Proteasome inhibitors and IMiDs can overcome some high‐risk cytogenetics in multiple myeloma but not gain 1q21

Abstract

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population-based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow-up of patients still alive at analysis was 40 months for the high-dose (HDT)-treated ones and 29 months for the whole population. Three hundred forty-seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14;16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3-yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P < 0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3-yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3-yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P < 0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation

“…Furthermore, our findings suggest a poor outcome for patients with CKS1B amplification even with a PI or an IMiD-based induction in >90% of patients, and the use of post-transplant maintenance therapy in approximately 80% of patients. Similar outcomes were reported by Nahi et al, who found that patients with 1q21 gain had a shorter overall survival, which was not overcome by treatment with PI, IMiD or auto-HCT [33]. In contrast to induction, a higher proportion of patients in the CKS1B group received a PI-based maintenance (30% vs. 13%) than the control, and still had a shorter PFS and OS.…”

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

“…In addition to the previously defined high-risk cytogenetic abnormalities, the 2016 International Myeloma Working Group consensus paper includes gain of 1q on FISH as a high-risk feature 10 ; this abnormality has also been shown to confer poor prognosis in other studies and analyses in MM 17,20,21 and has been suggested as 1 of the most important markers of poor prognosis with current treatments. 21 We therefore undertook a post hoc analysis of outcomes according to the presence of this abnormality, and incorporated patients with 1q21 amplification within the expanded high-risk group.…”

“…21 We therefore undertook a post hoc analysis of outcomes according to the presence of this abnormality, and incorporated patients with 1q21 amplification within the expanded high-risk group. As with the other high-risk subgroups and abnormalities, our findings showed a consistent PFS benefit with IRd vs placebo-Rd in patients with amp 1q21 alone (3% cutoff; HR, 0.781; 95% CI, 0.492-1.240) and in the expanded high-risk cytogenetics subgroup (HR, 0.664; 95% CI, 0.474-0.928).…”

“…[16][17][18][19] Additionally, gain of 1q21 on FISH has been shown to confer poor prognosis 17,20,21 ; in some reports, 1q21 amplification is considered a high-risk abnormality, 21,22 including in a 2016 consensus paper from the International Myeloma Working Group, 10 whereas other reports classify it as conferring intermediate or standard risk. 23,24 To date, although data on the use of novel agent-based treatments have demonstrated that these regimens improve outcomes in patients with MM vs previous or existing standards of care, progression-free survival The online version of this article contains a data supplement.…”

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

“…To date, outcome of MM patients carrying 1q21 gain remain poor, primarily due to failure to overcome drug resistance stemmed from this adverse CA 42, 43. To serve as a prognostic marker for this high‐risk subtype of MM, at least 3 criteria should be met, including that (1) it is often upregulated in MM and better increased with disease progression; (2) it must be amplified and/or overexpressed due to 1q21 gain; and (3) its expression must significantly correlate with poor prognosis of patients 44.…”