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Cited by 386Multiple Myeloma Research and TreatmentsBone health and treatmentsProtein Degradation and Inhibitors

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Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial

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Richardson, Paul G, Oriol, Albert, Beksac, Meral, Liberati, Anna Marina, Galli, Monica, Schjesvold, Fredrik, Lindsay, Jindriska, Weisel, Katja, White, Darrell, Facon, Thierry, San Miguel, Jesus, Sunami, Kazutaka, O'Gorman, Peter, Sonneveld, Pieter, Robak, Pawel, Semochkin, Sergey, Schey, Steve, Yu, Xin, Doerr, Thomas, Bensmaine, Amine, Biyukov, Tsvetan, Peluso, Teresa, Zaki, Mohamed, Anderson, Kenneth, Dimopoulos, Meletios, Abildgaard, Niels, Adler, Howard, Altuntas, Fevzi, Akay, Olga Meltem, Amin, Bipinkumar, Anagnostopoulos, Achilleas, Anderson, Larry, Anttila, Pekka, Araujo, Carla, Arce-Lara, Carlos, Aydin, Yildiz, Basu, Supratik, Battini, Ramakrishna, Beeker, Thaddeus, Benboubker, Lotfi, Ben-Yehuda, Dina, Bladé, Joan, Blau, Igor Wolfgang, Boccia, Ralph, Burke, Lillian, Byeff, Peter, Cascavilla, Nicola, Cavo, Michele, Chantry, Andrew, Charles, Yen, Chaudhry, Arvind, Corso, Alessandro, Coyne, Mark, De Arriba, Felipe, Delimpasi, Sosana, Desjardins, Pierre, Dhakal, Binod, Di Bartolomeo, Paolo, Di Raimondo, Francesco, Dürig, Jan, Engelhardt, Monika, Escoffre-Barbe, Martine, Esteves, Graca, Flogegard, Max, Gabrail, Nashat, Gamberi, Barbara, Garrison, Mitchell, Gay, Julie, Gisslinger, Heinz, Goldschmidt, Hartmut, Goncalves, Cristina, Gressot, Laurent, Grosicki, Sebastian, Hanna, Wahid, Hayden, Patrick, Henriques Bernardo, Maria Manuela, Hermann, Robert, Holden, Viran, Honkalehto, Kirsti, Huben, Marianne, Huffman, John, Hunter, Hannah, Hus, Marek, Jagasia, Madan, Jagganath, Sundar, Janakiram, Murali, Jaiyesimi, Ishmael, Jenner, Matthew, João, Cristina, Johnson, Peter, Jurcyszyn, Artur, Kalayoğlu Beşişik, Sevgi, Kambhampati, Suman, Kanate, Abraham, Karadoğan, Ihsan, Khojasteh, Ali, Kirkel, Dean, Komarnicki, Mieczyslaw, Krauth, Maria-Theresa, Kuriakose, Phillip, Larocca, Alessandra, Lauri, Birgitta, Leleu, Xavier, Lucio, Paulo, Luppi, Mario, Mangiacavalli, Silvia, Mariette, Clara, Matsue, Kosei, Mellqvist, Ulf-Henri, Mendeleeva, Larisa, Meshad, Michael, Miller, Carole, Mohrbacher, Ann, Moreau, Philippe, Morelli, Anna Maria, Müldür, Ercan, Naassan, Anthony, Nahi, Hareth, Nair, Rajesh, O'Dwyer, Mike, Öngören Aydin, Seniz, Openshaw, Thomas, O'Rourke, Timothy, Osswald, Michael, Overton, Lindsay, Pati, Asmin, Pavic, Michel, Pegourie, Brigitte, Pehlivan, Mustafa, Pierola, Ana Alfonso, Plesner, Torben, Pluta, Andrzej, Rabin, Neil, Ramasamy, Karthik, Rambaldi, Alessandro, Rodriguez, Paula, Röllig, Christoph, Rosenblatt, Jacalyn, Rosenbluth, Jonathan, Salomo, Morten, Samoylova, Olga, Sastre Moral, Jose, Sati, Hamdi, Selleri, Carmine, Shafeek, Salim, Shinagawa, Atsushi, Sleckman, Bethany, Smith, Clay, Sonmez, Mehmet, Stone, Chester, Streetly, Matthew, Suzuki, Kenshi, Taetle, Raymond, Tafuri, Agostino, Takezako, Naoki, Teke, Hava Üsküdar, Vapaatalo, Mirja, Vassilopoulos, George, Verma, Amit, Vidito, Sarah, Viterbo, Luisa, Vural, Filiz, Wang, Xiang Sean, Yağci, Munci, Yee, Andrew·2019·The Lancet Oncology
DOI 10.1016/s1470-2045(19)30152-4
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Abstract

Background As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β 2 microglobulin at screening. Bortezomib (1·3 mg/m 2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Interpretation Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Funding Celgene.

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Authors
Richardson, P. G., Oriol, A., Beksac, M., Liberati, A. M., Galli, M., Schjesvold, F., Lindsay, J., Weisel, K., White, D., Facon, T., San Miguel, J., Sunami, K., O'Gorman, P., Sonneveld, P., Robak, P., Semochkin, S., Schey, S., Yu, X., Doerr, T., Bensmaine, A., Biyukov, T., Peluso, T., Zaki, M., Anderson, K., Dimopoulos, M., Abildgaard, N., Adler, H., Altuntas, F., Akay, O. M., Amin, B., Anagnostopoulos, A., Anderson, L., Anttila, P., Araujo, C., Arce-Lara, C., Aydin, Y., Basu, S., Battini, R., Beeker, T., Benboubker, L., Ben-Yehuda, D., Bladé, J., Blau, I. W., Boccia, R., Burke, L., Byeff, P., Cascavilla, N., Cavo, M., Chantry, A., Charles, Y., Chaudhry, A., Corso, A., Coyne, M., De Arriba, F., Delimpasi, S., Desjardins, P., Dhakal, B., Di Bartolomeo, P., Di Raimondo, F., Dürig, J., Engelhardt, M., Escoffre-Barbe, M., Esteves, G., Flogegard, M., Gabrail, N., Gamberi, B., Garrison, M., Gay, J., Gisslinger, H., Goldschmidt, H., Goncalves, C., Gressot, L., Grosicki, S., Hanna, W., Hayden, P., Henriques Bernardo, M. M., Hermann, R., Holden, V., Honkalehto, K., Huben, M., Huffman, J., Hunter, H., Hus, M., Jagasia, M., Jagganath, S., Janakiram, M., Jaiyesimi, I., Jenner, M., João, C., Johnson, P., Jurcyszyn, A., Kalayoğlu Beşişik, S., Kambhampati, S., Kanate, A., Karadoğan, I., Khojasteh, A., Kirkel, D., Komarnicki, M., Krauth, M.-T., Kuriakose, P., Larocca, A., Lauri, B., Leleu, X., Lucio, P., Luppi, M., Mangiacavalli, S., Mariette, C., Matsue, K., Mellqvist, U.-H., Mendeleeva, L., Meshad, M., Miller, C., Mohrbacher, A., Moreau, P., Morelli, A. M., Müldür, E., Naassan, A., Nahi, H., Nair, R., O'Dwyer, M., Öngören Aydin, S., Openshaw, T., O'Rourke, T., Osswald, M., Overton, L., Pati, A., Pavic, M., Pegourie, B., Pehlivan, M., Pierola, A. A., Plesner, T., Pluta, A., Rabin, N., Ramasamy, K., Rambaldi, A., Rodriguez, P., Röllig, C., Rosenblatt, J., Rosenbluth, J., Salomo, M., Samoylova, O., Sastre Moral, J., Sati, H., Selleri, C., Shafeek, S., Shinagawa, A., Sleckman, B., Smith, C., Sonmez, M., Stone, C., Streetly, M., Suzuki, K., Taetle, R., Tafuri, A., Takezako, N., Teke, H. Ü., Vapaatalo, M., Vassilopoulos, G., Verma, A., Vidito, S., Viterbo, L., Vural, F., Wang, X. S., Yağci, M., & Yee, A.
Affiliations
  • Harvard University (US)
  • Josep Carreras Leukaemia Research Institute (ES)
  • University of Perugia (IT)
  • Ospedale Papa Giovanni XXIII (IT)
  • Oslo University Hospital (NO)
  • East Kent Hospitals University NHS Foundation Trust (GB)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Dalhousie University (CA)
  • Université de Lille (FR)
  • National Hospital Organization (JP)
  • Erasmus MC Cancer Institute (NL)
  • Medical University of Lodz (PL)
  • King's College London (GB)
  • Celgene (United States) (US)
  • National and Kapodistrian University of Athens (GR)
  • University College Dublin (IE)
Corresponding author
Richardson, Paul G
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2019-06
Volume
20
Issue
6
Pages
781-794
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(19)30152-4
OpenAlex
W2945852816
Cited by
386
References
39
Citations by year
2026: 24 · 2025: 50 · 2024: 42 · 2023: 61 · 2022: 59 · 2021: 71 · 2020: 55 · 2019: 21
FWCI
35.93
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
Celgene
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Oncology › Bone health and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
relapsed/refractory multiple myeloma, pomalidomide, bortezomib, dexamethasone, lenalidomide-refractory disease, progression-free survival, overall survival, treatment safety, triplet regimens, beta2-microglobulin, proteasome inhibitor combination, treatment-emergent adverse events
MeSH terms
Bortezomib, Lenalidomide, Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Dexamethasone, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma, Neoplasm Recurrence, Local, Prognosis, Thalidomide, Survival Rate, Salvage Therapy, Drug Resistance, Neoplasm, Young Adult

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