively all AML cases in which C-kit and FLT3 mutation status was assessed were retrieved; C-kit D816V mutation status had been assessed by Real time PCR; For FLT3 mutation, both Internal tandem duplication (ITD) and D835V mutation status had been assessed using PCR and gel electrophoresis; The data regarding morphological with immunophenotypic diagnosis, conventional karyotyping, FISH for translocation 8;21 (t (8;21)) and inversion16 / translocation16;16 (t (16;16) were also retrieved in all these cases along with follow-up from hospital records. Total 75 cases were included; Male/ Female ratio was 1.21:1 (41/34); Median age was 31 (Range: 2 - 64); 18 cases had translocation 8;21 (t (8;21)); 3 cases showed inversion16 / translocation16;16 (t (16;16); Out of the 18 cases which showed t (8;21), 10 cases had associated loss of sex chromosome. Eight cases had C-kit D816V mutation; three of which had t (8;21) while two had inversion 16. 12 cases had FLT3 mutations among which nine were ITD while three had D835V mutation. On karyotyping, one of these cases showed hyperdiploidy while the majority had normal karyotype. A single case had both C-kit D816V mutation and FLT3 D835V mutation with inversion 16 on karyotyping; Most common type of AML in both cases with FLT3 mutation and C-kit mutation was AML-M2 (FAB); Commonest karyotyping abnormality for cases with C-kit mutation was t(8;21); while for FLT3 mutation, the majority had normal karyotype; The single case which had both C-kit D816V mutation and FLT3 D835V mutation was alive event-free at three-year follow-up. Both FLT3 ITD and TKD mutations had a worse prognosis in our study. However, AML cases with C-kit mutation had a similar prognosis comparable to C kit negative cases. A large-scale study is required to elucidate the significance of this.

Encouraging Outcome of AML with t(8;16) Following Allogeneic Stem Cell Transplantation in First Remission - a Retrospective Analysis on Behalf of the Acute Leukemia Working Party of the EBMT

In the 2022 European Leukemia Net (ELN) risk classification, acute myeloid leukemia (AML) with translocation t(8;16) was newly classified as AML defined by specific cytogenetic abnormalities, associated with unfavorable prognosis. Translocation (8;16)(p11;p13) is a rare abnormality in AML with female preponderance and occurs more frequently in secondary AML (sAML), especially therapy-related, than in de novo disease. Clinically, AML with t(8;16) is associated with high risk of bleeding, occurrence of extramedullary manifestations, myelomonocytic differentiation, and signs of hemophagocytosis in the bone marrow. The translocation leads to the fusion of acetyltransferase KAT6A (also known as MOZ or MYST3) and CREB binding protein ( CREBBP) genes, both of them involved in hematopoiesis. ELN risk stratification of AML with t(8;16) was based on studies that included relatively low numbers of patients receiving allogeneic stem cell transplantation (alloSCT). In the largest report by Kayser et al. ( Br J Haematol 2021) 21 patients (15 transplanted in first complete remission [CR1], median follow-up 5.5 years) were analyzed. A 5-year overall survival (OS) of 38% was achieved after alloSCT compared to 11% in patients who received chemotherapy only. The aim of our study was to evaluate the outcome of patients with AML harboring t(8;16) after alloSCT in a larger cohort from the EBMT registry. All types of donor, conditioning regimen and graft were included. Sixty patients were identified, of whom 44 had been transplanted in CR1. Median follow-up from alloSCT was 72.3 months, median age was 46.3 years, and 73.3% were female. Karnofsky performance status was >80% in 59 patients, one had missing data. At 2 years after alloSCT, OS and leukemia free survival (LFS) of the entire cohort were 42.7% and 42.2%, respectively, (28.6% and 14.3% in patients transplanted in advanced disease). Cumulative incidence of relapse (RI) and non-relapse mortality (NRM) at two years was 36.9% and 15.3%, respectively, in patients transplanted in CR1, and 78.6% and 7.1%, respectively, in patients transplanted in advanced disease. The 44 patients transplanted in CR1 were analyzed in detail. Basic characteristics were comparable to the entire cohort as described above. Twenty-two of the patients had de novo, 22 had sAML. According to the ELN 2017 classification (not yet including t(8;16) as a factor for poor prognosis), 54.5% had an intermediate and 45.5% an adverse cytogenetic risk. Furthermore, 38.8% had a complex karyotype. Donors were matched related in 34%, matched unrelated in 54%, haploidentical in 5% and cord blood in 7%. Conditioning was myeloablative in 52.3%, whereas 47.7% had received reduced intensity conditioning. Among patients transplanted in CR1, 2- and 5-year OS from alloSCT was 48% and 39.9%, the respective LFS was 46.8% and 35.5%. On multivariate analysis (MVA), harboring t(8;16) within a complex karyotype was the major risk factor for outcome, being associated with higher RI (hazard ratio [HR] 3.38, p=0.01), lower LFS (HR 4.17, p=0.016), and lower OS (HR 3.08, p=0.017). In contrast, patients with t(8;16) outside of a complex karyotype achieved excellent results (Figure 1). Besides a complex karyotype, MVA revealed sAML as an additional, independent risk factor with a higher RI (HR 3.73, p=0.026). Age was the major factor for NRM, reaching 5% vs. 26.5% in patients below or above the median (p=0.02). In conclusion, according to the largest series analyzed in this setting so far, overall results after alloSCT in AML with t(8;16) transplanted in CR1 were favorable, especially in patients without multiple additional cytogenetic abnormalities, achieving a low risk of relapse and a 5-year OS >60%. Hence, alloSCT in CR1 appears to abrogate the unfavorable prognostic value of this translocation. Whether or not t(8;16) does have any additional influence on the outcome of patients with a complex karyotype remains to be evaluated. Figure Legend Figure 1: Outcome of AML with t(8;16) with and without complex karyotype

Cladribine Combined with Homoharringtonine and Cytarabine Achieves a High Remission Rate in Adult Patients with De Novo Acute Myeloid Leukemia, Especially for Adverse-Risk Group: A Prospective, Single Center, Single-Arm, Phase 2 Study

Background: For adult de novo acute myeloid leukemia (AML), the standard 3+7 induction regimen has approximately 60% complete remission (CR) rate. Recently, BCL-2 inhibitor plus intensive chemotherapies as novel induction regimens have shown an above 90% composite complete remission (CRc) rate, however still have limited response effect in an adverse risk group, especially for patients with specific cytogenetic abnormalities such as KMT2A rearrangements, FLT3, RAS, and TP53 mutations. Multiple studies have shown that homoharringtonine (HHT) can target leukemia diseases that have switched their anti-apoptotic dependence from BCL-2 to MCL-1. We recently demonstrated that cladribine (CdA) could eradicate BCL-2 inhibitor-resistant monocytic leukemia stem cells driven by RAS mutants and KMT2A rearrangements. (Pei S, et al. Cancer Discovery. 2023) Together, these clinical and basic findings suggest a rationale for combining CdA with HHT to treat AML patients. In this study, we report the efficacy and safety of a newly designed “CHA” regimen composed of CdA, HHT, and cytarabine (AraC) in adult patients with de novo AML. Methods: This is a prospective, single-center, single-arm phase 2 trial. Newly diagnosed AML patients aged 18-59 years were enrolled. The diagnosis, risk classification, and response evaluation were determined according to ELN 2022 criteria. All enrolled patients received the CHA regimen: CdA (5mg/m2, days 1-3), HHT (2mg/m2, days 1-5), and AraC (100mg/ m2, days 1-7) administered intravenously. The response was evaluated on day 28 via bone marrow routine and minimal residual disease (MRD) measurement by flow cytometry. The primary endpoint was CRc (CR plus CRi). Secondary endpoints were MRD, overall survival (OS), disease-free survival (DFS), event-free survival (EFS), and adverse events. Bone marrow (BM) samples on day 1 and 7 and peripheral blood (PB) samples on days 1-7 were collected for laboratory flow analysis to monitor the kinetics of leukemia reduction. We also treated primary AML specimens with single, dual, and triple combinations of CdA, HHT, and Ara-C to evaluate their anti-leukemic activity in vitro. Statistical analyses were carried out using SPSS 24.0. Survival curves were prepared using the Kaplan-Meier method. A two-tailed P value <0.05 was considered statistically significant. This trial is registered on ClinicalTrials.gov (NCT05906914). Results: A total of 33 patients were enrolled from August 1, 2021, to April 15, 2023. The median age was 49 years. 33% (11/33) of patients were at favorable risk, 42% (14/33) were at intermediate risk, and 24% (8/24) were at adverse risk. After one course of CHA induction therapy, the CRc rate was 87% (27 of 31 patients), and the CR rate was 84% (26 of 31 patients). The CR rates in the favorable, intermediate, and adverse-risk groups were 82% (9 of 11 patients), 75% (9 of 12 patients), and 100% (8 of 8 patients), respectively. Notably, six out of six patients with KMT2A rearrangement and ten out of ten patients with RAS mutations achieved MRD-negative CR. The overall MRD negativity was 89% (24 of 27 patients with CRc). In 31 evaluable patients, four patients did not reach CR; three of them held FLT3 mutations. 30-days treatment-related mortality (TRM) was 6% (2 of 33 patients), and both died of sepsis. The median neutrophil recovery time (from the end of chemotherapy to the neutrophil counts ≥0.5×109/L) and platelets recovery time (from the end of chemotherapy to platelets counts ≥20×109/L) were both 11 days. With a median follow-up time of 13 months (IQR: 6-17 months), the one-year OS was 86%, 1-year DFS was 89%, and the 1-year EFS was 76%. Flow cytometry analysis of serially collected PB and BM samples from nine randomly selected patients revealed that an average of 91.0% and 94.7% of leukemia burden was cleared in the PB and BM by day 7, respectively, demonstrating a rapid and effective response induced by CHA. Finally, our in vitro assay demonstrated a synergistic effect of CdA, HHT, and Ara-C on primary AML specimens including three patients with adverse-risk. Conclusion: We propose the CHA regimen as a novel, effective, and safe chemotherapy regimen for newly diagnosed adult AML patients with remarkable potency in treating adverse-risk group patients, especially those with KMT2A rearrangements and RAS mutations that are otherwise resistant to BCL-2 inhibitor-based therapies, but a limited effect on FLT3mutated AML patients.

Definitions, Biology, and Current Therapeutic Landscape of Myelodysplastic/Myeloproliferative Neoplasms.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., RUNX1), signaling molecules (e.g., NRAS, JAK2), splicing factors (e.g., SF3B, SRSF2), and epigenetic regulators (e.g., TET2, ASXL1, DNMT3A), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation.

GATA2 at 10: Emergence of Genotype-Phenotye correlations

GATA2 mutations cause adult-onset bone-marrow failure characterized by cytopenias, infections and increased risk of leukemia. We reviewed hospital records and referrals from 232 GATA2 mutation positive individuals from 122 families to gather hematopoietic and syndromic features.Mutations were categorized by effect on GATA2 protein: missense after the 2nd Zinc-finger (C-term, n = 10); missense in the 2nd Zinc-Finger (2nd Zf, n = 104); mutations producing stable truncated protein (truncation, n = 26); null alleles (mRNA instability, large deletions, n = 42); or enhancer (n = 50). Median age at first symptom presentation for the cohort was 20 years.Kaplan-Meier analysis for symptom onset showed differences in age at presentation across truncation and null mutations (median 15 and 18 years, respectively), 2nd Zf (22 years) and enhancer mutations (45 years). A similar analysis of four recurrently mutated 2nd ZF amino acids revealed later symptom onset for R361 and R398 mutations (median 22 and 34 years, respectively) compared to R396 or T354 (16 and 19 years, respectively). Mixed-effect Cox regression analysis corrected for relatedness across patients and confirmed these findings.There was decreased penetrance in enhancer (27/50, 54% symptomatic) and 2nd Zf (85/104, 81.7%) compared to truncation (24/26, 92.3%) and null (39/40, 97.5%) mutation patients. Grouping mutations by median onset before (null, truncation, R396, T354) or after (R361, R398, enhancer) age 20 revealed significantly increased incidence of cytopenias, HPV, myelodysplastic syndrome and hearing loss among the early onset mutation group. Additionally, age of cytopenia or myelodysplasia syndrome diagnosis was significantly younger in the early onset group (P = 0.0019, P = 0.0012 respectively).Males had more monosomy 7 (11/92 males, 4/142 females, P < 0.0001). Nontuberculous mycobacterial infection was the presenting symptom in 14/92 males vs 7/142 females (P = 0.0188). Warts/anogenital HPV were common (93/234, 39.7%). Non-hematologic manifestations included hearing loss (46/232; 19.8%), lymphedema (30/232; 12.8%), and non-hematologic malignancies (46/232, 19.8%), the majority being HPV-related ano-genital cancers. Hematologic malignancy occurred in 26/234 patients (11%).This comprehensive analysis demonstrates that GATA2 mutation type, and specific mutations, affect penetrance and expression. Gender is an independent risk for specific infectious complications and cytogenetic abnormalities.

Cytogenetic Abnormalities for Predicting the Risk of Metastases in Choroidal and Ciliary Body Melanoma.

Choroidal melanoma (CM) and ciliary body melanoma (CBM) are the two most common subtypes of uveal melanoma. Starting from the observation that CBM tends to have a higher metastatic potential than CM, we hypothesized that specific cytogenetic abnormalities could be associated with tumor location - reflecting distinct genetic signatures that would drive the risk of distant spread. Chromosomal alterations were investigated by molecular cytogenetic techniques in 217 and 97 patients with CM and CBM, respectively. Cox proportional hazards regression analysis was used to identify the independent predictors of distant metastasis. Patients with CBM had larger tumor sizes (P < 0.001), higher disease stages (P < 0.001), and more frequently showed distant metastasis (P = 0.002) than those with CM. On analyzing the entire study cohort, we found that specific chromosomal alterations - including chromosome 8p loss (P < 0.001), 1p loss (P < 0.001), and monosomy 3 (P < 0.005) - were independent predictors of distant metastasis. Based on a decision-tree learning algorithm, we identified three specific subgroups of patients with uveal melanoma at high risk of distant spread. Monosomy 3 occurred significantly more frequently in patients with T3 CBM tumors. Specific cytogenetic abnormalities - including chromosome 8p loss, 1p loss, and monosomy 3 - are independent risk factors for distant metastasis in uveal melanoma. Larger tumor size at presentation and monosomy 3 contribute to a higher metastatic risk in patients with CBM.

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma

Some cytogenetic abnormalities (CAs) are associated with poorer prognosis in multiple myeloma (MM); proteasome inhibitors appear to benefit patients with high-risk CAs. We evaluated 2247 MM patients from the TOURMALINE-MM1/-MM2/-MM3/-MM4 trials to assess the PFS benefit of ixazomib plus lenalidomide-dexamethasone (Rd) vs placebo-Rd (TOURMALINE-MM1/-MM2) or ixazomib vs placebo (TOURMALINE-MM3/-MM4) in specific high-risk CAs. After a pooled median follow-up of 25.6 months, the hazard ratio (HR) for PFS with ixazomib- vs placebo-based therapy for high-risk patients was 0.74 (95% confidence interval [CI]: 0.59–0.93; median PFS [mPFS] 17.8 vs 13.2 months), and 0.70 (95% CI: 0.62–0.80; mPFS 26.3 vs 17.6 months) for complementary standard-risk patients. The HR for expanded high-risk patients was 0.75 (95% CI: 0.64–0.87; mPFS 18.1 vs 14.1 months), and 0.71 (95% CI: 0.59–0.85; mPFS 36.1 vs 21.4 months) for complementary standard-risk patients. The HR for PFS with ixazomib- vs placebo-based therapy was 0.68 in patients with t(4;14) (95% CI: 0.48–0.96; mPFS 22.4 vs 13.2 months), and 0.77 for patients with amp1q21 (95% CI: 0.63–0.93; mPFS 18.8 vs 14.5 months). A PFS benefit was demonstrated with ixazomib- vs placebo-based therapy regardless of cytogenetic status, with greatest benefit observed in patients with t(4;14) and amp1q21.

Specific Cytogenetic Abnormalities at Diagnosis Predict Survival after Hematopoietic Cell Transplant in Poor-Risk Pediatric Acute Myeloid Leukemia: A PDWP/EBMT Study

Introduction: Cytogenetic abnormalities are an important prognostic factor for predicting overall survival (OS) and relapse incidence (RI) in children with acute myeloid leukemia (AML). Although allogeneic hematopoietic cell transplant (HCT) is generally recommended for patients with AML in first complete remission (CR1) and poor-risk (PR) cytogenetics, whether these cytogenetic and molecular features retain their prognostic value after HCT is unknown. Additionally, PR AML is a heterogeneous category that includes several distinct cytogenetic abnormalities, some of which might have a worse prognosis than others. In this study, we evaluated whether the cytogenetic risk classification at diagnosis of AML was predictive of post-HCT outcomes in pediatric patients. Methods: All patients <18 years of age at the time of HCT reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, who had received their first allogeneic HCT for AML in CR1 between 2005 and 2020, and who had their karyotype evaluation at diagnosis available were included in this analysis. Patients were subgrouped as (a) monosomy 7/del7q or monosomy 5/del5q, (b) 11q23 abnormality excluding t(9;11), (c) complex or monosomal karyotype, or (d) other. A complex karyotype was defined as one with three or more structural abnormalities, and a monosomal karyotype was defined as a monosomy with one or more structural abnormalities, excluding WHO-designated recurring translocations or inversions based on 2017 ELN recommendations. Other cytogenetic abnormality subgroup included t(6;9), t(3;5), t(9;22), t(8;16), inv(3) or t(3;3), t(16;21), abn(11p15), and del(12p) or abn(12p13). Cytogenetic subgroup, age at HCT, whether HCT was from a female donor to a male recipient, patient/donor CMV status, time from AML diagnosis to HCT, and year of HCT were included as predictors for OS, RI and non-relapse mortality (NRM) in the multivariate analysis. Results: We included 744 pediatric patients (42.2% female; median age at HCT: 8.6 years [range: 0.3-18 years]) from 139 participating centers in the study. Median follow-up after HCT was 4.4 years. Thirty-seven percent had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 15% met the criteria for other PR cytogenetic abnormalities. Only 7% had secondary AML. Pre-HCT minimal residual disease (MRD) data were available for 346 patients, 86% of whom were MRD negative at the time of HCT. Patients received grafts from a matched related donor (27%), a mismatched related donor (11%), an unrelated donor (46%), or a cord blood donor (16%). Of the total patients, 55% received bone marrow, 29% received peripheral blood-derived stem cells and the rest (16%) received cord blood as the stem cell source. Myeloablative conditioning was used in 97% of the patients. The OS and leukemia free survival for the entire cohort was 76% and 70% respectively at 2 years. In a multivariate model, 11q23 (hazard ratio [HR] = 0.59, P = 0.01) and other poor-risk cytogenetic abnormalities (HR = 0.49, P < 0.01) were associated with significantly better OS when compared with monosomy 7/del7q or monosomy 5/del5q. The "other PR cytogenetic abnormalities" category was also associated with a lower risk of disease relapse after HCT (HR = 0.4, P = 0.01). Receiving an HCT from an unrelated donor, as compared with a matched related donor, was associated with lower RI (HR = 0.58, P = 0.03). Additionally, older age at HCT (12-18 years) was associated with the highest risk of NRM (HR = 1.95, P = 0.02) and with worse OS (HR = 1.71, P < 0.01) than seen in younger patients (aged 4-12 years). Conclusion: PR cytogenetic abnormalities at diagnosis remain predictive of OS after HCT for AML in pediatric patients. Monosomy 7/del7q or monosomy 5/del5q confer a poor prognosis even after HCT, whereas 11q23 abnormality and other PR cytogenetic abnormalities predict a favorable outcome after HCT. Our data also suggest that an HCT from an unrelated donor may offer greater protection against relapse than an HCT from a matched related donor, but this requires further validation. Efforts for improving conditioning regimens and transplant techniques should focus on reducing NRM and reducing RI in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Outcomes of Multiple Myeloma in Hispanic Versus Non-Hispanic Patients in Central California

Background: Multiple Myeloma (MM) accounts for roughly 10% of all hematologic cancers in the U.S., with 37% of MM patients being non-white minorities. Advanced stage at diagnosis and specific cytogenetic abnormalities are associated with high-risk disease and poor prognosis. Studies evaluating these risk factors, however, consisted of mostly Caucasian patients with an underrepresentation of ethnic minorities. In the phase III DETERMINATION trial, ~18% of the study population was Black compared to only ~6% Hispanic, with the rest being Caucasian. Although this study showed significant overall progression free survival (PFS) benefit in transplant patients, this was not seen in the Black patient subgroup. To further investigate outcomes of other ethnic MM patients in the Central Valley of CA, we analyzed characteristics and outcomes of MM patients who were seen at Community Medical Centers in Fresno CA (49.6% Hispanic population). Methods: Patients diagnosed with MM at Community Medical Centers from January 2011 to December 2020 were included. High risk disease was defined by the Mayo Clinic mSMART 3.0 classification. Demographic and disease-relevant information including age at diagnosis, gender, ethnicity (Hispanic vs non-Hispanic), insurance, median income by zip code, laboratory data at diagnosis (hemoglobin, creatinine, corrected Ca, LDH, beta 2 microglobulin), immunoglobulin type, light chain type, cytogenetic abnormalities, stage (R-ISS), 1st line treatment (doublet vs triplet), transplant status, and treatment response (IMWG response criteria) were collected. Comparisons between Hispanics and non-Hispanics were made by Fisher's exact test and nonparametric equality-of-medians test where appropriate. Outcomes were compared via log-rank testing and Kaplan-Meier estimates for 2 year PFS and overall survival (OS). Univariate cox proportional hazard model for survival was used to examine the association of demographic and MM variables with mortality risk after first line therapy. Results: 117 MM patients were included with 42 high risk patients identified (11 Hispanic, 31 non-Hispanic). Median age at diagnosis of Hispanics vs non-Hispanics was 61.7 vs 66.5 years (p=0.046). Hispanic vs non-Hispanic median income was $49734.50 vs $62588.90 (p=0.003). Insurance status differed significantly with more Hispanics having Medi-Cal and non-Hispanics having private/Medicare (p=0.001). 13 non-Hispanics had 17p del vs 0 Hispanics (p=0.001). Hispanics and non-Hispanics did not have significantly different responses to first line therapy per IMWG criteria (p=0.535). Hispanic and non-Hispanic patients experienced similar 2 year PFS and OS (PFS: 63% vs. 60%, p=0.744; OS: 94% vs 85%, p=0.145). 14 Hispanics and 20 non-Hispanics underwent autologous stem cell transplant. No significant difference in 2 year PFS was seen in transplanted Hispanics vs transplanted non-Hispanics (p=0.228) and transplanted Hispanics vs non-transplant Hispanics (p=0.297). High risk transplanted Hispanics showed significantly worse 2 year PFS vs standard risk transplanted Hispanics (25% vs 80%, p=0.009). Transplanted Hispanics differed from non-transplant Hispanics by median age (55.5 vs 67, p=0.05) and income ($56510.00 vs $42418.00, p=0.01). Conclusions: Hispanic MM patients were younger at diagnosis, earned a lower median income, and had more Medicaid coverage compared to non-Hispanics. These differences did not translate to a difference in first line therapy, treatment response, or survival. Transplanted Hispanics were younger and had higher income than non-transplant Hispanics, suggesting that socioeconomic factors may play a role in transplant eligibility. Undergoing transplant, however, did not show a significant PFS benefit compared to Hispanics and non-Hispanics who did not undergo transplant. High risk Hispanics still had inferior PFS compared to standard risk Hispanics after transplant. Additional studies and longer follow-up are needed to confirm these findings. If validated, they could potentially influence treatment decisions for Hispanic MM patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Killer Cell Immunoglobulin-like Receptor Profile in Acute Myeloid Leukemia with Heterogenous Cytogenetic Abnormalities and Its Association with Clinical Outcome

Introduction: Acute myeloid leukemia (AML) is associated with heterogeneous cytogenetic abnormalities which contributes towards biology and prognosis of the disease. Natural killer (NK) cells are the first line of defense against tumor cells. NK cells interact with AML cells via multiple receptors including killer cell immunoglobulin-like receptor (KIR). Evidence of susceptibility of AML cells to NK cells in the context of KIR-ligand mismatch NK immunotherapy has suggested a role of KIR repertoire in the development and clinical outcome of AML. The aim of this study is to determine the KIR profile of AML patients with different cytogenetic abnormalities and to evaluate its association with clinical outcome. Methods: Peripheral blood was collected from patients diagnosed with AML after informed consent in accordance with Declaration of Helsinki and approved from Ethical Review Board of Aga Khan University. Peripheral blood mononuclear cells were isolated and subjected to genomic DNA extraction. KIR genotyping was performed by polymerase chain reaction using sequence-specific primers (Vilches et al, Tissue Antigens 2007). Relationship between KIR loci in AML and healthy individuals was compared using chi-square test. Statistical analysis was performed using SPSS statistics (version 26) and a p value of <0.05 was considered statistically significant. Results: KIR genotyping was performed on 35 cases of AML with mean age of 39 years (range:16-58). Number of male and female patients was 25 and 10 respectively. We found 3 (8.57%) patients with AA KIR haplotype while 33 (91.42%) patients showed Bx haplotype (Figure 1). All the patients with AA haplotype harbored t(15;17) (q22; q21) which has a favorable prognosis while patients with Bx KIR haplotype showed cytogenetic abnormalities with favorable, intermediate, and adverse prognosis. The B-content score of patients with Bx KIR haplotype (n=32) was scored from 1 to 4 based on the total sum of B loci (Cooley et al, Blood 2010). We found that majority of cases had a B-content score of 2 (53.12%) while 7 (21.87%), 6(18.75%) and 2 (6.25%) patients had a score of 1, 3 and 4 respectively. Cytogenetic profile associated with favorable, intermediate, and adverse prognostic risk was found in all groups of patients irrespective of B-content score (Table 1). A standard induction treatment was given to 26 patients with Bx KIR haplotype. Around 67% of patients with B-content score of 1 to 3 showed complete remission (CR) while 100% of patients with B-content score of 4 showed CR after first induction chemotherapy. Estimated KIR gene frequency (gf) in these AML patients was compared with 78 normal individuals recruited from Aga Khan University in Karachi (Norman et al, Gene and Immunity 2002). We found no difference in gf of KIR locus 2DL3 (0.55 vs 0.70), 3DL1 (0.75 vs 0.56), 2DL2 (0.52 vs 0.42), 2DL5 (0.42 vs 0.53), 2DS1 (0.44 vs 0.31), 2DS2 (0.42 vs 0.31),2DS5 (0.28 vs 0.28) and 3DS1 (0.28 vs 0.34) in AML cases vs normal individuals. However, we found significant difference in gene frequency of KIR2DL1 (0.42 vs 0.68) [p=0.002], 2DS4 (0.75 vs 0.47) [p=0.007] and 2DS3 (0.07 vs 0.26) [p=0.002] in AML cases compared to healthy individuals. Conclusion: We found that the majority of patients diagnosed with AML harboring heterogenous cytogenetic abnormalities exhibit a Bx KIR haplotype with B-content score of 2. We did not find any specific cytogenetic abnormality to be associated with a particular B-content score. As we look at our data closely, it seems that it is the cytogenetic abnormality and not the B-content score that dictates the outcome after first induction chemotherapy. We found that patients with AML have decrease in gene frequency of 2DL1 (inhibitory KIR) and 2DS3 (activating KIR) while an increase in gene frequency of 2DS4 (activating KIR) compared to healthy individuals. Further studies are required to determine if variable gene frequency of these 3 KIR loci contributes towards the development of AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathological characteristics of high-risk multiple myeloma in Hispanic versus non-Hispanic patients in central California.

8056 Background: Roughly 37% of Multiple Myeloma (MM) patients in the U.S. are non-white minorities. Advanced stage at diagnosis and specific cytogenetic abnormalities are associated with high-risk disease and poor prognosis. Few studies evaluated these risk factors in ethnic minorities. To further investigate, we analyzed ethnic variations in characteristics and outcomes of high-risk MM patients who were treated at our institution in Fresno, CA (49.6% Hispanic population). Methods: Patients diagnosed with high-risk MM at Community Medical Centers from 1-1-2011 to 12-31-2020 were included. High risk was defined by Mayo Clinic mSMART 3.0 classification. Demographic and disease-relevant information were collected. Cytogenetics, R ISS stage, 1st line treatment (doublet vs triplet), and treatment response (IMWG response criteria) were evaluated. Hispanic and non Hispanic comparisons were made by Fisher’s exact test where appropriate. Progression Free Survival (PFS) and Overall Survival (OS) were evaluated by Kaplan-Meier estimates and compared via log-rank test. Univariate cox proportional hazard model for survival was used to examine the association of variables with mortality risk after 1st line therapy. Results: 147 MM patients were screened. 42 high risk patients were identified: 11 (26%) Hispanic, 31 (74%) non Hispanic (22 white, 8 African American, 1 East Indian). Median age at diagnosis was 65. 26 (61%) were females. 25 (59%) were R ISS stage 3. Hispanic vs non Hispanic median income was $46119 vs $65080 (p=0.035). 6 Hispanics had Medi-Cal insurance vs 2 non-Hispanics (54.6% vs 6.5%, p=0.003). More Hispanics had Lambda light chain disease (73% vs 26%; p=0.01). 13 non Hispanics had del 17p vs 0 Hispanics (p=0.009). 40/42 patients (95%) received triplet therapy. 4 Hispanics received ASCT vs 9 non Hispanics (40% vs 33.3%, p=0.716). Hispanics and non Hispanics did not have significantly different treatment responses per IMWG criteria (p=0.799). No significant difference in PFS was seen between Hispanics and non Hispanics (805 vs 793 days; p=0.089); OS was better in Hispanics (1062 days vs 453 days; p=0.008). Per univariate cox proportional Hazard model, female sex (HR 4.34) and age (HR 1.05) were associated with higher mortality while Hispanic ethnicity was associated with lower mortality (HR 0.19). Conclusions: Hispanic and non Hispanic high risk MM patients differed significantly in median income, insurance, and del 17p incidence. These did not translate to a difference in 1st line therapy or treatment response. OS in our study is higher in Hispanic high-risk MM patients compared to other ethnicities and warrants further investigation. [Table: see text]

25. Novel translocation t(5;19)(q35;p13.3) in a patient with T-Cell large granular lymphocytic leukemia: report of a rare case

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare malignant neoplasm of mature cytotoxic T cells that accounts for 2-3% of mature small lymphocytic leukemias. Lymphocytosis and neutropenia are common in patients with T-LGLL. Characteristically, T cell receptor (TCR) gene rearrangement is present most cases of T-LGLL. Typically, the neoplastic cells express CD2, CD3, CD8, CD57, and ab TCR. Most T-LGLL cases have a normal karyotype and no specific recurrent cytogenetic abnormality has been established thus far.

The prognostic impact of cigarette smoking on survival in acute myeloid leukemia with TP53 mutations and/or 17p deletions.

Cigarette smoking has been associated with increased risk of developing acute myeloid leukemia (AML) in adults. There is limited data on the impact of smoking in AML patients with certain cytogenetic abnormalities. The aim of this study is to assess whether cigarette smoking affected the survival outcome of patients with newly diagnosed AML with TP53 alterations. We conducted a retrospective study of patients who were diagnosed with AML at the Thomas Jefferson Hospital with presence of TP53 mutations and/or 17p deletions. Patients' sex, age, race, smoking status (ever vs. never), cytogenetics, mutational profile, induction regimen, and induction response were analyzed. A total of 102 patients were included in the study with a median follow-up of 27.8months. Among 100 patients who had documentation of smoking status, 59 patients (59%) were ever-smokers and 41 (41%) were never-smokers. Kaplan-Meier survival analysis showed that never-smokers did not differ in overall survival (OS) when compared to ever-smokers (P = 0.34). Univariate analysis revealed that age and cytogenetics had a statistically significant impact on survival. In multivariate analysis incorporating sex, age, race, smoking status, cytogenetics, and induction regimen as covariates, cytogenetics and induction regimen were independent prognostic factors for OS. In summary, no significant difference in OS was found between ever- and never-smokers in AML patients with TP53 alterations. Additional studies are needed to examine the prognostic impact of cigarette smoking in AML with specific cytogenetic abnormalities.

Integrated analysis of genotype and phenotype reveals clonal evolution and cytogenetically driven disruption of myeloid cell maturation in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogenous collection of clonal bone marrow diseases characterized by cytopenias, abnormal karyotypes, molecular abnormalities, and dysplasia by flow cytometry and/or morphology. The progression of MDS to severe cytopenias and/or overt leukemia is associated with the accumulation of additional cytogenetic abnormalities, suggesting clonal evolution. The impact of these accumulated abnormalities on myeloid maturation and the severity of the disease is poorly understood. Bone marrow specimens from 16 patients with cytogenetic abnormalities were flow cytometrically sorted into three myeloid populations: progenitors, immature myeloid cells, and mature myeloid cells. Fluorescence in situ hybridization analysis was performed on each to determine the distribution of chromosomal abnormalities during myeloid maturation. Our findings revealed three distinct distributions of cytogenetic abnormalities across myeloid maturation, each of which corresponded to specific cytogenetic abnormalities. Group 1 had continuous distribution across all maturational stages and contained patients with a single cytogenetic aberration associated with good-to-intermediate prognosis; Group 2 had accumulation of abnormalities in immature cells and contained patients with high-risk monosomy 7; and Group 3 had abnormalities defining the founding clone equally distributed across maturational stages while subclonal abnormalities were enriched in progenitor cells and contained patients with multiple, non-monosomy 7, abnormalities with evidence of clonal evolution. Our findings demonstrate that low-risk abnormalities (e.g., del(20q) and trisomy 8) occurring in the founding clone display a markedly different disease etiology, with respect to myeloid maturation, than monosomy 7 or abnormalities acquired in subclones, which result in a disruption of myeloid cell maturation in MDS.

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies

Prognostic Value of Specific High-Risk Cytogenetic Abnormalities and Ethnicity in Outcomes after Autologous Stem Cell Transplant in Multiple Myeloma

Background:Chromosomal abnormalities in multiple myeloma (MM) patients, identified by either conventional metaphase cytogenetics or fluorescence in situ hybridization (FISH), stratify those at high risk of relapse and poorer survival after treatment. However the prognostic value of high-risk (HR) features in regard to survival after autologous hematopoietic stem cell transplantation is unclear. In addition, recent epidemiologic studies describe difference between Hispanic and non-Hispanic whites (NHW) in incidence, age at presentation, time to initial treatment, and rate of auto-HSCT within one year of diagnosis, but the presence of cytogenetic abnormalities as a prognostic factor in Hispanic patients has not yet been described.Methods:We conducted a retrospective analysis of 367 MM patients at the University of Miami Sylvester Comprehensive Cancer center who underwent auto-HSCT between January 2014 and December 2020. Patients were classified as HR if either conventional cytogenetics or FISH demonstrated at least one of the following: 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16). All other patients with normal chromosomal studies or with trisomies and/or hyperdiploidy were considered standard risk (SR). Survival analysis were performed using the log-rank test, with significance at p-value < 0.05.Results:Male patient comprised 58% of our patient population with 43% of patients of Hispanic ethnicity. Of the 367 patients who underwent auto-HSCT, 183 (50%) had at least one HR cytogenetic abnormality. Overall, HR patients exhibited inferior PFS (32.9m vs 50.6m, p=0.017) and OS (median not reached/NR for both, p=0.0086) compared to SR patients.When evaluating outcomes with specific HR cytogenetic abnormalities, we identified cohorts that did not exhibit survival benefit, either in overall survival (OS) or progression-free survival (PFS) after transplant compared to SR patients, in particular patients with 17p-, 13q-, or 1q+ (Table 1). Patients with 1p-, t(14;16) or t(4;14) derived partial benefit from transplant in terms of PFS but not OS. Notably, patients with 1p- exhibited significantly worse OS compared to other HR patients (38.3m vs NR, p=0.007).We next evaluated differences in outcome when stratifying across ethnicity. Of the 183 patients with HR cytogenetic abnormalities, 75 (41%) were of Hispanic ethnicity, while 58 (32%) were NHW and 46 (25%) were of African-American (AA) ethnicity. The proportion of patients with SR or each individual HR cytogenetic abnormality was mostly equivalent amongst each ethnicity with the exception of 13q- (35% of Hispanic patients, vs. 44% of NHW and 26% of AA patients). Nevertheless, we observed that Hispanic patients with either t(4;14) or 13q- had significantly worse OS and PFS than their NHW and AA counterparts, and similarly observed inferior OS in Hispanic patients with 1q+ (Table 2).Conclusion:In our single-center retrospective analysis of HR MM patients undergoing auto-HSCT, we have identified specific patient populations that derive some survival benefit from transplant as well as populations that did not derive any benefit. Additionally, we demonstrate that despite similar incidence of certain HR abnormalities when comparing across ethnicities, Hispanic patients with particular chromosomal abnormalities have inferior overall survival outcomes after transplant. Further investigation is warranted to identify patient-specific and treatment-related factors leading to inferior outcomes in this patient population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Early Mortality and Aggressive Presentation Lead to Poor Outcomes in Patients with Newly Diagnosed Double Hit and Triple Hit Multiple Myeloma

INTRODUCTIONmSMART classifies high-risk Multiple Myeloma patients into Double Hit and Triple Hit Myeloma (DH/THM) on the basis of the number of high-risk cytogenetic abnormalities detected. The outcome of these patients with the use of proteasome inhibitors and IMiDs with upfront Auto HSCT is not known in the real-world setting. We retrospectively studied the outcome of these patients in a resource constrained setting.METHODSThe case records of all newly diagnosed multiple myeloma patients who fulfilled the criteria for active myeloma between January 2018 and December 2020 were identified. The diagnosis of double hit and triple hit myeloma was based on mSMART classification (Presence of two or more of the following: IgH-FGFR3 translocation, IgH-MAF translocation, TP53 deletion, gain of chromosome 1q). Their case records were retrieved and information regarding baseline characteristics, therapy and outcomes was noted.RESULTSA total of 55 patients with newly diagnosed DH/THM were treated at our center during the study period. Median age of the cohort was 60 years with almost an equal number of male and female patients (M= 26; F= 29). Renal failure (serum creatinine >2.0mg/dl) was present in 33 patients (60%) while bone lesions, anemia (Hemoglobin <10 gm/dl) and hypercalcemia (serum calcium >12mg/dl) were present in 44 (80%), 51 (92.7%) and 24 (43.6%) patients respectively. Six patients (10.9%) fulfilled the criteria for plasma cell leukemia.All but 2 patients had gain of 1q with at least 3 copies. The most common cytogenetic combination was IgH-FGFR3 translocation with gain of 1q, which was seen in 28 patients (50.9%). This was followed by co-occurrence of TP53 deletion with gain of chromosome 1q in 11 patients (20%). Nine patients (16.4%) had triple hit myeloma.Bortezomib was used in the initial therapy of 43 patients (78.2%) and IMiDs (lenalidomide, thalidomide and pomalidomide) were used in the initial therapy of 32 patients (58.2%). Most patients received triplet therapy (N=32; 58.2%) with the most common regimen being RVd. Nine patients (16.4%) died within the first month of diagnosis and another 7 died in next month [15 patients in 2 months (29.1%)]. The most common cause of death within 2 months was progressive disease (N=13; 81.3%). Twenty-two patients (40%) achieved VGPR or better with anti-myeloma therapy and 7 patients (12.7%) underwent autologous HCT. Of the 39 evaluable patients, 21 patients (53.8%) relapsed during follow up with a median EFS of 8 months. Of the 7 patients who underwent transplant, 5 patients have had a follow-up of more than 1 year, of whom 3 have relapsed. One patient with post-transplant relapse died with progressive disease and CMV colitis.Median follow up of the entire cohort was 11 months (Range- 0 to 35 months). After excluding patients who died within the first 2 months of diagnosis, the median follow up was 14 months (Range- 3 to 35 months). Thirty-three patients (60%) patients died during follow-up. The most common cause of death was active or progressive disease (25 patients, 78.1%). Median OS for the cohort was 13 months. On univariate analysis, survival was better for patients without renal injury at presentation (29 months vs 6 months; p=0.007) and patients with <5% circulating plasma cells (14 months vs 2 months; p=0.045). Patients who achieved VGPR had a better OS than patients who did not (Not reached vs 3 months; p=0.000) as did patients who underwent auto transplant (Not reached vs 10 months; p=0.023). OS did not significantly differ with TP53 deletion status, or number of copies of 1q (3 or greater than 3). In the multi-variate analysis, presence of renal failure (Hazard ratio- 2.663; p-0.017) and >5% circulating plasma cells (Hazard ratio- 3.082; p-0.020) were significantly associated with increased risk of mortality, while achievement of VGPR or better with therapy was associated with longer survival (Hazard ratio- 0.174; p-0.001).DISCUSSIONThe outcome of DH/THM remains poor in the real-world setting. The outcome was not affected by specific high-risk cytogenetic abnormalities or their combination in our study. Progressive disease within the first two months of diagnosis was the most common cause of death in more than 1/3 rd of the patients. Novel therapies and protocols are required to improve outcomes for this group of multiple myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

Biological Significance and Prognostic Value of Cytogenetics in 160 Patients with Multiple Myeloma: Predictivity of 13 and/or 14 Monosomies

Until recently, MM was defined using strict clinical pathological criteria that required evidence of specific end-organ damage (CRAB) attributable to the underlying clonal plasma cell disorder. In the case of absence of end-organ damage, patients with clonal plasma cell proliferation were diagnosed either with monoclonal gammopathy of undetermined significance (MGUS) or with smoldering multiple myeloma (SMM). Further, on one hand there have been on-going revisions of the diagnostic criteria for MM and SMM, on the other there have also been revisions of the molecular classification of these disorders; namely, staging and risk. These revisions regarding both the diagnostic criteria and the molecular classification of these disorders are very important because recent advances in understanding these disorders have led to significant progress in the treatment of MM and SMM, in our understanding of disease biology, and in prognostic evaluation for cancer patients. The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care, comparing clinical trial data. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. The initial cytogenetic classification of SMM also has implications for prognosis as patients with t(4;14) translocation, 17p deletion, and 1q amplification have a higher risk of progression from SMM to MM. Although patients with trisomies are considered to have a better prognosis when diagnosed with MM, they have a higher risk of progression from SMM to MM compared to patients with t(11;14). It is possible that trisomic MM manifests earlier with more obvious bone disease, producing in essence a lead-time bias. Thus, the time from SMM to MM is shortened while the time from MM to death appears longer. There are several molecular subtypes of MM, associated with several unique differences in disease presentation and prognosis. For example, trisomic MM appears to respond particularly well to lenalidomide-based therapy, while t(4;14) MM requires bortezomib-based induction and maintenance for good outcome. In terms of clinical presentation, t(4;14) MM appears to have a lower propensity for bone disease at diagnosis, while t(14;16) MM is often associated with high levels of serum free light chains (FLC) and a higher risk of acute renal failure at diagnosis. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. The abnormalities such as t(4;14), t(14;16), t(14;20), gain(1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM. In our center we evaluated the cytogenetics data at the onset of the disease, after 1st line therapy, after transplantation and during maintenance therapy to analyze any changes in the cytogenetic panel and additional anomalies and if all this is correlated with the characteristics of the disease, patient, and risk predictor. In particular, we evaluated 160 patients and analyzed the clinical evolution in patients in which monosomies 13 and/or 14 were present, currently not classifiable in prognostic terms. The significance of these monosomies was evaluated based on the various stages of the disease and the type of therapy administered. DisclosuresNo relevant conflicts of interest to declare.