@article{3122238,
    title = "Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial",
    author = "Richardson, P.G. and Oriol, A. and Beksac, M. and Liberati, A.M. and Galli, M. and Schjesvold, F. and Lindsay, J. and Weisel, K. and White, D. and Facon, T. and San Miguel, J. and Sunami, K. and O'Gorman, P. and Sonneveld, P. and Robak, P. and Semochkin, S. and Schey, S. and Yu, X. and Doerr, T. and Bensmaine, A. and Biyukov, T. and Peluso, T. and Zaki, M. and Anderson, K. and Dimopoulos, M. and Abildgaard, N. and Adler, H. and Altuntas, F. and Akay, O.M. and Amin, B. and Anagnostopoulos, A. and Anderson, L. and Anttila, P. and Araujo, C. and Arce-Lara, C. and Aydin, Y. and Basu, S. and Battini, R. and Beeker, T. and Benboubker, L. and Ben-Yehuda, D. and Bladé, J. and Blau, I.W. and Boccia, R. and Burke, L. and Byeff, P. and Cascavilla, N. and Cavo, M. and Chantry, A. and Charles, Y. and Chaudhry, A. and Corso, A. and Coyne, M. and De Arriba, F. and Delimpasi, S. and Desjardins, P. and Dhakal, B. and Di Bartolomeo, P. and Di Raimondo, F. and Dürig, J. and Engelhardt, M. and Escoffre-Barbe, M. and Esteves, G. and Flogegard, M. and Gabrail, N. and Gamberi, B. and Garrison, M. and Gay, J. and Gisslinger, H. and Goldschmidt, H. and Goncalves, C. and Gressot, L. and Grosicki, S. and Hanna, W. and Hayden, P. and Henriques Bernardo, M.M. and Hermann, R. and Holden, V. and Honkalehto, K. and Huben, M. and Huffman, J. and Hunter, H. and Hus, M. and Jagasia, M. and Jagganath, S. and Janakiram, M. and Jaiyesimi, I. and Jenner, M. and João, C. and Johnson, P. and Jurcyszyn, A. and Kalayoğlu Beşişik, S. and Kambhampati, S. and Kanate, A. and Karadoğan, I. and Khojasteh, A. and Kirkel, D. and Komarnicki, M. and Krauth, M.-T. and Kuriakose, P. and Larocca, A. and Lauri, B. and Leleu, X. and Lucio, P. and Luppi, M. and Mangiacavalli, S. and Mariette, C. and Matsue, K. and Mellqvist, U.-H. and Mendeleeva, L. and Meshad, M. and Miller, C. and Mohrbacher, A. and Moreau, P. and Morelli, A.M. and Müldür, E. and Naassan, A. and Nahi, H. and Nair, R. and O'Dwyer, M. and Öngören Aydin, S. and Openshaw, T. and O'Rourke, T. and Osswald, M. and Overton, L. and Pati, A. and Pavic, M. and Pegourie, B. and Pehlivan, M. and Pierola, A.A. and Plesner, T. and Pluta, A. and Rabin, N. and Ramasamy, K. and Rambaldi, A. and Rodriguez, P. and Röllig, C. and Rosenblatt, J. and Rosenbluth, J. and Salomo, M. and Samoylova, O. and Sastre Moral, J. and Sati, H. and Selleri, C. and Shafeek, S. and Shinagawa, A. and Sleckman, B. and Smith, C. and Sonmez, M. and Stone, C. and Streetly, M. and Suzuki, K. and Taetle, R. and Tafuri, A. and Takezako, N. and Teke, H.Ü. and Vapaatalo, M. and Vassilopoulos, G. and Verma, A. and Vidito, S. and Viterbo, L. and Vural, F. and Wang, X.S. and Yağci, M. and Yee, A. and OPTIMISMM trial investigators",
    journal = "The lancet oncology",
    year = "2019",
    volume = "20",
    number = "6",
    pages = "781-794",
    publisher = "The Lancet Publishing Group",
    doi = "10.1016/S1470-2045(19)30152-4",
    keywords = "beta 2 microglobulin;  bortezomib;  dexamethasone;  lenalidomide;  pomalidomide;  antineoplastic agent;  bortezomib;  dexamethasone;  lenalidomide;  pomalidomide;  thalidomide, adult;  age;  aged;  anemia;  arthralgia;  Article;  asthenia;  backache;  bronchitis;  cancer survival;  clinical assessment;  clinical protocol;  constipation;  controlled study;  coughing;  diarrhea;  disease exacerbation;  dizziness;  drug efficacy;  drug safety;  dyspnea;  faintness;  fatigue;  female;  fever;  follow up;  headache;  human;  hyperglycemia;  hypokalemia;  insomnia;  intention to treat analysis;  major clinical study;  male;  multiple cycle treatment;  multiple myeloma;  muscle weakness;  nausea;  neutropenia;  peripheral edema;  pneumonia;  priority journal;  progression free survival;  randomized controlled trial;  relapse;  sensory neuropathy;  thrombocytopenia;  treatment duration;  treatment response;  tremor;  upper respiratory tract infection;  viral upper respiratory tract infection;  vomiting;  adolescent;  clinical trial;  drug effect;  drug resistance;  middle aged;  multicenter study;  multiple myeloma;  pathology;  phase 3 clinical trial;  prognosis;  salvage therapy;  survival rate;  tumor recurrence;  young adult, Adolescent;  Adult;  Aged;  Antineoplastic Combined Chemotherapy Protocols;  Bortezomib;  Dexamethasone;  Drug Resistance, Neoplasm;  Female;  Follow-Up Studies;  Humans;  Lenalidomide;  Male;  Middle Aged;  Multiple Myeloma;  Neoplasm Recurrence, Local;  Prognosis;  Salvage Therapy;  Survival Rate;  Thalidomide;  Young Adult",
    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 β2 microglobulin at screening. Bortezomib (1·3 mg/m2)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. © 2019 Elsevier Ltd"
}