Abstract
PIM447, a novel pan-PIM inhibitor, has shown preclinical activity in multiple myeloma (MM). In the multicenter, open-label, first-in-human study, patients with relapsed and/or refractory MM were enrolled to determine the maximum-tolerated dose (MTD) or recommended dose (RD), safety, pharmacokinetics, and preliminary anti-myeloma activity of PIM447. PIM447 was administered in escalating oral doses of 70–700 mg once daily (q.d.) for 28-day continuous cycles. Seventy-nine patients with a median of four prior therapies were enrolled. Seventy-seven patients (97.5%) had an adverse event (AE) suspected as treatment related, with treatment-related grade 3/4 AEs being mostly hematologic. Eleven dose-limiting toxicities occurred, and an MTD of 500 mg q.d. and an RD of 300 mg q.d. were established. The main reason for discontinuation was disease progression in 54 patients (68.4%). In the entire study population, a disease control rate of 72.2%, a clinical benefit rate of 25.3%, and an overall response rate of 8.9% were observed per modified International Myeloma Working Group criteria. Median progression-free survival at the RD was 10.9 months. PIM447 was well tolerated and demonstrated single-agent antitumor activity in relapsed/refractory MM patients, providing proof of principle for Pim (Proviral Insertions of Moloney Murine leukemia virus) kinase inhibition as a novel therapeutic approach in MM.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Novartis supports the publication of scientifically rigorous analysis that is relevant to patient care, regardless of a positive or negative outcome. Qualified external researchers can request access to anonymized patient-level data, respecting patient informed consent, through www.clinicalstudydatarequest.com, according to requirements noted on the web portal.
References
Dimopoulos MA, Richardson PG, Moreau P, Anderson KC. Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol. 2015;12:42–54.
Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant. 2016;51:479–91.
Holstein SA, Richardson PG, Laubach JP, McCarthy PL. Management of relapsed multiple myeloma after autologous stem cell transplant. Biol Blood Marrow Transplant. 2015;21:793–8.
Usmani S, Ahmadi T, Ng Y, Lam A, Desai A, Potluri R, et al. Analysis of real-world data on overall survival in multiple myeloma patients with > / = 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or double refractory to a PI and an IMiD. Oncologist. 2016;21:1355–61.
Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011;11:23–34.
Cuypers HT, Selten G, Quint W, Zijlstra M, Maandag ER, Boelens W, et al. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell. 1984;37:141–50.
van der Lugt NM, Domen J, Verhoeven E, Linders K, van der Gulden H, Allen J, et al. Proviral tagging in E mu-myc transgenic mice lacking the Pim-1 proto-oncogene leads to compensatory activation of Pim-2. EMBO J. 1995;14:2536–44.
Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E, et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet. 2002;32:153–9.
van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, et al. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989;56:673–82.
Brault L, Gasser C, Bracher F, Huber K, Knapp, Schwaller J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95:1004–15.
Qian KC, Studts J, Wang L, Barringer K, Kronkaltis A, Peng C, et al. Expression, purification, crystallization and preliminary crystallographic analysis of human Pim-1 kinase. Acta Crystallogr Sect F. 2005;61:96–9.
Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K, et al. The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia. 2011;25:1182–8.
Keane NA, Reidy M, Natoni A, Raab MS, O’Dwyer M. Targeting the Pim kinases in multiple myeloma. Blood Cancer J. 2015;5:e325.
Burger MT, Nishiguchi G, Han W, Lan J, Simmons R, Atallah G, et al. Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a potent and selective proviral insertion site of moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitor in clinical trials for hematological malignancies. J Med Chem. 2015;58:8373–86.
Garcia PD, Langowski JL, Wang Y, Chen M, Castillo J, Fanton C, et al. Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res. 2014;20:1834–45.
Lu J, Zavorotinskaya T, Dai Y, Niu XH, Castillo J, Sim J, et al. Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation. Blood. 2013;122:1610–20.
Paino T, Garcia-Gomez A, Gonzalez-Mendez L, San-Segundo L, Hernandez-Garcia S, Lopez-Iglesias AA, et al. The novel pan-PIM kinase inhibitor, PIM447, displays dual antimyeloma and bone-protective effects, and potently synergizes with current standards of care. Clin Cancer Res. 2017;23:225–38.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008;27:2420–39.
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med. 1998;17:1103–20.
Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia . 2006;20:1467–73.
He J, Abdel-Wahab O, Nahas MK, Wang K, Rampal RK, Intlekofer AM, et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016;127:3004–14.
Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106:3777–84.
Salvini M, Bonello F, Boccadoro M, Larocca A. Management of adverse events induced by next-generation immunomodulatory drug and proteasome inhibitors in multiple myeloma. Expert Rev Anticancer Ther. 2017;17:75–87.
Mikkers H, Nawijn M, Allen J, Brouwers C, Verhoeven E, Jonkers J, et al. Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004;24:6104–15.
An N, Kraft AS, Kang Y. Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol. 2013;6:12.
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;130:974–81.
Baz RC, Martin TG III, 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;127:2561–8.
Richardson PG, Rocafiguera AO, Beksac M, Liberati AM, Galli A, Schjesvold F, et al. Pomalidomide (POM), bortezomib, and low-dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36 Suppl 15:Abstract 8001.
Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. N Engl J Med. 2018;379:1811–1822. https://doi.org/10.1056/NEJMoa1805762.
Guenther A, Baumann P, Burger R, Kellner C, Klapper W, Schmidmaier R, et al. Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study. Haematologica. 2015;100:541–7.
Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307–18.
Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev. 2003;17:1841–54.
Cervantes-Gomez F, Chen LS, Orlowski RZ, Gandhi V. Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2013;13:S317–29.
Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011;118:693–702.
Keeton EK, McEachern K, Dillman KS, Palakurthi S, Cao Y, Grondine MR, et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014;123:905–13.
Adam K, Lambert M, Lestang E, Champenois G, Dusanter-Fourt I, Tamburini J, et al. Control of Pim2 kinase stability and expression in transformed human haematopoietic cells. Biosci Rep. 2015;35:e00274.
Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science . 2014;343:305–9.
Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–9.
Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, et al. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21:803–9.
Hao HWD, Vanasse G, Caponigro G. The pan-PIM inhibitor PIM447 enhances the antitumor activity of lenalidomide in multiple myeloma cells via synergistic inhibition of c-MYC. Cancer Res. 2016;76 Suppl 14:Abstract 4630.
Meja K, Stengel C, Sellar R, Huszar D, Davies BR, Gale RE, et al. PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways. Br J Haematol. 2014;167:69–79.
Acknowledgements
We thank all the patients, their families, the study investigators, study nurses, and clinical research associates from the participating trial centers that supported this trial. We thank Kinjal Mody for all the operational support with this clinical program. We also thank Amirtha Ganesh, PhD (Novartis Healthcare Pvt Ltd), for providing medical editorial assistance with this manuscript. This work was financially supported by Novartis Pharmaceuticals Corporation.
Author contributions
KGV and FX conceptualized and designed the study. MSR, SKT, EMO, Y-TG, AG, NH, MT, SZ, FX, CS, KGV, and SKK participated in collection/assembly data and or analysis/interpretation of data and also wrote the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
SZ, FX, CS, KGV are all employees of Novartis and SZ, FX, and KGV own stocks of Novartis. The other authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
41375_2019_482_MOESM2_ESM.pdf
Suppl- Figure 2: Foundation T7 gene assay interrogates 404 genes for base substitutions, insertion-deletions, and copy number changes
Rights and permissions
About this article
Cite this article
Raab, M.S., Thomas, S.K., Ocio, E.M. et al. The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and/or refractory multiple myeloma. Leukemia 33, 2924–2933 (2019). https://doi.org/10.1038/s41375-019-0482-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-019-0482-0
This article is cited by
-
Targeting Pim kinases in hematological cancers: molecular and clinical review
Molecular Cancer (2023)
-
Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias
Nature Cancer (2023)
-
IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes
Nature Communications (2021)
-
A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma
International Journal of Hematology (2021)
-
High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms
Endocrine Pathology (2020)