Cytogenetic Abnormalities and Treatment with New Drugs on Clinical Trials Are Important Prognostic Markers for Myeloma in the Era of ISS and FISH Analysis
Authors: Soekojo Cinnie Yentia , Lin Adeline , Poon Michelle , Koh Liang Piu , Tan Lip Kun , Ooi Melissa G. , Chng Wee Joo 
Published: October 2019

Abstract
Background:The revised ISS staging system highlights the importance of lactate dehydrogenase (LDH), fluorescence in situ hybridization (FISH) and the International Staging System (ISS) for prognostication of multiple myeloma (MM) patients. As a result, the continued utility of conventional karyotyping, has been called into question.
At the same time, novel agents have significantly improved patient outcome. However, it is still unclear if novel agents benefit all patients or a particular subgroup of patients. In particular, the impact of treatment with the latest approved drugs and early drug access through clinical trials, especially in Asian countries, is unknown.
Methods:Patients who were diagnosed with MM from year 1999 at the National University Hospital, Singapore, were recruited. We evaluated the correlation between cytogenetic abnormalities (normal, hyperdiploid, and non-hyperdiploid) to the overall survival (OS) for patients with different ISS stage, Revised ISS stage, and ISS-iFISH stage. We evaluated the role of novel agents on OS for patients with ISS Stage I or II/III disease. We divided the patients into 3 groups: patients who received novel agents (bortezomib, thalidomide, lenalidomide) at induction and relapse, patients who did not receive novel agents at induction but received novel agents at relapse, and patients who never received any novel agents, and evaluated differences in OS between these groups within the ISS stage. We also evaluated the impact of access to clinical trials and treatment with the newest generations of novel agents (carfilzomib, ixazomib, pomalidomide) on OS.
Results:A total of 252 patients were in our database, with 180, 105 and 132 patients evaluable for ISS, ISS-iFISH and revised ISS respectively. Karyotype significantly affected OS of patients with ISS Stage I (p=0.009), and there was a trend for patients with ISS Stage II/III (p=0.10). Karyotype significantly affected the outcome of patients with ISS-iFISH stage I or II/III (p=0.000 and 0.006 respectively). Similarly, karyotype has significant impact on OS of patients with Revised ISS stage I and II/III respectively (p=0.004 and 0.052 respective). In all cases, patients with non-hyperdiploid MM do particularly badly.
For the evaluation of the benefit of novel agents, 213 patients were evaluable..There were 39 patients in ISS Stage I group and 174 patients in ISS Stage II/III group. For patients with ISS stage II/III, the difference in OS in those who received novel agents at induction, the group which did not receive novel agents at induction but received novel agents at relapse, and those who never received any novel agents was statistically significant with p-value of 0.009. Conversely, the impact of novel agents on patients with ISS Stage I is not significant (p=0.885).
Patients who were enrolled in clinical trials had significantly better OS with p-value of 0.002. Similarly, patients who received newest generations of novel agents (almost all on clinical trials) had significantly better OS with p-value of 0.014.
In multivariate analysis adjusting for ISS-iFISH stage, treatment history with novel agents, and access to clinical trials, karyotypic abnormalities are significantly associated with OS (p-value of 0.001). Treatment history with novel agents is the other independent factor for OS. ISS-iFISH stage and access to clinical trials are not significant factors on the multivariate analysis (p-value 0.537 and 0.609 respectively). Access to clinical trials may lose its significance on multivariate analysis because of the relatively low number of patients on clinical trials.
Conclusion:Our analysis showed that cytogenetics still has an important role in MM prognostication even in the setting of FISH and ISS. In particular, non-hyperdiploid karyotype portends a very bad prognosis. Novel agents have the least impact on outcomes for ISS stage I patients. In resource poor countries, this may help to stratify treatment. Lastly, access to clinical trials and treatment with the newest generations of novel agents are important prognostic factors in our cohort. This highlights the importance of drug access, which remains a significant challenge in many Asian countries.
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Disclosures
No relevant conflicts of interest to declare.