Concepts of Double Hit and Triple Hit Disease in Multiple Myeloma, Entity and Prognostic Significance

Abstract

Risk assessment in newly diagnosed multiple myeloma patients (NDMM) is the first and the most crucial determinant of treatment. With the utilization of fiSH analysis as a part of routine practice, high riskMultiple Myeloma (MM) is defined as having at least one of the mutations related with poor prognosis including; t(4;14) t(14;16), t(14;20), del 17p, p53 mutation, gain 1q and del 1p. M-Smart MM risk stratification guideline by Mayo Clinic has proposed a concept similar to high grade lymphomas. Having two of the high risk genetic abnormalities were defined as double hit MM and having any three as triple hit MM. Based on these definitions which may bring a much more clinically relatable understanding in MM prognosis, we aimed to assess our database regarding these two concepts and their probable significance in terms of outcome and prognosis. We retrospectively evaluated 159 newly diagnosed multiple myeloma patients and their clinical course. Among these patients; twenty-four patients have one high risk determinant and also seven and two patients were classified as double hit MM and triple hit MM respectively. Overall survival (OS) of the patients with double hit MM was 6 months, 32.0 months for patients with single high risk abnormality and 57.0 months for patients with no high risk abnormality. Univariate analysis showed that Double Hit and Triple Hit MM is a predictive of low OS. Hazard Ratio of patients with one high risk abnormality was 1.42, double-hit MM patients was 5.55, and triple-hit MM patients was 7.3. Despite the development of novel drugs and their effects of prolonging survival, the treatment has not been individualized. Understanding the biology of each patient as a unique process will be the success of the treatment. As it is known that some MM patients harbor high risk genetic abnormalities according to fiSH analysis, we can continue the argument that some patients bring an even higher risk and that can be defined as double or triple hit MM.

Autologous peripheral blood stem cell transplantation as front-line therapy for myeloma with double-hit and triple-hit in a real-world study

“…All the patients were followed up and the last follow-up time was April 30, 2020. To analyze the role of APBSCT as front-line therapy for myeloma with double-hit or triple-hit, we reviewed some published data [ 3 , 4 ] and compared our results with them. Statistical analysis was conducted using SPSS 22.0 software (SPSS, Chicago, IL).…”

Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma

“…This eventually gives rise to highly aggressive subclones that expand to extramedullary sites and show high resistance to cytotoxic insults. For example, the presence of subclones harboring additional abnormality of chromosome 1q amplification and/or deletion of chromosome 17p is strongly associated with dismal outcomes [35,36,41,42]. Thus, in the absence of a universal molecular target in the background of high cytogenetic and molecular heterogeneity, clonal evolution is the critical biologic event to be prevented or overcome for improvement of therapeutic outcomes of patients with MM.…”

Genetic Predictors of Mortality in Patients with Multiple Myeloma

“… 17 , 62 Presence of more than one high-risk abnormality is seen in less than 5% of newly diagnosed MM including t(4;14), t(14;16), t(14;20), del(17p)/TP53 mutation, gain(1q), del(1p) and constitutes “double-hit” or “multi-hit“ myeloma, associated with significantly poorer prognosis. 91 , 92 Similarly, coexistence of del(6q) and del(1p32) with del(17p) significantly worsens the prognosis of patients. 60 …”

“…17,62 Presence of more than one high-risk abnormality is seen in less than 5% of newly diagnosed MM including t(4;14), t(14;16), t (14;20), del(17p)/TP53 mutation, gain(1q), del(1p) and constitutes "double-hit" or "multi-hit" myeloma, associated with significantly poorer prognosis. 91,92 Similarly, coexistence of del(6q) and del (1p32) with del(17p) significantly worsens the prognosis of patients. 60 Conversely, using a genomic scar score (GSS), whole-genome sequencing studies have also identified a subgroup of MM patients characterized by low GSS (low mutational burden, specific mutation signatures pattern and fewer structural variants) and a very good overall survival.…”