BACKGROUND: Ixazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients. METHODS: Ninety patients have been included. Ixazomib-thalidomide-dexamethasone (4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly) was scheduled for eight cycles followed by maintenance with ixazomib for one year. RESULTS: The overall response rate was 51.1%, 23.3% achieved CR or VGPR and 10% MR resulting in a clinical benefit rate of 61.1%. In patients completing ≥2 cycles, the rates were 60.5%, 27.6% and 68.4%, respectively. Median progression-free survival (PFS) was 8.5 months in all, and 9.4 months in those completing ≥2 cycles. Response rates, PFS and overall survival (OS) were similar in patients with and without t(4;14) and/or del(17p), but PFS and OS was significantly shorter in patients with gain of 1q21. Multivariate regression analysis revealed gain of 1q21 as the most important factor associated with OS. Ixazomib maintenance resulted in an upgrade in the depth of response in 12.4% of patients. Grade 3/4 toxicities were relatively rare. CONCLUSIONS: Ixazomib-thalidomide-dexamethasone followed by ixazomib maintenance therapy is active and well tolerated in patients with RRMM. TRIAL REGISTRATION NUMBER: NCT02410694.

Department of Hematology University of Leipzig Leipzig Germany

Department of Internal Medicine 1 Ordensklinikum Linz Barmherzige Schwestern Linz Austria

Department of Internal Medicine 3 Kepler Universitaetsklinikum GmbH Med Campus 3 Linz Austria

Department of Internal Medicine 3 with Haematology Medical Oncology Hemostaseology Infectiology and Rheumatology Oncologic Center Salzburg Cancer Research Institute Laboratory for Immunological and Molecular Cancer Research Paracelsus Medical University Salzburg Cancer Cluster Salzburg Austria

Department of Internal Medicine 5 Hematology and Oncology Medical University Innsbruck Innsbruck Austria

Department of Medicine 1 Center for Oncology and Hematology Wilhelminenspital Vienna Austria

Department of Medicine 1 Hematology with Stem Cell Transplantation Hemostaseology and Medical Oncology Ordensklinikum Linz Elisabethinen Linz Austria

Division of Hematology and Medical Oncology Department of Internal Medicine 2 Wuerzburg University Medical Center Wuerzburg Germany

Fakultní Nemocnice Ostrava Ostrava Czech Republic

Oncotyrol Center for personalized Cancer Medicine Innsbruck Austria

University Medical Center of Hamburg Eppendorf Hamburg Germany and University of Tuebingen Tuebingen Germany

Wilhelminen Cancer Research Institute Department of Medicine 1 Center for Oncology and Hematology Wilhelminenspital Vienna Austria

Zobrazit více v PubMed

Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15:1503–1512. doi: 10.1016/S1470-2045(14)71125-8. PubMed DOI

Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817–2825. doi: 10.1182/blood-2012-05-425934. PubMed DOI PMC

Zanwar Saurabh, Abeykoon Jithma Prasad, Kapoor Prashant. Ixazomib: a novel drug for multiple myeloma. Expert Review of Hematology. 2018;11(10):761–771. doi: 10.1080/17474086.2018.1518129. PubMed DOI

Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014;124:1047–1055. doi: 10.1182/blood-2014-01-548941. PubMed DOI PMC

Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, et al. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015;5:e338. doi: 10.1038/bcj.2015.60. PubMed DOI PMC

Al-Salama ZT, Garnock-Jones KP, Scott LJ. Ixazomib: a review in relapsed and/or refractory multiple myeloma. Target Oncol. 2017;12:535–542. doi: 10.1007/s11523-017-0504-7. PubMed DOI

Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955–2962. doi: 10.1182/blood-2016-01-631200. PubMed DOI PMC

Zweegman S, Schjesvold FH, van der Holt B, Levin M-D, Stege CAM, Waage A, et al. Ixazomib-thalidomide-low dose dexamethasone (ITd) induction followed by maintenance therapy with ixazomib or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; results from the randomized phase II HOVON-126/Nmsg 21#13 Trial. Blood. 2018;132(Suppl 1):800-. doi: 10.1182/blood-2018-99-111650. PubMed DOI PMC

Dimopoulos MA, Grosicki S, Jedrzejczak WW, Nahi H, Gruber A, Hansson M, et al. All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Eur J Cancer. 2018;106:89–98. doi: 10.1016/j.ejca.2018.09.011. PubMed DOI

Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621–1634. doi: 10.1056/NEJMoa1516282. PubMed DOI

Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017;130:2610–2618. doi: 10.1182/blood-2017-06-791228. PubMed DOI

Dimopoulos MA, Gay F, Schjesvold FH, Beksac M, Hajek R, Weisel K, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 tourmaline-MM3 trial. Blood. 2018;132(Suppl 1):301. doi: 10.1182/blood-2018-99-112079. DOI

Perrot, A., Corre, J. & Avet-Loiseau, H. Risk stratification and targets in multiple myeloma: from genomics to the bedside. Am Soc Clin Oncol Educ Book. 38, 675–680 (2018) PubMed

Palumbo A, Bringhen S, Mateos M-V, Larocca A, Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125:2068–2074. doi: 10.1182/blood-2014-12-615187. PubMed DOI PMC

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452. DOI

Bland JM, Altman DG. The logrank test. BMJ. 2004;328:1073. doi: 10.1136/bmj.328.7447.1073. PubMed DOI PMC

Fisher RA. The logic of inductive inference. J. Royal Stat. Soc. 1935;98:39–82. doi: 10.2307/2342435. DOI

Cox DR. Regression Models and Life-Tables. J. Royal Stat. Soc. Ser. B (Methodol.) 1972;34:187–220.

Cook G, Parrish C, Yong K, Cavenagh J, Snowden JA, Drayson MT, et al. Ixazomib, thalidomide and dexamethasone is an effective and well tolerated re-induction regimen leading to salvage autologous stem cell transplantation (sASCT): results from the re-induction interim analysis of UK-MRA myeloma XII (ACCoRD) trial. Blood. 2018;132(Suppl 1):255-. doi: 10.1182/blood-2018-99-112116. DOI

Krishnan A., Kapoor P., Palmer J. M., Tsai N. C., Kumar S., Lonial S., et al. Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Leukemia. 32, 1567–1574 (2018). PubMed PMC

Kumar SK, Grzasko N, Delimpasi S, Jedrzejczak WW, Grosicki S, Kyrtsonis MC, et al. Phase 2 study of all-oral ixazomib, cyclophosphamide and low-dose dexamethasone for relapsed/refractory multiple myeloma. Br. J. Haematol. 2019;184:536–546. doi: 10.1111/bjh.15679. PubMed DOI

Baz RC, Martin TG, 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127:2561–2568. doi: 10.1182/blood-2015-11-682518. PubMed DOI

Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–981. doi: 10.1182/blood-2017-05-785246. PubMed DOI PMC

Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N. Engl. J. Med. 2018;379:1811–1822. doi: 10.1056/NEJMoa1805762. PubMed DOI

Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27–38. doi: 10.1016/S1470-2045(15)00464-7. PubMed DOI

Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016;375:754–766. doi: 10.1056/NEJMoa1606038. PubMed DOI

Nahi H, Vatsveen TK, Lund J, Heeg BM, Preiss B, Alici E, et al. Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21. Eur. J. Haematol. 2016;96:46–54. doi: 10.1111/ejh.12546. PubMed DOI

Grzasko N, Hajek R, Hus M, Chocholska S, Morawska M, Giannopoulos K, et al. Chromosome 1 amplification has similar prognostic value to del(17p13) and t(4;14)(p16;q32) in multiple myeloma patients: analysis of real-life data from the Polish Myeloma Study Group. Leuk. Lymphoma. 2017;58:1–15. doi: 10.1080/10428194.2016.1272684. PubMed DOI

Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006;108:1724–1732. doi: 10.1182/blood-2006-03-009910. PubMed DOI PMC

Shaughnessy JD, Jr., Qu P, Usmani S, Heuck CJ, Zhang Q, Zhou Y, et al. Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3. Blood. 2011;118:3512–3524. doi: 10.1182/blood-2010-12-328252. PubMed DOI PMC

Zhan F, Colla S, Wu X, Chen B, Stewart JP, Kuehl WM, et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood. 2007;109:4995–5001. doi: 10.1182/blood-2006-07-038703. PubMed DOI PMC

Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, et al. Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin. Cancer Res. 2013;19:6030–6038. doi: 10.1158/1078-0432.CCR-12-3211. PubMed DOI

Pessoa de Magalhães Filho Roberto José, Crusoe Edvan, Riva Eloisa, Bujan Willen, Conte Guilhermo, Navarro Cabrera Juan Ramon, Garcia Diana Katerine, Vega Guilhermo Quintero, Macias Jose, Oliveros Alvear Jose Willian, Royg Mercedes, Neves Lidiane Andino, Lopez Dopico Jose Luis, Espino German, Ortiz Douglas Rosales, Socarra Zurelis, Fantl Dorotea, Ruiz-Arguelles Guillermo J., Maiolino Angelo, Hungria Vania Tietsche de Moraes, Harousseau Jean-Luc, Durie Brian. Analysis of Availability and Access of Anti-myeloma Drugs and Impact on the Management of Multiple Myeloma in Latin American Countries. Clinical Lymphoma Myeloma and Leukemia. 2019;19(1):e43–e50. doi: 10.1016/j.clml.2018.08.005. PubMed DOI

Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front. Mol. Neurosci. 2015;8:77. doi: 10.3389/fnmol.2015.00077. PubMed DOI PMC

Reduced alpha diversity of the oral microbiome correlates with short progression-free survival in patients with relapsed/refractory multiple myeloma treated with ixazomib-based therapy (AGMT MM 1, phase II trial)

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02410694