Treatment of Multiple Myeloma with High-Risk Cytogenetics: A Consensus of the International Myeloma Working Group

Journal Club Library published on September 30, 2016

Blood. 2016;127(24):2955-2962.

Article summary written by Patrick Brooks, PharmD, Medical Director, Oncology

Multiple myeloma (MM) is a heterogeneous hematologic malignancy characterized by various cytogenetic abnormalities; these abnormalities are used to identify patients with high-risk disease, which may be defined as an overall survival (OS) less than three years.1 In August of 2015, the International Myeloma Working Group (IMWG) published a revision to the International Staging System (R-ISS). The R-ISS now identifies patients with high-risk chromosomal abnormalities by the presence of del(17p13) and/or t(4;14) and/or t(14;16).2

Fluorescence in situ hybridization (FISH) is the currently recommended technique for detecting chromosomal abnormalities in patients with MM. Karyotyping is not recommended due to lower sensitivity compared to FISH. Other techniques with higher sensitivity, including single-nucleotide polymorphism-based mapping arrays and comparative genomic hybridization, are reserved for clinical trials at this time. Gene expression profiling can be useful for prognostication, but may require bioinformatics support.1

FISH can detect key chromosomal abnormalities in MM, resulting from immunoglobulin heavy chain translocations, hyperdiploidy, and chromosomal deletions or gains (Table 1). High-risk cytogenetics include del(17p13), t(4;14), t(14;16), t(14;20), and any non-hyperdiploid karyotype. It is important to note that patients with a combination of three or more chromosomal abnormalities are deemed ultra-high-risk, with an OS less than two years. However, testing of del(17p13), t(4;14), and t(14;16) by FISH is the current recommendation for detecting chromosomal abnormalities in patients with newly diagnosed MM.1

Table 1. Cytogenetic Abnormalities Detected by FISH in Patients with Multiple Myeloma1


(Enlarge Table)

Adapted from Reference 1

In June 2016, the IMWG expanded the utility of chromosomal abnormalities from disease staging to treatment selection, publishing recommendations for therapy in patients with newly diagnosed MM, which outlines the impact of specific therapies on abrogating the adverse effect of the high-risk chromosomal abnormalities on treatment outcomes (Table 2). In patients with del(17p) and t(4;14), bortezomib and carfilzomib improved complete response (CR), progression-free survival (PFS) and OS; lenalidomide improved PFS in these patients, but not OS. The IMWG recommends high-dose therapy plus autologous stem cell transplant in transplant-eligible patients with high-risk chromosomal abnormalities, as this standard therapy improved outcomes across prognostic groups. The group also recommends the combination of a proteasome inhibitor and dexamethasone with lenalidomide or pomalidomide in patients with newly diagnosed MM and high-risk chromosomal abnormalities, which may be an important consideration for those who are transplant-ineligible.1

Table 2. Therapeutic Recommendations Based on High-Risk Chromosomal Abnormalities in Newly Diagnosed MM1

Therapy High-Risk CA IMWG Consensus

Thalidomide

Any

Does not abrogate adverse effects of CA in TE patients

Lenalidomide

del(17p) and t(4;14)

Reduces adverse effect on PFS, but not OS in TE patients
No data to suggest improvement in non-TE patients

Pomalidomide

del(17p)

May improve response and OS in RRMM patients

Bortezomib

del(17p) or t(4;14)

Reduces adverse effect on CR, PFS and OS

del(17p) and t(4;14)

No effect in TE patients
VMP may partly restore PFS in non-TE patients

Carfilzomib

del(17p) and t(4;14)

KRd reduces adverse effect on PFS

HDT + ASCT

Any

HDT + double ASCT for patients with HR CA

ASCT=autologous stem cell transplant; CA=chromosomal abnormality; CR=complete response; HDT=high-dose therapy; HR=high-risk; IMWG=International Myeloma Working Group; KRd=carfilzomib/lenalidomide/dexamethasone; OS=overall survival; PFS=progression-free survival; RRMM=relapsed/refractory multiple myeloma; TE=transplant-eligible; VMP=bortezomib/melphalan/prednisone

Further subgroup analyses, clinical trials designed for high-risk chromosomal abnormalities, and utilization of more advanced molecular techniques, such as gene expression profiling, will all provide additional insight into the predictive impact of cytogenetic abnormalities. Health care providers may then benefit from increased use of genetic mutations to guide therapeutic decisions for their patients with MM.

 

References

  1. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962.

  2. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
Last modified: September 30, 2016