The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE-MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

Alfred Health Monash University Melbourne Australia

Dana Farber Cancer Institute Boston MA USA

Department of Haematology and Bone Marrow Transplantation Tel Aviv Medical Centre Tel Aviv Israel

Department of Haematology and Stem Cell Transplantation St István and St László Hospital Semmelweis University Budapest Hungary

Department of Haematology UMC Utrecht Cancer Centre Utrecht The Netherlands

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA USA

Division of Hematology and Oncology Froedtert Hospital and the Medical College of Wisconsin Milwaukee WI USA

Division of Hematology Mayo Clinic Rochester MN USA

McGill University Health Center Royal Victoria Hospital Montreal Canada

Millennium Pharmaceuticals Inc a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Cambridge MA USA

Servicio de Hematología Hospital Universitario de Salamanca Salamanca Spain

Universitätsklinik Würzburg Medizinische Klinik und Poliklinik 2 Würzburg Germany

University Hospital Hôtel Dieu Nantes France

University of Perugia SC Oncoematologia AO S Maria di Terni Terni Italy

Wellington Blood and Cancer Centre Wellington Regional Hospital Wellington New Zealand

Wilhelminenspital der Stadt Wien Vienna Austria

Zobrazit více v PubMed

Atrash, S. , Tullos, A. , Panozzo, S. , Bhutani, M. , Van, R.F. , Barlogie, B. & Usmani, S.Z. (2015) Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer Journal, 5, e272. PubMed PMC

Battisti, W.P. , Wager, E. , Baltzer, L. , Bridges, D. , Cairns, A. , Carswell, C.I. , Citrome, L. , Gurr, J.A. , Mooney, L.A. , Moore, B.J. , Peña, T. , Sanes‐Miller, C.H. , Veitch, K. , Woolley, K.L. & Yarker, Y.E. ; International Society for Medical Publication Professionals . (2015) Good publication practice for communicating company‐sponsored medical research: GPP3. Annals of Internal Medicine, 163, 461–464. PubMed

Baz, R. , Lin, H.M. , Hui, A.M. , Harvey, R.D. , Colson, K. , Gallop, K. , Swinburn, P. , Laubach, J. , Berg, D. & Richardson, P. (2015) Development of a conceptual model to illustrate the impact of multiple myeloma and its treatment on health‐related quality of life. Supportive Care in Cancer, 23, 2789–2797. PubMed

Benboubker, L. , Dimopoulos, M.A. , Dispenzieri, A. , Catalano, J. , Belch, A.R. , Cavo, M. , Pinto, A. , Weisel, K. , Ludwig, H. , Bahlis, N. , Banos, A. , Tiab, M. , Delforge, M. , Cavenagh, J. , Geraldes, C. , Lee, J.J. , Chen, C. , Oriol, A. , de la Rubia, J. , Qiu, L. , White, D.J. , Binder, D. , Anderson, K. , Fermand, J.P. , Moreau, P. , Attal, M. , Knight, R. , Chen, G. , Van, O.J. , Jacques, C. , Ervin‐Haynes, A. , Avet‐Loiseau, H. , Hulin, C. & Facon, T. (2014) Lenalidomide and dexamethasone in transplant‐ineligible patients with myeloma. New England Journal of Medicine, 371, 906–917. PubMed

Chen, C. , Reece, D.E. , Siegel, D. , Niesvizky, R. , Boccia, R.V. , Stadtmauer, E.A. , Abonour, R. , Richardson, P. , Matous, J. , Kumar, S. , Bahlis, N.J. , Alsina, M. , Vescio, R. , Coutre, S.E. , Pietronigro, D. , Knight, R.D. , Zeldis, J.B. & Rajkumar, V. (2009) Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. British Journal of Haematology, 146, 164–170. PubMed PMC

Chen, C. , Baldassarre, F. , Kanjeekal, S. , Herst, J. , Hicks, L. & Cheung, M. (2013) Lenalidomide in multiple myeloma‐a practice guideline. Current Oncology, 20, e136–e149. PubMed PMC

Cornell, R.F. & Kassim, A.A. (2016) Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplantation, 51, 479–491. PubMed PMC

Delforge, M. , Blade, J. , Dimopoulos, M.A. , Facon, T. , Kropff, M. , Ludwig, H. , Palumbo, A. , Van, D.P. , San‐Miguel, J.F. & Sonneveld, P. (2010) Treatment‐related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncology, 11, 1086–1095. PubMed

Dimopoulos, M. , Spencer, A. , Attal, M. , Prince, H.M. , Harousseau, J.L. , Dmoszynska, A. , San, M.J. , Hellmann, A. , Facon, T. , Foa, R. , Corso, A. , Masliak, Z. , Olesnyckyj, M. , Yu, Z. , Patin, J. , Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. New England Journal of Medicine, 357, 2123–2132. PubMed

Dimopoulos, M.A. , Richardson, P.G. , Moreau, P. & Anderson, K.C. (2015a) Current treatment landscape for relapsed and/or refractory multiple myeloma. Nature Reviews Clinical Oncology, 12, 42–54. PubMed

Dimopoulos, M.A. , Terpos, E. , Niesvizky, R. & Palumbo, A. (2015b) Clinical characteristics of patients with relapsed multiple myeloma. Cancer Treatment Reviews, 41, 827–835. PubMed

Gupta, N. , Goh, Y.T. , Min, C.K. , Lee, J.H. , Kim, K. , Wong, R.S. , Chim, C.S. , Hanley, M.J. , Yang, H. , Venkatakrishnan, K. , Hui, A.M. , Esseltine, D.L. & Chng, W.J. (2015) Pharmacokinetics and safety of ixazomib plus lenalidomide‐dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study. Journal of Hematology & Oncology, 8, 103. PubMed PMC

Gupta, N. , Hanley, M.J. , Venkatakrishnan, K. , Perez, R. , Norris, R.E. , Nemunaitis, J. , Yang, H. , Qian, M.G. , Falchook, G. , Labotka, R. & Fu, S. (2016a) Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment. British Journal of Clinical Pharmacology, 82, 728–738. PubMed PMC

Gupta, N. , Hanley, M.J. , Harvey, R.D. , Badros, A. , Lipe, B. , Kukreti, V. , Berdeja, J. , Yang, H. , Hui, A.M. , Qian, M. , Zhang, X. , Venkatakrishnan, K. & Chari, A. (2016b) A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis. British Journal of Haematology, 174, 748–759. PubMed PMC

Hesketh, P.J. , Bohlke, K. , Lyman, G.H. , Basch, E. , Chesney, M. , Clark‐Snow, R.A. , Danso, M.A. , Jordan, K. , Somerfield, M.R. & Kris, M.G. (2016) Antiemetics: American Society of Clinical Oncology Focused Guideline Update. Journal of Clinical Oncology, 34, 381–386. PubMed

Kumar, S.K. , Dispenzieri, A. , Lacy, M.Q. , Gertz, M.A. , Buadi, F.K. , Pandey, S. , Kapoor, P. , Dingli, D. , Hayman, S.R. , Leung, N. , Lust, J. , McCurdy, A. , Russell, S.J. , Zeldenrust, S.R. , Kyle, R.A. & Rajkumar, S.V. (2014a) Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia, 28, 1122–1128. PubMed PMC

Kumar, S.K. , Bensinger, W.I. , Zimmerman, T.M. , Reeder, C.B. , Berenson, J.R. , Berg, D. , Hui, A.M. , Gupta, N. , Di, B.A. , Yu, J. , Shou, Y. & Niesvizky, R. (2014b) Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood, 124, 1047–1055. PubMed PMC

Kumar, S.K. , Berdeja, J.G. , Niesvizky, R. , Lonial, S. , Laubach, J.P. , Hamadani, M. , Stewart, A.K. , Hari, P. , Roy, V. , Vescio, R. , Kaufman, J.L. , Berg, D. , Liao, E. , Di, B.A. , Estevam, J. , Gupta, N. , Hui, A.M. , Rajkumar, V. & Richardson, P.G. (2014c) 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 Oncology, 15, 1503–1512. PubMed

Kumar, S. , Berdeja, J.G. , Niesvizky, R. , Lonial, S. , Laubach, J.P. , Hamadani, M. , Stewart, A.K. , Hari, P.N. , Roy, V. , Vescio, R. , Kaufman, J.L. , Berg, D. , Liao, E. , Hui, A.‐M. , Rajkumar, S.V. & Richardson, P.G. (2014d) Long‐term ixazomib maintenance is tolerable and improves depth of response following ixazomib‐lenalidomide‐dexamethasone induction in patients (pts) with previously untreated multiple myeloma (MM): phase 2 study results. Blood, 124, 82.

Kumar, S.K. , LaPlant, B. , Roy, V. , Reeder, C.B. , Lacy, M.Q. , Gertz, M.A. , Laumann, K. , Thompson, M.A. , Witzig, T.E. , Buadi, F.K. , Rivera, C.E. , Mikhael, J.R. , Bergsagel, P.L. , Kapoor, P. , Hwa, L. , Fonseca, R. , Stewart, A.K. , Chanan‐Khan, A. , Rajkumar, S.V. & Dispenzieri, A. (2015a) Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer Journal, 5, e338. PubMed PMC

Kumar, S.K. , LaPlant, B. , Reeder, C.B. , Roy, V. , Buadi, F.K. , Gertz, M.A. , Laumann, K. , Bergsagel, P.L. , Dispenzieri, A. , Kapoor, P. , Mikhael, J.R. , Stewart, A.K. , Hayman, S.R. , Hwa, L. , Witzig, T.E. , Ailawadhi, S. , Dingli, D. , Go, R.S. , Lin, Y. , Rivera, C.E. , Rajkumar, S.V. & Lacy, M.Q. (2015b) Randomized phase 2 trial of two different doses of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood, 126, 3050. PubMed PMC

Leleu, X. , Masszi, T. , Bahlis, N.J. , Viterbo, L. , Baker, B.W. , Gimsing, P. , Maisnar, V. , Samoilova, O. , Rosinol, L. , Langer, C. , Song, K. , Izumi, T. , Cleeland, C. , Berg, D. , Lin, H.M. , Zhu, Y. , Skacel, T. , Jhaveri, M. , Seal, B. , Moreau, P. & Richardson, P.G. (2016) Patient‐reported quality of life with ixazomib‐lenalidomide‐dexamethasone (IRd) vs placebo‐Rd in relapsed/refractory multiple myeloma patients in the global, placebo‐controlled TOURMALINE‐MM1 study. Haematologica, 101, 261.

Lonial, S. , Waller, E.K. , Richardson, P.G. , Jagannath, S. , Orlowski, R.Z. , Giver, C.R. , Jaye, D.L. , Francis, D. , Giusti, S. , Torre, C. , Barlogie, B. , Berenson, J.R. , Singhal, S. , Schenkein, D.P. , Esseltine, D.L. , Anderson, J. , Xiao, H. , Heffner, L.T. & Anderson, K.C. (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood, 106, 3777–3784. PubMed PMC

Lonial, S. , Dimopoulos, M. , Palumbo, A. , White, D. , Grosicki, S. , Spicka, I. , Walter‐Croneck, A. , Moreau, P. , Mateos, M.V. , Magen, H. , Belch, A. , Reece, D. , Beksac, M. , Spencer, A. , Oakervee, H. , Orlowski, R.Z. , Taniwaki, M. , Rollig, C. , Einsele, H. , Wu, K.L. , Singhal, A. , San‐Miguel, J. , Matsumoto, M. , Katz, J. , Bleickardt, E. , Poulart, V. , Anderson, K.C. & Richardson, P. (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. New England Journal of Medicine, 373, 621–631. PubMed

Mikhael, J. (2016) Management of carfilzomib‐associated cardiac adverse events. Clinical Lymphoma, Myeloma and Leukemia, 16, 241–245. PubMed

Moreau, P. & Touzeau, C. (2015) Multiple myeloma: from front‐line to relapsed therapies. American Society of Clinical Oncology Educational Book, e504–e511. PubMed

Moreau, P. , Pylypenko, H. , Grosicki, S. , Karamanesht, I. , Leleu, X. , Grishunina, M. , Rekhtman, G. , Masliak, Z. , Robak, T. , Shubina, A. , Arnulf, B. , Kropff, M. , Cavet, J. , Esseltine, D.L. , Feng, H. , Girgis, S. , van de Velde, H. , Deraedt, W. & Harousseau, J.L. (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non‐inferiority study. Lancet Oncology, 12, 431–440. PubMed

Moreau, P. , Masszi, T. , Grzasko, N. , Bahlis, N.J. , Hansson, M. , Pour, L. , Sandhu, I. , Ganly, P. , Baker, B.W. , Jackson, S.R. , Stoppa, A.M. , Simpson, D.R. , Gimsing, P. , Palumbo, A. , Garderet, L. , Cavo, M. , Kumar, S. , Touzeau, C. , Buadi, F.K. , Laubach, J.P. , Berg, D.T. , Lin, J. , Di, B.A. , Hui, A.M. , van de Velde, H. & Richardson, P.G. (2016) Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine, 374, 1621–1634. PubMed

Nooka, A.K. (2013) Management of hematologic adverse events in patients with relapsed and/or refractory multiple myeloma treated with single‐agent carfilzomib. Oncology (Williston Park, N Y), 27(Suppl. 3), 11–18. PubMed

Osborne, T.R. , Ramsenthaler, C. , Siegert, R.J. , Edmonds, P.M. , Schey, S.A. & Higginson, I.J. (2012) What issues matter most to people with multiple myeloma and how well are we measuring them? A systematic review of quality of life tools. European Journal of Haematology, 89, 437–457. PubMed

Osborne, T.R. , Ramsenthaler, C. , de Wolf‐Linder, S. , Schey, S.A. , Siegert, R.J. , Edmonds, P.M. & Higginson, I.J. (2014) Understanding what matters most to people with multiple myeloma: a qualitative study of views on quality of life. BMC Cancer, 14, 496. PubMed PMC

Palumbo, A. , Rajkumar, S.V. , Dimopoulos, M.A. , Richardson, P.G. , San, M.J. , Barlogie, B. , Harousseau, J. , Zonder, J.A. , Cavo, M. , Zangari, M. , Attal, M. , Belch, A. , Knop, S. , Joshua, D. , Sezer, O. , Ludwig, H. , Vesole, D. , Blade, J. , Kyle, R. , Westin, J. , Weber, D. , Bringhen, S. , Niesvizky, R. , Waage, A. , von Lilienfeld‐Toal, M. , Lonial, S. , Morgan, G.J. , Orlowski, R.Z. , Shimizu, K. , Anderson, K.C. , Boccadoro, M. , Durie, B.G. , Sonneveld, P. & Hussein, M.A. (2008) Prevention of thalidomide‐ and lenalidomide‐associated thrombosis in myeloma. Leukemia, 22, 414–423. PubMed

Palumbo, A. , Blade, J. , Boccadoro, M. , Palladino, C. , Davies, F. , Dimopoulos, M. , Dmoszynska, A. , Einsele, H. , Moreau, P. , Sezer, O. , Spencer, A. , Sonneveld, P. & San, M.J. (2012) How to manage neutropenia in multiple myeloma. Clinical Lymphoma, Myeloma and Leukemia, 12, 5–11. PubMed

Pawlyn, C. , Khan, M.S. , Muls, A. , Sriskandarajah, P. , Kaiser, M.F. , Davies, F.E. , Morgan, G.J. & Andreyev, H.J. (2014) Lenalidomide‐induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood, 124, 2467–2468. PubMed

Rajkumar, S.V. (2012) Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma? Hematology American Society Hematology Education Program Book, 2012, 354–361. PubMed

Reece, D. , Kouroukis, C.T. , LeBlanc, R. , Sebag, M. , Song, K. & Ashkenas, J. (2012) Practical approaches to the use of lenalidomide in multiple myeloma: a canadian consensus. Advances in Hematology, 2012, 621958. PubMed PMC

Richardson, P.G. , Sonneveld, P. , Schuster, M.W. , Irwin, D. , Stadtmauer, E.A. , Facon, T. , Harousseau, J.L. , Ben‐Yehuda, D. , Lonial, S. , Goldschmidt, H. , Reece, D. , San‐Miguel, J.F. , Blade, J. , Boccadoro, M. , Cavenagh, J. , Dalton, W.S. , Boral, A.L. , Esseltine, D.L. , Porter, J.B. , Schenkein, D. & Anderson, K.C. (2005) Bortezomib or high‐dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 352, 2487–2498. PubMed

Richardson, P.G. , Delforge, M. , Beksac, M. , Wen, P. , Jongen, J.L. , Sezer, O. , Terpos, E. , Munshi, N. , Palumbo, A. , Rajkumar, S.V. , Harousseau, J.L. , Moreau, P. , Avet‐Loiseau, H. , Lee, J.H. , Cavo, M. , Merlini, G. , Voorhees, P. , Chng, W.J. , Mazumder, A. , Usmani, S. , Einsele, H. , Comenzo, R. , Orlowski, R. , Vesole, D. , Lahuerta, J.J. , Niesvizky, R. , Siegel, D. , Mateos, M.V. , Dimopoulos, M. , Lonial, S. , Jagannath, S. , Blade, J. , Miguel, J.S. , Morgan, G. , Anderson, K.C. , Durie, B.G. & Sonneveld, P. (2012) Management of treatment‐emergent peripheral neuropathy in multiple myeloma. Leukemia, 26, 595–608. PubMed

Richardson, P.G. , Hofmeister, C.C. , Rosenbaum, C.A. , Htut, M. , Vesole, D.H. , Berdeja, J. , Liedtke, M. , Chari, A. , Smith, S.D. , Lebovic, D. , Berg, D. , Liao, E. , Gupta, N. , Di Bacco, A. , Estevam, J. , Hui, A.‐M. & Baz, R. (2013) Twice‐weekly oral MLN9708 (ixazomib citrate), an investigational proteasome inhibitor, in combination with lenalidomide (len) and dexamethasone (dex) in patients (pts) with newly diagnosed multiple myeloma (MM): final phase 1 results and phase 2 data. Blood, 122, 535.

Richardson, P.G. , Baz, R. , Wang, M. , Jakubowiak, A.J. , Laubach, J.P. , Harvey, R.D. , Talpaz, M. , Berg, D. , Liu, G. , Yu, J. , Gupta, N. , Di, B.A. , Hui, A.M. & Lonial, S. (2014) Phase 1 study of twice‐weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood, 124, 1038–1046. PubMed PMC

San Miguel, J.F. , Schlag, R. , Khuageva, N.K. , Dimopoulos, M.A. , Shpilberg, O. , Kropff, M. , Spicka, I. , Petrucci, M.T. , Palumbo, A. , Samoilova, O.S. , Dmoszynska, A. , Abdulkadyrov, K.M. , Schots, R. , Jiang, B. , Mateos, M.V. , Anderson, K.C. , Esseltine, D.L. , Liu, K. , Cakana, A. , van de Velde, H. & Richardson, P.G. (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. New England Journal of Medicine, 359, 906–917. PubMed

San Miguel, J.F. , Sonneveld, P. , Orlowski, R.Z. , Moreau, P. , Rosinol, L. , Moslehu, J.J. , Faber, E.A. , Voorhees, P.M. , Marquez, L. , Desai, A. , van de Velde, H. , Elliott, J. , Shi, H. , Dow, E. , Jobanputra, N. , Esseltine, D.L. , Niculescu, L. , Anderson, K.C. , Lonial, S. & Richardson, P.G. (2013) Quantifying the risk of heart failure associated with proteasome inhibition: a retrospective analysis of heart failure reported in phase 2 and phase 3 studies of Bortezomib (BTZ) in Multiple Myeloma (MM). Blood, 122, 3187.

Smith, T.J. , Bohlke, K. , Lyman, G.H. , Carson, K.R. , Crawford, J. , Cross, S.J. , Goldberg, J.M. , Khatcheressian, J.L. , Leighl, N.B. , Perkins, C.L. , Somlo, G. , Wade, J.L. , Wozniak, A.J. & Armitage, J.O. (2015) Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology, 33, 3199–3212. PubMed

Stern, R.S. (2012) Clinical practice. Exanthematous drug eruptions. New England Journal of Medicine, 366, 2492–2501. PubMed

Stewart, A.K. , Rajkumar, S.V. , Dimopoulos, M.A. , Masszi, T. , Spicka, I. , Oriol, A. , Hajek, R. , Rosinol, L. , Siegel, D.S. , Mihaylov, G.G. , Goranova‐Marinova, V. , Rajnics, P. , Suvorov, A. , Niesvizky, R. , Jakubowiak, A.J. , San‐Miguel, J.F. , Ludwig, H. , Wang, M. , Maisnar, V. , Minarik, J. , Bensinger, W.I. , Mateos, M.V. , Ben‐Yehuda, D. , Kukreti, V. , Zojwalla, N. , Tonda, M.E. , Yang, X. , Xing, B. , Moreau, P. & Palumbo, A. (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 372, 142–152. PubMed

Tamura, D. , Arao, T. , Tanaka, K. , Kaneda, H. , Matsumoto, K. , Kudo, K. , Aomatsu, K. , Fujita, Y. , Watanabe, T. , Saijo, N. , Kotani, Y. , Nishimura, Y. & Nishio, K. (2010) Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2/M transition. Cancer Science, 101, 1403–1408. PubMed PMC

Tariman, J.D. (2007) Lenalidomide: a new agent for patients with relapsed or refractory multiple myeloma. Clinical Journal of Oncology Nursing, 11, 569–574. PubMed

Tinsley, S.M. , Kurtin, S.E. & Ridgeway, J.A. (2015) Practical management of lenalidomide‐related rash. Clinical Lymphoma, Myeloma and Leukemia, 15, S64–S69. PubMed

Valkovic, T. , Gacic, V. , Ivandic, J. , Petrov, B. , Dobrila‐Dintinjana, R. , Dadic‐Hero, E. & Nacinovic‐Duletic, A. (2015) Infections in hospitalised patients with multiple myeloma: main characteristics and risk factors. Turkish Journal of Haematology, 32, 234–242. PubMed PMC

Weber, D.M. , Chen, C. , Niesvizky, R. , Wang, M. , Belch, A. , Stadtmauer, E.A. , Siegel, D. , Borrello, I. , Rajkumar, S.V. , Chanan‐Khan, A.A. , Lonial, S. , Yu, Z. , Patin, J. , Olesnyckyj, M. , Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. New England Journal of Medicine, 357, 2133–2142. PubMed

Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice

Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors

Adverse event management in the TOURMALINE-MM3 study of post-transplant ixazomib maintenance in multiple myeloma

Real-world effectiveness and safety of ixazomib-lenalidomide-dexamethasone in relapsed/refractory multiple myeloma

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses