Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

Buckinghamshire Healthcare NHS Trust Amersham Bucks UK

Department of Haematology Oxford University Hospitals NHS Foundation Trust Oxford UK

Department of Haematology University Hospital Southampton NHS Foundation Trust Southampton UK

Department of Hemato Oncology University Hospital Olomouc Olomouc Czech Republic

Department of Hemato Oncology University Hospital Ostrava Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology Metaxa Cancer Hospital Piraeus Greece

Department of Hematology Theagenio Cancer Hospital Thessaloniki Greece

EUCAN Medical Affairs Takeda Pharmaceuticals International AG Glattpark Opfikon Zurich Switzerland

NIHR BRC Blood Theme Oxford UK

NIHR BRC Research Education and Training Group Oxford UK

Plasma Cell Dyscrasias Unit Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Alexandra General Hospital 80 Vasilissis Sophias 11528 Athens Greece

Zobrazit více v PubMed

Maiese EM, Ainsworth C, Le Moine JG, Ahdesmaki O, Bell J, Hawe E (2018) Comparative efficacy of treatments for previously treated multiple myeloma: a systematic literature review and network meta-analysis. Clin Ther 40(3):480–494 e423. https://doi.org/10.1016/j.clinthera.2018.01.014 PubMed DOI

Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, Giralt S, Mateos MV, Leleu X, Anderson KC (2018) Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia 32(2):252–262. https://doi.org/10.1038/leu.2017.329 PubMed DOI

Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosinol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ, Investigators E (2016) 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 17(1):27–38. https://doi.org/10.1016/S1470-2045(15)00464-7 PubMed DOI

Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P, Investigators P (2016) Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375(14):1319–1331. https://doi.org/10.1056/NEJMoa1607751 PubMed DOI

Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Rollig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P (2016) Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood 128(4):497–503. https://doi.org/10.1182/blood-2016-02-700872 PubMed DOI PMC

Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Rollig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P, Investigators E (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373(7):621–631. https://doi.org/10.1056/NEJMoa1505654 PubMed DOI

Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG, Group T-MS (2016) Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374(17):1621–1634. https://doi.org/10.1056/NEJMoa1516282 PubMed DOI

Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P, Investigators C (2016) Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375(8):754–766. https://doi.org/10.1056/NEJMoa1606038 PubMed DOI

Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF (2016) Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood 127(6):713–721. https://doi.org/10.1182/blood-2015-09-665018 PubMed DOI PMC

Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A, Investigators A (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372(2):142–152. https://doi.org/10.1056/NEJMoa1411321 PubMed DOI

Bergin K, McQuilten Z, Moore E, Wood E, Spencer A (2017) Myeloma in the real world: what is really happening? Clin Lymphoma Myeloma Leuk 17(3):133–144 e131. https://doi.org/10.1016/j.clml.2016.12.002 PubMed DOI

Blimark CH, Turesson I, Genell A, Ahlberg L, Bjorkstrand B, Carlson K, Forsberg K, Juliusson G, Linder O, Mellqvist UH, Nahi H, Kristinsson SY, Swedish Myeloma R (2018) Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish myeloma registry. Haematologica 103(3):506–513. https://doi.org/10.3324/haematol.2017.178103 PubMed DOI PMC

Chen CC, Parikh K, Abouzaid S, Purnomo L, McGuiness CB, Hussein M, Wade RL (2017) Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib. J Manag Care Spec Pharm 23(2):236–246. https://doi.org/10.18553/jmcp.2017.23.2.236 PubMed DOI

Hajek R, Jarkovsky J, Maisnar V, Pour L, Spicka I, Minarik J, Gregora E, Kessler P, Sykora M, Frankova H, Campioni M, DeCosta L, Treur M, Gonzalez-McQuire S, Bouwmeester W (2018) Real-world outcomes of multiple myeloma: retrospective analysis of the Czech registry of monoclonal gammopathies. Clin Lymphoma Myeloma Leuk 18(6):e219–e240. https://doi.org/10.1016/j.clml.2018.04.003 PubMed DOI

Jagannath S, Abonour R, Durie BGM, Gasparetto C, Hardin JW, Narang M, Terebelo HR, Toomey K, Wagner L, Srinivasan S, Kitali A, Yue L, Flick ED, Agarwal A, Rifkin RM (2018) Heterogeneity of second-line treatment for patients with multiple myeloma in the connect MM registry (2010-2016). Clin Lymphoma Myeloma Leuk 18(7):480–485 e483. https://doi.org/10.1016/j.clml.2018.04.007 PubMed DOI

Jagannath S, Roy A, Kish J, Lunacsek O, Globe D, Eaddy M, Kuriakose ET, Willey J, Butler-Bird S, Siegel D (2016) Real-world treatment patterns and associated progression-free survival in relapsed/refractory multiple myeloma among US community oncology practices. Expert Rev Hematol 9(7):707–717. https://doi.org/10.1080/17474086.2016.1195254 PubMed DOI

Knauf W, Aldaoud A, Hutzschenreuter U, Klausmann M, Dille S, Wetzel N, Janicke M, Marschner N, the TLN-Group (Tumour Registry Lymphatic Neoplasms) (2018) Survival of non-transplant patients with multiple myeloma in routine care differs from that in clinical trials-data from the prospective German tumour registry lymphatic neoplasms. Ann Hematol 97(12):2437–2445. https://doi.org/10.1007/s00277-018-3449-8 PubMed DOI PMC

Orlowski RZ (2018) Letter—incorporating real-world evidence and patient value criteria into value-based frameworks for relapsed/refractory multiple myeloma. J Manag Care Spec Pharm 24(5):487. https://doi.org/10.18553/jmcp.2018.24.5.487 PubMed DOI

Raab MS, Cavo M, Delforge M, Driessen C, Fink L, Flinois A, Gonzalez-McQuire S, Safaei R, Karlin L, Mateos MV, Schoen P, Yong K (2016) Multiple myeloma: practice patterns across Europe. Br J Haematol 175(1):66–76. https://doi.org/10.1111/bjh.14193 PubMed DOI

Shah JJ, Abonour R, Gasparetto C, Hardin JW, Toomey K, Narang M, Srinivasan S, Kitali A, Zafar F, Flick ED, Rifkin RM (2017) Analysis of common eligibility criteria of randomized controlled trials in newly diagnosed multiple myeloma patients and extrapolating outcomes. Clin Lymphoma Myeloma Leuk 17(9):575–583 e572. https://doi.org/10.1016/j.clml.2017.06.013 PubMed DOI

Terpos E, Suzan F, Goldschmidt H (2018) Going the distance: are we losing patients along the multiple myeloma treatment pathway? Crit Rev Oncol Hematol 126:19–23. https://doi.org/10.1016/j.critrevonc.2018.03.021 PubMed DOI

Yong K, Delforge M, Driessen C, Fink L, Flinois A, Gonzalez-McQuire S, Safaei R, Karlin L, Mateos MV, Raab MS, Schoen P, Cavo M (2016) Multiple myeloma: patient outcomes in real-world practice. Br J Haematol 175(2):252–264. https://doi.org/10.1111/bjh.14213 PubMed DOI PMC

Richardson PG, San Miguel JF, Moreau P, Hajek R, Dimopoulos MA, Laubach JP, Palumbo A, Luptakova K, Romanus D, Skacel T, Kumar SK, Anderson KC (2018) Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J 8(11):109. https://doi.org/10.1038/s41408-018-0141-0 PubMed DOI PMC

Gupta N, Hanley MJ, Xia C, Labotka R, Harvey RD, Venkatakrishnan K (2019) Clinical pharmacology of Ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet 58(4):431–449. https://doi.org/10.1007/s40262-018-0702-1 PubMed DOI

Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H (2016) International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17(8):e328–e346. https://doi.org/10.1016/S1470-2045(16)30206-6 DOI

Hajek R, Terpos E, Lee HC, Chari A, Costello CL, Puig N, Leleu X, Berdeja JG, Davies FE, Weisel K, Usmani SZ, Hungria VTM, Boccadoro M, Rifkin RM, Zonder JA, Cook G, Brožová L, Bařinová M, Ren K, Cacioppo R, Skacel T, Stull DM, Maisnar V (2018) 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 132(Suppl 1):1971 DOI

Ziff M, Cheesman S, Kyriakou C, Mehta A, Papanikolaou X, Rabin N, Wechalekar A, Yong K, Popat R (2017) Real world use of ixazomib with lenalidomide and dexamethasone for patients with relapsed and relapsed refractory multiple myeloma. Haematologica 102(s2):786–787

Mateos MV, Masszi T, Grzasko N, Hansson M, Sandhu I, Pour L, Viterbo L, Jackson SR, Stoppa AM, Gimsing P, Hamadani M, Borsaru G, Berg D, Lin J, Di Bacco A, van de Velde H, Richardson PG, Moreau P (2017) Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1. Haematologica 102(10):1767–1775. https://doi.org/10.3324/haematol.2017.170118 PubMed DOI PMC

Boccadoro M, Usmani SZ, Chari A, Rifkin R, Abonour R, Berdeja J, Cook G, Costello C, Goldschmidt H, Hajek R, Hungria V, Lee HC, Leleu X, Omel J, Spencer A, Thompson MA, Vela-Ojeda J, Zonder JA, Puig N, Aguarón A, Davies FE, Demers B, Ren K, Yu S, Skacel T, Stull DM, Terpos E (2018) A global treatment standard in multiple myeloma (MM) remains elusive despite advances in care over 15 years: first results from INSIGHT MM, the largest global prospective, observational MM study. Hemasphere 2(s1):591

Vij R, Khare S, Perez S, Popov S, Chen C (2016) Subgroup analysis of US patients in preamble, an ongoing multinational observational study in multiple myeloma. Blood 128(22):2362 DOI

Kuter D, Cook G, Goldschmidt H, Cella D, Zyczynski T, Davis C, Popov S, Vij R (2016) An ongoing multinational observational study in multiple myeloma (PREAMBLE): preliminary report on progression-free survival. Haematologica 101(s1):520

Mohty M, Terpos E, Mateos MV, Cavo M, Lejniece S, Beksac M, Bekadja MA, Legiec W, Dimopoulos M, Stankovic S, Duran MS, De Stefano V, Corso A, Kochkareva Y, Laane E, Berthou C, Salwender H, Masliak Z, Peceliunas V, Willenbacher W, Silva J, Louw V, Nemet D, Borbenyi Z, Abadi U, Pedersen RS, Cernelc P, Potamianou A, Couturier C, Feys C, Thoret-Bauchet F, Boccadoro M, Investigators E (2018) Multiple myeloma treatment in real-world clinical practice: results of a prospective, multinational, noninterventional study. Clin Lymphoma Myeloma Leuk 18(10):e401–e419. https://doi.org/10.1016/j.clml.2018.06.018 PubMed DOI

Hari P, Romanus D, Luptakova K, Blazer M, Yong C, Raju A, Farrelly E, Labotka R, Morrison VA (2018) The impact of age and comorbidities on practice patterns and outcomes in patients with relapsed/refractory multiple myeloma in the era of novel therapies. J Geriatr Oncol 9(2):138–144. https://doi.org/10.1016/j.jgo.2017.09.007 PubMed DOI

Minarik J, Hajek R, Jungova A, Mistrik M, Pika T, Gregora E, Radocha J, Straub J, Pour L, Wrobel M, Brozova L, Bacovsky J, Krhovska P, Hradska K, Jindra P, Pavlicek P, Machalkova K, Spicka I, Stork M, Jelinek T, Plonkova H, Scudla V, Maisnar V (2018) Ixazomib, lenalidomide and dexamethasone for relapsed and refractory multiple myeloma - data from the Czech registry of monoclonal gammopathies. Hemasphere 2(S1):247

Varga G, Nagy Z, Demeter J, Kosztolanyi S, Szomor A, Alizadeh H, Deak B, Schneider T, Plander M, Szendrei T, Varoczy L, Illes A, Batai A, Peto M, Mikala G (2019) Real world efficacy and safety results of ixazomib lenalidomide and dexamethasone combination in relapsed/refractory multiple myeloma: data collected from the Hungarian ixazomib named patient program. Pathol Oncol Res 25:1615–1620. https://doi.org/10.1007/s12253-019-00607-2 PubMed DOI PMC

Kumar S, Moreau P, Hari P, Mateos MV, Ludwig H, Shustik C, Masszi T, Spencer A, Hajek R, Romeril K, Avivi I, Liberati AM, Minnema MC, Einsele H, Lonial S, Berg D, Lin J, Gupta N, Esseltine DL, Richardson PG (2017) Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. Br J Haematol 178(4):571–582. https://doi.org/10.1111/bjh.14733 PubMed DOI PMC

Chari A, Romanus D, Farrelly E, Huang H, Blazer M, Raju A, Noga S, Richardson P (2018) Randomized clinical trial (RCT) representativeness & outcomes in relapsed/refractory multiple myeloma (RRMM) real world (RW) patients: comparison of ASPIRE, TOURMALINE-MM1, POLLUX, & ELOQUENT RCTs. Hemasphere 2(S1):610

Schmitz S, Maguire A, Morris J, Ruggeri K, Haller E, Kuhn I, Leahy J, Homer N, Khan A, Bowden J, Buchanan V, O'Dwyer M, Cook G, Walsh C (2018) The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma. BMC Med Res Methodol 18(1):66. https://doi.org/10.1186/s12874-018-0509-7 PubMed DOI PMC

van Beurden-Tan CHY, Franken MG, Blommestein HM, Uyl-de Groot CA, Sonneveld P (2017) Systematic literature review and network meta-analysis of treatment outcomes in relapsed and/or refractory multiple myeloma. J Clin Oncol 35(12):1312–1319. https://doi.org/10.1200/JCO.2016.71.1663 PubMed DOI

Bringhen S, Milan A, Ferri C, Wasch R, Gay F, Larocca A, Salvini M, Terpos E, Goldschmidt H, Cavo M, Petrucci MT, Ludwig H, Auner HW, Caers J, Gramatzki M, Boccadoro M, Einsele H, Sonneveld P, Engelhardt M, European Hematology Association tEMN, the Italian Society of Arterial H (2018) Cardiovascular adverse events in modern myeloma therapy-incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA). Haematologica 103(9):1422–1432. https://doi.org/10.3324/haematol.2018.191288 PubMed DOI PMC

Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy

Management of patients with multiple myeloma beyond the clinical-trial setting: understanding the balance between efficacy, safety and tolerability, and quality of life