Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma

Heinz Ludwig, Wolfram Poenisch, Stefan Knop, Alexander Egle, Martin Schreder, Daniel Lechner, Roman Hajek, Eberhard Gunsilius, Karl Jochen Krenosz, Andreas Petzer, Katja Weisel, Dietger Niederwieser, Hermann Einsele, Wolfgang Willenbacher, Thomas Melchardt, Richard Greil, Niklas Zojer, Heinz Ludwig, Wolfram Poenisch, Stefan Knop, Alexander Egle, Martin Schreder, Daniel Lechner, Roman Hajek, Eberhard Gunsilius, Karl Jochen Krenosz, Andreas Petzer, Katja Weisel, Dietger Niederwieser, Hermann Einsele, Wolfgang Willenbacher, Thomas Melchardt, Richard Greil, Niklas Zojer

Abstract

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.

Conflict of interest statement

H.L.: research funding: Takeda, Amgen; Speaker’s Bureau: Takeda, Amgen, Janssen, BMS, Celgene; Consultancy Fees: PharmaMar; S.K.: Consultancy Fees: Takeda; E.G.: Honoraria: Takeda, Janssen, Amgen, BMS; Advisory Board: Takeda, Janssen, Amgen, Novartis; A.P.: Honoraria, Advisory Board: Takeda, Celgene; K.W.: Honoraria: Novartis, Janssen, Celgene, Amgen, Onyx, Takeda, BMS; Consultancy Fees: Janssen, Celgene, Amgen, BMS, Takeda, Onyx; R.G.: Research Funding: Roche, Celgene, Takeda, Novartis; Personal Fees: Roche, Takeda, BMS, Amgen; H.E.: Speaker’s Bureau, Advisory Board: Celgene, Janssen, Amgen, BMS, Novartis; Consultancy Fees, Honoraria: Celgene, Janssen, BMS, Amgen; W.W.: Research Funding: Amgen, BMS, Celgene, Janssen, Novartis, Roche, Takeda; Advisory Board/Consultancy fees: Amgen, BMS, Celgene, Janssen, Novartis, Pfizer, Roche, Sandoz, Takeda; T.M.: Honoraria: Takeda. NZ.: Honoraria: Janssen, Celgene, Takeda, Amgen. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Progression-free and overall survival in the intent-to-treat group
Fig. 2
Fig. 2
Progression-free survival (PFS) and overall survival (OS) in patients with one vs. ≥2 prior treatment lines (a, c). PFS and OS in patients with GFR < 60 ml/min and those with GFR ≥ 60 ml/min (b, d)
Fig. 3
Fig. 3
Progression-free survival (PFS) and overall survival (OS) in patients with and without high-risk (t(4;14) and/or del(17p) cytogenetics (a, d)). PFS and OS in patients with and without gain of 1q21 (b, e). PFS and OS in patients with high-risk (t(4;14) and/or del(17p) cytogenetics, with gain of 1q21 alone or neither one (c, f))

References

    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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)
    1. 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.
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452.
    1. Bland JM, Altman DG. The logrank test. BMJ. 2004;328:1073. doi: 10.1136/bmj.328.7447.1073.
    1. Fisher RA. The logic of inductive inference. J. Royal Stat. Soc. 1935;98:39–82. doi: 10.2307/2342435.
    1. Cox DR. Regression Models and Life-Tables. J. Royal Stat. Soc. Ser. B (Methodol.) 1972;34:187–220.
    1. 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.
    1. 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).
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe