Fluorescent in Situ Hybridization Analysis in Multiple Myeloma: Enhancing Risk Stratification, Autologous Transplant Utilization and Treatment Decisions in Limited-Resource Settings
Authors: Yawalkar Rashmi , E.V. Mrudula , GS Reshmy , Paul Mobin , Jha Vidya , Nair Anjaly , Unni Manoj , Ganapathy Rema , Harimadhavan Monisha , Haridas Nikhil Krishna , Yadav Chitresh , C Anjusha , Sreenaryanan Chitra , Vinayakumar Syamaprasad , Mony Ullas , Sidharthan Neeraj 
Published: December 2023

Introduction:
Multiple myeloma (MM) is a heterogeneous and incurable disease with a high risk of relapse. Recent advancements in MM treatment, such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies, have improved outcomes. Risk stratification plays a crucial role in prognosis, with cytogenetic abnormalities being an important predictor. However, conventional karyotyping is limited in its sensitivity, while interphase Fluorescent In Situ Hybridization (FISH) has emerged as a powerful prognostic marker. In lower- and middle-income countries (LMICs), where MM management faces challenges, identifying high-risk patients through FISH can guide treatment decisions and improve outcomes, even in the absence of novel drugs like Daratumumab.
Methods:
We conducted a retrospective study on newly diagnosed MM (NDMM) patients from January 2016 to December 2022 in two South Indian centres. Patients receiving at least 16 weeks of induction chemotherapy ± autologous stem cell transplant (ASCT) were included. The cohort was divided into two groups: those with FISH results evaluable (FRE group) and those with FISH results unavailable (FRU group). FISH analysis used 5 probes (Del13q14.3, TP53/ CEN 17, IgH (14q32.3)/ FGFR3 (4p16), IgH (14q32.3)/CCND1 (11q13), IgH (14q32.3)/MAF (16q23)) till March 2020 and 7 probes (XL CDKN2C/CKS1B, XL t(4;14) FGFR3/IGH DF, XL 5p15/9q22/15q22 Hyperdiploidy, XL t(11;14) MYEOV/IGH, XL IGH BA, XL t(14;16) IGH/MAF DF, XL TP53/17cen) from April 2020. Data collected included demographics, International Staging System (ISS), mSMART 3.0-based FISH risk stratification, induction regimen, ASCT, maintenance, relapse and response. Survival analyses employed Kaplan-Meier (KM) and log-rank tests. IBM SPSS Version 26 Software was used for analysis.
Results:
Of the 427 screened NDMM patients, 333 were included: 192 (57.7%) in FRE and 141(42.3%) in FRU group. Baseline characteristics were comparable, except for hypercalcemia being significantly higher in FRE (p-0.015). In FRE, 128(66.67%) had standard risk, and 64 (33.33%) had high-risk MM. VRd induction was more frequently used in FRE (p-&lt;0.001) with no significant difference in induction response. A higher percentage of FRE patients underwent ASCT (22.9% vs. 9.93%, p&lt;0.002), achieving more complete responses post-transplant (p&lt;0.001). FRE group also showed an increased use of doublet maintenance (p-0.014). No significant difference observed in the mortality (p-0.069). ASCT correlated with better median PFS (64 Vs. 37 months, p-0.013).
Conclusions:
In this resource-limited setting, the availability of FISH results seemed to have an impact on MM patient management and outcomes. FRE patients received more aggressive induction therapy, resulting in better response rates and increased ASCT utilization. Additionally, dual-agent maintenance was preferred for high-risk patients in FRE. However, it is essential to acknowledge that this was a retrospective analysis, and other factors may have influenced the outcomes, even though both cohorts were mostly matched. Notably, none of the patients had received Daratumumab as induction therapy, suggesting that FISH availability in LMICs may positively impact patient outcomes even in the absence of access to novel drugs. Further validation through multicenter prospective investigations is warranted to strengthen these findings and explore the broader implications of incorporating FISH into risk stratification strategies. By utilizing FISH, LMICs can enhance MM management and form tailored treatment strategies, thereby improving care for NDMM patients.