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Hanley N. Abramson
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Abramson, H.N. Kinase Inhibitors in the Treatment of Multiple Myeloma. Encyclopedia. Available online: https://encyclopedia.pub/entry/41797 (accessed on 17 July 2025).
Abramson HN. Kinase Inhibitors in the Treatment of Multiple Myeloma. Encyclopedia. Available at: https://encyclopedia.pub/entry/41797. Accessed July 17, 2025.
Abramson, Hanley N.. "Kinase Inhibitors in the Treatment of Multiple Myeloma" Encyclopedia, https://encyclopedia.pub/entry/41797 (accessed July 17, 2025).
Abramson, H.N. (2023, March 02). Kinase Inhibitors in the Treatment of Multiple Myeloma. In Encyclopedia. https://encyclopedia.pub/entry/41797
Abramson, Hanley N.. "Kinase Inhibitors in the Treatment of Multiple Myeloma." Encyclopedia. Web. 02 March, 2023.
Kinase Inhibitors in the Treatment of Multiple Myeloma
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24032645

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease’s five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common.

myeloma melflufen cereblon E3 ligase modulators

1. Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the TEC family that plays a major role in B-cell development [1]. It also is expressed in T cells and NK cells where it is an important contributor to their activation as well [2][3]. The oral irreversible (by virtue of its covalent binding to Cys-481 in the ATP binding pocket) BTK inhibitor ibrutinib (Figure 1), which has been approved for the treatment of CLL, mantle cell lymphoma (MCL), and Waldenstrom’s macroglobulinemia among others, also has been studied for possible application in MM owing to reports of robust expression of BTK in myeloma cells [4].
Ijms 24 02645 g007 550
Figure 1. Bruton’s tyrosine kinase inhibitors with anti-myeloma activity.
In a phase II trial (NCT01478581), ibrutinib provided only modest efficacy when used alone or in combination with dexamethasone in 69 RRMM patients [5]. Combinations of ibrutinib with proteasome inhibitors also have been investigated based on potential synergy noted in preclinical work. Enrollment in one such trial (NCT02902965) that included bortezomib/dexamethasone was suspended and eventually terminated when an increase in serious and fatal infections was noted in the study group, thus making attainment of the study’s target PFS unlikely [6]. It is noteworthy that opportunistic infections have been reported as a significant risk in a number of ibrutinib-based studies [7][8]. A phase I/II study (NCT01962792) of ibrutinib plus carfilzomib/dexamethasone showed median PFS and OS of 7.4 months and 35.9 months, respectively, in 59 heavily pretreated (median of three prior treatments) MM patients. While 18 (31%) of the patients experienced upper respiratory infections, most were of grade 1 or 2 and none were fatal [9].
Ibrutinib also has been combined with lenalidomide/dexamethasone in a recently reported phase I dose-escalation study of 15 RRMM subjects who had received a median of four prior therapies (NCT03015792). Initial results reported a median PFS of 3.8 months and, although only one patient attained a partial response (ORR, 7%), clinical benefit as defined by the trial criteria was realized in 12 of the patients (80%). Overall, hematologic adverse effects (≥grade 3) were noted in 20% of the study participants (99675) [10].
Acalabrutinib, a second-generation oral irreversible BTK inhibitor, approved by the FDA for both MCL and CLL, was the subject of a now-completed phase Ib trial for RRMM (NCT02211014). The trial consisted of two arms: acalabrutinib alone (n = 13) and with dexamethasone (n = 14). No efficacy was demonstrated in either cohort, while serious adverse events were recorded in 38% and 64%, respectively, of the participants.

2. Transforming Growth Factor Receptor Inhibitors

The transforming growth factor (TGF)-b is a cytokine which effects diverse cellular processes, including growth, differentiation, migration, and cell death. The membrane-bound receptor for TGF-b contains a C-terminal domain possessing serine/threonine kinase activity. Activation of the TGF-b receptor causes phosphorylation of Smads, which in turn translocate to the nucleus where they bind to specific DNA sequences to regulate transcription of target genes [11].
The observation that MM cells demonstrate increased secretion of TGF-b linked to impaired immune surveillance and catabolic bone remodeling [12] led to a phase Ib trial (NCT03143985) of the TGF-b blocker vactosertib and pomalidomide in RRMM. Initial data on 15 patients, conducted without inclusion of steroids, showed that disease progression occurred in only three subjects, while the rest experienced some degree of progression-free benefit. Adverse events were reported as manageable [13].

3. Raf-Mek-Erk Pathway Inhibitors

The Ras gene is known to be the most frequently mutated oncogene in cancer, being found in approximately 19% of all malignancies [14]. The prevalence of Ras mutations, primarily as KRAS and NRAS, in NDMM has been estimated in one study as about 46%, rising to 64% in RRMM [15]. Such mutations manifest as increased sequential activation of the three serine/threonine protein kinases that together constitute the Raf/Mek/Erk (MAPK) downstream intracellular signaling pathway. V600E/K mutations of the Raf family member BRAF are frequently found in melanoma and other solid tumor types for which the MAPK blocking agents dabrafenib and trametinib, inhibitors of BRAF and Mek, respectively, are used clinically in combination. In addition, this mutation, which is associated with poor prognosis, is found in 2–4% of NDMM patients and about 8% in the RRMM setting [15]. Dabrafenib and trametinib, both in combination and separately, currently are under investigation in RRMM (NCT03091257), as is encorafenib (anti-BRAF) with binimetinib (anti-Mek) (NCT02834364; BIRMA). Although no results have been reported from either study, data are available from another trial that included the Mek inhibitor cobimetinib, which despite lacking single-agent activity, demonstrated potential but limited anti-myeloma efficacy when used together with venetoclax and/or atezolizumab (NCT03312530) [16]. Vemurafanib, another BRAF blocker, whether employed alone [17] or with cobimetinib [18], has been reported to elicit some partial responses in V600E RRMM as recorded in case reports, as well as in a small cohort of patients in another trial (NCT01524978) [19].

4. PI3K-Akt-mTOR Pathway Inhibitors

Another signaling pathway that operates downstream of Ras, the PI3K-Akt (protein kinase B)-mTOR (mammalian target of rapamycin) route, has received some attention in the search for new targets to treat RRMM but with largely disappointing results [20]. For example, the Akt inhibitor perifosine, which showed initial promise against MM in preclinical and early patient studies, failed to live up to expectations in a subsequent discontinued phase III study [21]. Trials combining the Mek blocker trametinib with Akt inhibitors afuresertib (GSK2110183) (NCT01476137) or uprosertib (GSK2141795) (NCT01951495) generally have yielded modest results [22][23], while data have yet to be reported from an ongoing trial (NCT02144038) of the oral PI3K inhibitor alpelisib (BYL719) with LGH447, a Pim blocker. The major mTOR inhibitors, everolimus and temsirolimus, have fared poorly as single agents in MM trials [24][25], while the few myeloma-based trials that have included mTOR blockers in various combinations heretofore have not produced published results.

References

  1. Good, L.; Benner, B.; Carson, W.E. Bruton’s tyrosine kinase: An emerging targeted therapy in myeloid cells within the tumor microenvironment. Cancer Immunol. Immunother. 2021, 70, 2439–2451.
  2. Bao, Y.; Zheng, J.; Han, C.; Jin, J.; Han, H.; Liu, Y.; Lau, Y.L.; Tu, W.; Cao, X. Tyrosine kinase Btk is required for NK cell activation. J. Biol. Chem. 2012, 287, 23769–23778.
  3. Xia, S.; Liu, X.; Cao, X.; Xu, S. T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia. Cell. Mol. Immunol. 2020, 17, 1042–1052.
  4. Liu, Y.; Dong, Y.; Jiang, Q.L.; Zhang, B.; Hu, A.M. Bruton’s tyrosine kinase: Potential target in human multiple myeloma. Leuk. Lymphoma 2014, 55, 177–181.
  5. Richardson, P.G.; Bensinger, W.I.; Huff, C.A.; Costello, C.L.; Lendvai, N.; Berdeja, J.G.; Anderson, L.D., Jr.; Siegel, D.S.; Lebovic, D.; Jagannath, S.; et al. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: Phase 2 trial results. Br. J. Haematol. 2018, 180, 821–830.
  6. Hajek, R.; Pour, L.; Ozcan, M.; Martin Sánchez, J.; García Sanz, R.; Anagnostopoulos, A.; Oriol, A.; Cascavilla, N.; Terjung, A.; Lee, Y.; et al. A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Eur. J. Haematol. 2020, 104, 435–442.
  7. Woyach, J.A. Ibrutinib and Aspergillus: A Btk-targeted risk. Blood 2018, 132, 1869–1870.
  8. Rogers, K.A.; Mousa, L.; Zhao, Q.; Bhat, S.A.; Byrd, J.C.; El Boghdadly, Z.; Guerrero, T.; Levine, L.B.; Lucas, F.; Shindiapina, P.; et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia 2019, 33, 2527–2530.
  9. Chari, A.; Cornell, R.F.; Gasparetto, C.; Karanes, C.; Matous, J.V.; Niesvizky, R.; Lunning, M.; Usmani, S.Z.; Anderson, L.D., Jr.; Chhabra, S.; et al. Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma. Hematol. Oncol. 2020, 38, 353–362.
  10. Ailawadhi, S.; Parrondo, R.D.; Moustafa, M.A.; LaPlant, B.R.; Alegria, V.; Chapin, D.; Roy, V.; Sher, T.; Paulus, A.; Chanan-Khan, A.A. Ibrutinib, lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma: Phase I trial results. Hematol. Oncol. 2022, 40, 695–703.
  11. Neuzillet, C.; Tijeras-Raballand, A.; Cohen, R.; Cros, J.; Faivre, S.; Raymond, E.; de Gramont, A. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 2015, 147, 22–31.
  12. Kyrtsonis, M.C.; Repa, C.; Dedoussis, G.V.; Mouzaki, A.; Simeonidis, A.; Stamatelou, M.; Maniatis, A. Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma. Med. Oncol. 1998, 15, 124–128.
  13. Malek, E.; Hwang, S.J.; Caimi, P.F.; Metheny, L.L.; Tomlinson, B.K.; Cooper, B.W.; Boughan, K.M.; Otegbeye, F.; Gallogly, M.; Driscoll, J.J.; et al. Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-beta signaling pathway. J. Clin. Oncol. 2021, 39, 8039.
  14. Prior, I.A.; Hood, F.E.; Hartley, J.L. The frequency of Ras mutations in cancer. Cancer Res. 2020, 80, 2969–2974.
  15. Xu, J.; Pfarr, N.; Endris, V.; Mai, E.K.; Md Hanafiah, N.H.; Lehners, N.; Penzel, R.; Weichert, W.; Ho, A.D.; Schirmacher, P.; et al. Molecular signaling in multiple myeloma: Association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis 2017, 6, e337.
  16. Schjesvold, F.; Ribrag, V.; Rodriguez-Otero, P.; Robak, P.J.; Hansson, M.; Hajek, R.; Amor, A.A.; Martinez-Lopez, J.; Onishi, M.; Gallo, J.D.; et al. Safety and preliminary efficacy results from a phase Ib/II study of cobimetinib as a single agent and in combination with venetoclax with or without atezolizumab in patients with relapsed/refractory multiple myeloma. Blood 2020, 136, 45–46.
  17. Sharman, J.P.; Chmielecki, J.; Morosini, D.; Palmer, G.A.; Ross, J.S.; Stephens, P.J.; Stafl, J.; Miller, V.A.; Ali, S.M. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2014, 14, e161–e163.
  18. Mey, U.J.M.; Renner, C.; von Moos, R. Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation. Hematol. Oncol. 2017, 35, 890–893.
  19. Raje, N.; Chau, I.; Hyman, D.M.; Ribrag, V.; Blay, J.Y.; Tabernero, J.; Elez, E.; Wolf, J.; Yee, A.J.; Kaiser, M.; et al. Vemurafenib in patients with relapsed refractory multiple myeloma harboring BRAF(V600) mutations: A cohort of the histology-independent VE-BASKET study. JCO Precis. Oncol. 2018, 2, 1–9.
  20. Pan, D.; Richter, J. Where we stand with precision therapeutics in myeloma: Prosperity, promises, and pipedreams. Front. Oncol. 2021, 11, 819127.
  21. Richardson, P.G.; Nagler, A.; Ben-Yehuda, D.; Badros, A.; Hari, P.N.; Hajek, R.; Spicka, I.; Kaya, H.; LeBlanc, R.; Yoon, S.S.; et al. Randomized, placebo-controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib. eJHaem 2020, 1, 94–102.
  22. Trudel, S.; Bahlis, N.J.; Venner, C.P.; Hay, A.E. Biomarker driven phase II clinical trial of trametinib in relapsed/refractory multiple myeloma with sequential addition of the AKT inhibitor, GSK2141795 at time of disease progression to overcome treatment failure: A trial of the Princess Margaret phase II consortium. Blood 2016, 128, 4526.
  23. Tolcher, A.W.; Patnaik, A.; Papadopoulos, K.P.; Rasco, D.W.; Becerra, C.R.; Allred, A.J.; Orford, K.; Aktan, G.; Ferron-Brady, G.; Ibrahim, N.; et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother. Pharmacol. 2015, 75, 183–189.
  24. Calimeri, T.; Ferreri, A.J.M. m-TOR inhibitors and their potential role in haematological malignancies. Br. J. Haematol. 2017, 177, 684–702.
  25. Gunther, A.; Baumann, P.; Burger, R.; Kellner, C.; Klapper, W.; Schmidmaier, R.; Gramatzki, M. Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: A phase I study. Haematologica 2015, 100, 541–547.
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