ISSN (print) 1997-6933     ISSN (online) 2500-2139
Vol. 17 No. 3 (2024), LYMPHOID TUMORS
Vol. 17 No. 3 (2024)
LYMPHOID TUMORS

KRAS/NRAS Gene Mutations and the Efficacy of Bortezomib-Based Triplet Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma

Published 01.07.2024
Anna Mikhailovna Sergeeva
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0003-4863-4902
V.L. Surin
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-1890-4492
Yu.A. Chabaeva
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-8044-598X
A.A. Kraizman
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0003-1934-8800
M.V. Solovev
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-7944-6202
S.M. Kulikov
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-6288-7570
L.P. Mendeleeva
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-4966-8146
2024-3
PDF_2024-17-3_256-265 (Russian)

Keywords

multiple myeloma
KRAS and NRAS gene mutations
bortezomib-based triplet therapy
CD138+ plasma cells

How to Cite

Sergeeva A.M., Surin V.L., Chabaeva Y.A., Kraizman A.A., Solovev M.V., Kulikov S.M., Mendeleeva L.P. KRAS/NRAS Gene Mutations and the Efficacy of Bortezomib-Based Triplet Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma. Clinical Oncohematology. 2024;(3):256–265. doi:10.21320/2500-2139-2024-17-3-256-265.
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Abstract

AIM. To identify the KRAS and NRAS gene mutations in patients with newly diagnosed multiple myeloma (ММ) and to classify them according to the depth of antitumor response to bortezomib-based triplet induction therapy.

MATERIALS & METHODS. The trial enrolled 89 patients with newly diagnosed MM prior to chemotherapy. Among them, there were 45 women and 44 men aged 30–82 years (median 58.5 years). ММ was diagnosed according to IMWG criteria (2014). Bone marrow (BM) plasma cells were isolated from the aspirate using gradient method with subsequent immunomagnetic CD138 marker selection. The KRAS and NRAS gene mutations in BM CD138+ cells were identified with Sanger sequencing method. The proteomic programs MutationTaster, Polyphen2, and FATHMM-XF were used for mutation analysis in the KRAS and NRAS genes. All patients received bortezomib-based triplet chemotherapy as first-line treatment. The response depth was assessed after completing 6 cycles of PAD and VCD regimens. Antitumor response was evaluated according to IMWG (2016) criteria.

RESULTS. The mutation rate in the gene family RAS was 42 % (37/89). The analysis focused on the data from 33 patients with mutations detected and response identified after 6 cycles of treatment. In 22 out of 33 patients, deep response was not achieved, whereas 11 patients showed complete remission (CR) + very good partial remission (VGPR). In the group of patients without mutations in the gene family RAS, the response to therapy meeting the CR + VGPR criteria was 64 % (27/42). The differences appeared to be significant (p = 0.008). The clinical data and the evaluation of primary treatment outcomes provided the basis for distinguishing a group of 9 prognostically unfavorable mutations: NRAS Gly13Asp, Gln61His; KRAS Gly12Ala, Gly12Asp, Gly12Val, Gly13Asp, Gln61Arg, Gln61His, and Ala146Val.

CONCLUSION. The mutations in KRAS and NRAS belonging to the gene family RAS had a negative effect on the efficacy of the bortezomib-based triplet induction therapy. Mutation variants in the RAS family genes differed in prognostic significance. The analysis results helped to identify the mutation variants associated with the worse response to therapy: NRAS Gly13Asp, Gln61His; KRAS Gly12Ala, Gly12Asp, Gly12Val, Gly13Asp, Gln61Arg, Gln61His, and Ala146Val.

PDF_2024-17-3_256-265 (Russian)

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