RESEARCH PAPER
 
KEYWORDS
TOPICS
ABSTRACT
Introduction and objective:
Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM.

Material and methods:
Nine patients aged 52–82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months.

Results:
One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses.

Conclusions:
Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

 
REFERENCES (41)
1.
Kazmi SM, Nusrat M, Gunaydin H, et al. Outcomes among high-risk and standard-risk multiple myeloma patients treated with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation. Clin Lymphoma Myeloma Leuk. 2015; 15(11): 687–693.
 
2.
Mikhael JR, Dingli D, Roy V, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013; 88(4): 360–376.
 
3.
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.
 
4.
Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12): 2210–2221.
 
5.
Kuiper R, van Duin M, van Vliet MH, et al. Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System. Blood. 2015; 126(17): 1996–2004.
 
6.
Gupta N, Hanley MJ, Xia C, et al. Clinical pharmacology of Ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet. 2019; 58(4): 431–449.
 
7.
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 374(17): 1621–1634.
 
8.
Ross F, Avet-Loiseau H, Ameye G, et al. Report from the european myeloma network on interphase fish in multiple myeloma and related disorders. Haematologica. 2012; 97(8): 1272–1277.
 
9.
Dmoszynska A, Chocholska S. Molecular biology methods in the diagnosis of multiple myeloma, In: Witt M, Dawidowska M, Szczepanski T. editors, 2012. Molecular Aspects of Hematologic Malignancies: Diagnostic Tools and Clinical Applications. Berlin Heidelberg: Springer-Verlag 443–449.
 
10.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The Lancet Oncology. 2016; 17: e328-e346.
 
11.
Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28(5): 1122–1128.
 
12.
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.
 
13.
Maiese EM, Ainsworth C, Le Moine JG, et al. Comparative efficacy of treatments for previously treated multiple myeloma: a systematic literature review and network meta-analysis. Clin Ther. 2018; 40(3): 480–494.
 
14.
Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018; 32(2): 252–262.
 
15.
Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017; 130(8): 963–973.
 
16.
Jagannath S, Abonour R, Durie BGM, et al. Heterogeneity of second-line treatment for patients with multiple myeloma in the connect MMregistry (2010–2016). Clin Lymphoma Myeloma Leuk. 2018; 18(7): 480–485.
 
17.
Chari A, Romanus D, Palumbo A, et al. Randomized Clinical Trial Representativeness and Outcomes in Real-World Patients: Comparison of 6 Hallmark Randomized Clinical Trials of Relapsed/Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2020; 20(1): 8–17.
 
18.
Richardson PG, Avet-Loiseau H, Palumbo A, et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III Tourmaline-MM1 study. J Clin Oncol. 2016; 34(suppl): 8018.
 
19.
Avet-Loiseau H, Bahlis NJ, Chng WJ, et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017; 130: 2610–2618.
 
20.
Avet-Loiseau H, Fonseca R, Siegel D, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016; 128(9): 1174–1180.
 
21.
Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012; 119(4): 940–948.
 
22.
Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010; 28(30): 4630–4634.
 
23.
Mateos MV, Oriol A, Mart´inez-L ´opez J, et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012; 120(13): 2581–2588.
 
24.
Ling YH, Liebes L, Ng B, et al. PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther. 2002; 1(10): 841–849.
 
25.
Ling YH, Liebes L, Jiang JD, et al. Mechanisms of proteasome inhibitor PS-341-induced G(2)-Mphase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res. 2003; 9(3): 1145–1154.
 
26.
Herrero AB, Rojas EA, Misiewicz-Krzeminska I, et al. Molecular mechanisms of p53 deregulation in cancer: an overview in multiple myeloma. Int J Mol Sci. 2016; 17(12): E2003.
 
27.
An G, Li Z, Tai YT, et al. The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res. 2015; 21(9): 2148–2156.
 
28.
Lonial S, Dimopoulos M, Palumbo A, et al. ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373(7): 621–631.
 
29.
Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, openlabel, phase 3 trial. Lancet. 2017; 389(10068): 519–527.
 
30.
Tomas P, Miroslava V, Jiri M, et al. Translocation t(8;14) in multiple myeloma defines patients with very poor prognosis – single centre experience. Cl Lymph Myelom Leuk. 2015; 15: e122-e122.
 
31.
Paner A, Patel P, Dhakal B. The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma. Blood Rev. 2020; 41: 100643.
 
32.
Leiba M, Duek A, Amariglio N, et al. Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable? Genes Chromosomes Cancer. 2016; 55(9): 710–718.
 
33.
Boyd KD, Ross FM, Chiecchio L et al. A novel prognostic model in myeloma based on cosegregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012; 26(2): 349–355.
 
34.
Nahi H, V °atsveen TK, Lund J, et al. Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21. Eur J Haematol. 2016; 96(1): 46–54.
 
35.
Dash AB, Zhang J, Shen L, et al. Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-?B pathway activation. Eur J Haematol. 2020; 105(3): 274–285.
 
36.
Ziff M, Cheesman S, Kyriakou Ch, et al. Real world use of ixazomib with lenalidomide and dexamethasone for patients with relapsed and relapsed refractory multiple myeloma. EHA Library. 2017; 05/18/17;182689; PB1975.
 
37.
Hajek R, Terpos E, Lee HC, et al. Ixazomib plusl-dexamethasone (IRd) in relapsed/refractory multiple myeloma (MM) patients (Pts)–effectiveness in routine clinical practice is similar to the efficacy in the phase 3 tourmaline-MM1 trial: a pooled analysis from the insight MM observational study and the Czech registry of monoclonal gammopathies (RMG). Blood. 2018; 132(Suppl 1): 1971.
 
38.
Terpos E, Ramasamy K, Maouche N, et al. Real-world Effectiveness and Safety of Ixazomib-Lenalidomide-Dexamethasone in relapsed/refractory Multiple Myeloma. Ann Hematol. 2020; 99(5): 1049–1061.
 
39.
Minarik J, Pika T, Radocha J, et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer, 2021; 21(1): 73.
 
40.
Cohen YC, Magen H, Lavi N, et al. Ixazomib-based regimens for relapsed/refractory multiple myeloma: are real-world data compatible with clinical trial outcomes? A multi-site Israeli registry study. Ann Hematol. 2020; 99(6): 1273–1281.
 
41.
Takakuwa T, Yamamura R, Ohta K, et al. Outcomes of ixazomib/lenalidomide/dexamethasone for multiple myeloma: A multicenter retrospective analysis. Eur J Haematol. 2021; 106(4): 555–562.
 
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