Outcomes of Double-Hit and Single High Risk Cytogenetic Newly Diagnosed Myeloma in Transplant Eligible Patients
Authors: Rahman Raeef L , Khaliq Aroog , Laharwal Mehak M , Atrash Shebli , McGuirk Joseph P. , Mahmoudjafari Zahra , Mushtaq Muhammad Umair , Abdallah Al-Ola , Ahmed Nausheen , Mewawalla Prerna , Snyder Jordan 
Published: December 2024

Introduction:
High-risk multiple myeloma (HRMM) poses challenges in treatment due to the increased risk of early relapse and higher mortality. Various clinical, cytogenetic, and gene expression features have been utilized to identify high-risk patients. Given the poor outcomes associated with high-risk cytogenetic groups, there have been endeavors to identify treatments and combinations that could potentially improve the prognosis of patients with these abnormalities. Our study aims to assess the outcomes of patients with newly diagnosed multiple myeloma with double-hit and single high-risk cytogenetics (SHRC) who underwent autologous stem cell transplants (ASCT) in two centers.
Methods:
A retrospective study was conducted involving the University of Kansas Health System and Allegheny General Hospital (AGH) in collaboration with US Myeloma Innovations Research Collaborative (USMIRC) from January 2009 to January 2024. The study reviewed results of metaphase cytogenetic and fluorescence in situ hybridization (FISH) studies of bone marrow aspiration samples from all patients. High-risk cytogenetics were defined as -17/del(17p), t(4;14), t(14;16), or t(14;20) with and without 1 gain chromosome on FISH. Double-hit MM was defined by the coexistence of two high-risk abnormalities. The study utilized the Kaplan-Meier method and a regression model for survival analysis, and group comparisons were performed using the Wilcoxon rank sum test and Pearson's Chi-squared test.
Results:
In our analysis, 111 patients who underwent ASCT had a median age of 59 years (range 33-85). Of these patients, 83 (75%) were Caucasian. The majority, 65 patients (59%), had IgG isotype, while 41 patients (37%) had Revised International Staging System (R-ISS) stage III disease, and 15% had extramedullary disease. Double hit was present in 66 patients (59%). Ninety-seven patients (87.4%) received triplet induction therapy, with the most common regimen being VRD (bortezomib, lenalidomide, dexamethasone). Most patients received proteasome inhibitor-based (PI) therapy (96.4%), followed by immunomodulatory agent-based therapy (81%), and anti-CD38 monoclonal antibody-based therapy (5.4%). Regarding the conditioning regimen, melphalan at 200 mg/m2 was used in 96 patients (86%) and at 140 mg/m2 in 14 patients (13%). The overall response rate (ORR) post-induction therapy was 92%, with 68 patients (61.2%) achieving a very good partial response or better. After ASCT, the ORR was 91%. The median progression free survival (PFS) for all patients was 31.5 months (95% CI: 28.2-37.8), and the median overall survival (OS) was 80.8 months (70.3-103.4). Median PFS for those with double hit was 30 months (95% CI: 20-34) while SHRC was 40 months (95% CI: 30-57) (p&lt;0.001), while median OS in double hit vs. SHRC was 78 (95% CI: 54-110) vs. 90 (95% CI: 69-138) months (p&lt;0.001). Post-ASCT, 94 patients (85%) received maintenance therapy, with 59 (63%) receiving single-agent therapy and 30 (32%) receiving doublet therapy. The most common maintenance therapy involved lenalidomide-based therapy in 78 patients (83%), while 35% received PI-based therapy and 6 patients (6.4%) received daratumumab-based therapy. The most common causes of death were progressive disease 44 (69%) patients, non-relapse mortality due to infection/sepsis occurred in 6 (9%) patients, and cardiac/arrhythmia issues occurred in 2 (4%) patients.
Conclusion:
Our study reveals that a specific subset of HRMM with double-hit is associated with a poorer prognosis in patients who undergo ASCT compared to those with single high-risk cytogenetics, in terms of PFS and OS. The advent of newer therapies such as BCMA-directed therapies may influence the treatment approach for HRMM patients. Further prospective studies are necessary to delve into these findings and refine treatment strategies for HRMM.