Analysis Of The Influence Of Cytogenetic Abnormalities On The Survival Of Patients With Multiple Myeloma

BACKGROUND : Multiple myeloma(MM)is a cytogenetically heterogeneous clonal plasma cell proliferative disorder,which occurs in the elderly and accounts for 10%of all hematological malignancies.It is characterized by malignant proliferation of monoclonal plasma cells in the bone marrow and the presence of monoclonal immunoglobulin in serum or urine.Typical clinical manifestations include hypercalcemia,bone lesions,anemia,renal dysfunction,and infection caused by decreased immunity,hyperviscosity and other target organ damage.Multiple myeloma has obvious heterogeneity in clinical manifestations and prognosis of the disease vary widely.In recent years,the deepening of understanding of tumors provides a theoretical basis for the treatment of MM and new drug development,including immunomodulatory drugs(IMi Ds),proteasome inhibitors(PIs),monoclonal antibodies and histone deacetylase(HADC)blockers have been widely used in clinical practice,so that the overall survival of MM patients is prolonged,but it is still incurable.Different MM patients have very different treatment responses.Studies have confirmed that MM cytogenetic abnormalities have an important impact on prognosis.How to evaluate patient prognosis more effectively has become one of the focuses of international research.Fluorescence in situ hybridization(FISH)is currently the standard method for detecting cytogenetic abnormalities of MM patients.However,it is still controversial how to conduct risk stratification of MM patients by FISH results.The critical value of the clinical significance of different chromosomal abnormalities detected by fluorescence in situ hybridization is still unclear.Therefore,this study retrospectively analyzed the the clinical characteristics of 533 patients with multiple myeloma in our hospital.The effects of different number and combination of chromosomal abnormalities detected by fluorescence in situ hybridization on the prognosis of patients were analyzed,aimed at studying the relationship between cytogenetic abnormalities and the prognosis of patients with multiple myeloma,and providing Evidence-based medicine evidence for the risk classifications and the individualized treatment.Methods: A total of 533 patients with newly diagnosed multiple myeloma who were admitted to Shanghai Changzheng Hospital were enrolled.All patients were tested for cytogenetic abnormalities by fluorescence in situ hybridization.The information of the patient at the first treatment were collected mainly included the gender,age,and M protein type,DS stage,ISS stage,LDH,PLT,bone marrow plasma cell count,treatment,transplantation method,FISH test results.Statistical analysis was performed using SAS Version 9.4 and R version 3.4.1.Measurement data were expressed as mean ± standard deviation,and count data was expressed in terms of numbers and percentages.The K-Adaptive Partitioning method was used to calculate the most significant cut-off values??for the prognosis of t(11;14),t(4;14),t(14;16),1q21+,17p-,13q-,and compare with the cutoff values recommended by the EMN.Patients were classified based on different cut-off values ??of FISH,and the differences in survival were compared by univariate and multivariate analysis.Then all patients were divided into four subgroups: no chromosomal abnormalities,1 chromosomal abnormality,2 chromosomal abnormalities,and more than 2 chromosomal abnormalities,and the survival differences between each group were compared.Kaplan-Meier test was used for survival analysis.Log-rank test was used to analyze the indicators by univariate analysis and survival curves.The COX proportional regression model was used to explore the influencing factors of survival rate.The single factor analysis P<0.05 was included.Multi-factor models,multi-factor models are further filtered by stepwise methods,and the final inclusion variables will be used as independent factors.All tests were performed on both sides,with a statistical significance of p < 0.05.RESULTS:(1)The rate of Ig H translocation,1q21+,17p-,13q-detected by FISH was 64.73%(345/533),55.16%(294/533),12.76%(68/533),45.59%(243/533)respectively.For patients with Ig H translocation,further tests were performed for t(11;14)(q13;q32),t(4;14)(p16;q32),t(14;16)(q32;q23),and the incidence rates of t(11;14),t(4;14),and t(14;16)were 13.32%(71/533),17.45%(93/533),and 1.88%(10/533),respectively.(2)Using the K-Adaptive Partitioning method to calculate the chromosomal abnormal cut-off values ??are as follows: 17p-20.1%,13q-85%,1q21 + 39%,Ig H translocation 57.5%,t(11,14)55.5%,t(14,16)0%,t(4,14)53.5%.(3)Multivariate analysis according to the cutoff values recommended by the EMN.Independent prognostic factors for PFS included: 1q21 gains [HR,1.667(95% CI,1.226-2.266),P = 0.001],del(17p)[HR,1.836(95% CI,1.247-2.704),P = 0.002],age [HR,1.020(95% CI,1.004-1.036),P = 0.012],ISS stage 3 [HR,2.641(95% CI,1.791-3.893),P<0.001 ],LDH is greater than the normal range [HR,1.002(95% CI,1.001-1.003),P <0.001],M protein type is Ig D [HR,2.140(95% CI,1.285-3.562),P = 0.003].The independent prognostic factors for OS were similar: 1q21+ [HR,1.681(95% CI,1.235-2.289),P <0.001],del(17p)[HR,1.758(95% CI,1.197-2.581),P = 0.004],age [HR,1.017(95% CI,1.001-1.033),P =0.033],ISS stage 3 [HR,2.730(95% CI,1.866-3.995),P < 0.001],LDH greater than normal The range was [HR,1.002(95% CI,1.001-1.003),P <0.001],and the M protein type was Ig D [HR,2.106(95% CI,1.255-3.534),P = 0.005].(4)According to the calculation of the best cut-off value by the K-Adaptive Partitioning method,the independent prognostic factors associated with PFS include: del(13q)[HR,1.441(95% CI,1.035-2.007),P = 0.031],1q21+ [HR,1.737(95% CI,1.289-2.340),P <0.001],del(17p)[HR,1.816(95% CI,1.236-2.669),P =0.002],age [HR,1.023(95)% CI,1.007-1.039),P= 0.005],ISS stage 3 [HR,2.545(95% CI,1.720-3.766),P <0.001],LDH is greater than the normal range [HR,1.002(95% CI,1.001-)1.003),P <0.001],M protein type is Ig D[HR,2.157(95% CI,1.293-3.598),P = 0.003].The independent prognostic factors for OS were: del(13q)[HR,1.780(95% CI,1.278-2.478),P <0.001],1q21+ [HR,1.761(95% CI,1.303-2.308),P <0.001],del(17p)[HR,1.785(95% CI,1.214-2.623),P =0.003],age [HR,1.020(95% CI,1.004-1.036),P = 0.014],ISS 3 [HR,2.730(95% CI,1.863-4.000),P<0.001],LDH is greater than the normal range [HR,1.002(95% CI,1.001-1.003),P<0.001],M protein type is Ig D [HR,2.176(95% CI,1.292-3.666),P = 0.003].(5)In multivariate analysis,del(13q)became an independent prognostic factor according to the chromosomal abnormality cutoff values calculated by K-Adaptive Partitioning method,to further verify whether del(13q)is usually associated with other high-risk cytogenetic aberration,such as 17 p deletion or t(4;14).We divided the patients into 4 groups,respectively del(13q)abnormal and 17p-or t(4;14)abnormal,del(13q)abnormal and 17 pand t(4;14)normal,del(13q)normal and 17p-and t(4;14)normal,del(13q)abnormal and17p-or t(4;14)normal,according to the cutoff values recommended by the EMN,multivariate analysis suggested only del(13q)abnormalities and 17p-or t(4;14)abnormalities were PFS [HR,1.625(95% CI,1.126-2.346),P=0.009] and OS[HR,1.892 Independent prognostic factors(95% CI,1.311-2.731),P <0.001];according to the cutoff values calculated by K-Adaptive Partitioning method,the independent prognostic factor associated with PFS was del(13q)abnormality and 17p-or t(4;14)abnormal group [HR,1.928(95% CI,1.234-3.014),P=0.004],the independent prognostic factor associated with OS was del(13q)abnormality and 17p-or t(4;14)abnormal group [HR,2.646(95% CI,1.691-4.140),P < 0.001] and del(13q)abnormalities and 17p-and t(4;14)normal groups[HR,1.612(95% CI,1.047-2.480),P=0.03].(6)The effect of chromosomal abnormalities on prognosis was analyzed.According to the cutoff values recommended by the EMN,only more than 2 abnormal groups in the 4 groups were independent prognostic factors for OS [HR,2.557(95% CI,1.524-4.290),P < 0.001].None of the multivariate analyses were independent prognostic factors for PFS;then,according to the cutoff values calculated by K-Adaptive Partitioning method,the independent prognostic factors associated with PFS in the 4 groups were more than 2 abnormal groups [HR,2.182(95% CI,1.383-3.442),P<0.001],independent prognostic factors associated with OS were 2 abnormal groups [HR,2.182(95% CI,1.383-3.442),P <0.001] and more than 2 abnormal groups Group [HR,2.950(95% CI,1.932-4.503),P < 0.001].Conclusion: The K-Adaptive Partitioning method was used to calculate the chromosomal abnormal cutoff value as follows: 17p-20.1 %,13q-85%,1q21+ 39%,Ig H translocation 57.5%,t(11,14)55.5%,t(14,16)0%,t(4,14)53.5%.According to the cutoff values recommended by the EMN,age,ISS stage 3,LDH,M protein being Ig D type,17 pand 1q21+ were statistically independent predictors of the OS and PFS,and analysis based on the cutoff value obtained by K-Adaptive Partitioning method suggested that 13q-is also an independent factor affecting prognosis.13q-is an independent factor affecting prognosis and is not associated with 17p-or t(4,14),but only when the 13q-expression value is large,the effect on prognosis is more significant.The number of chromosomal abnormalities will affect the prognosis of MM patients.A single chromosomal abnormality has little effect on the prognosis of MM patients.However,when the number of two or more chromosomes is abnormal,the prognosis of MM patients will be worse,and the greater the number of chromosomal abnormalities,the worse the patient's prognosis.