Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group

The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.

Important points:

1. The International Myeloma Working Group has updated the definition for high-risk multiple myeloma based on cytogenetics. ​
2. Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified as high-risk abnormalities. ​
3. Treatment strategies for high-risk cytogenetic diseases include proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. ​
4. Bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). ​
5. Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. ​
6. Fluorescence in situ hybridization (FISH) is the standard technique for analysis of cytogenetic abnormalities. ​
7. FISH testing for t(4;14) and del(17p13) is sufficient for routine diagnosis. ​
8. Other diagnostic techniques for cytogenetic abnormalities include conventional karyotyping, single-nucleotide polymorphism-based mapping arrays, comparative genomic hybridization, and gene expression profiling.
9. IgH translocations and genomic imbalances are high-risk cytogenetic abnormalities in multiple myeloma. ​
10. The presence of multiple adverse cytogenetic abnormalities has a progressive impact on overall survival. ​
11. Trisomies in patients with high-risk cytogenetic abnormalities may reduce their adverse impact. ​
12. Hyperdiploidy is associated with improved progression-free survival and overall survival. ​
13. The presence of hyperdiploidy does not change the outcome in patients with an adverse cytogenetic abnormality. ​

Authors:

Pieter Sonneveld, Herve Avet-Loiseau, Sagar Lonial, Saad Usmani, David Siegel, Kenneth C. Anderson, Wee-Joo Chng, Philippe Moreau, Michel Attal, Robert A. Kyle,Jo Caers, Jens Hillengass, Jesus San Miguel, Niels W. C. J. van de Donk, Hermann Einsele, Joan Blade, Brian G. M. Durie, Hartmut Goldschmidt, Maria-VictoriaMateos, Antonio Palumbo, Robert Orlowski

Citation:

Blood, 127(24), 2955-2962.