Pathway-Directed Therapy in Multiple Myeloma
Abstract
:Simple Summary
Abstract
1. Introduction
2. RAS/RAF/MEK/ERK-Pathway Directed Therapies
3. PI3K/AKT-Pathway-Directed Therapies
3.1. AKT
3.2. MTOR
4. PIM-Directed Therapies
5. Transcription Factor-Directed Therapies
5.1. C-MYC Directed Therapies
5.2. p53 Directed Therapies
5.3. Other TF-Directed Therapies
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study | Drugs | Study Type | Efficacy | Patient Selection |
---|---|---|---|---|
RAS/RAF/MEK/ERK-pathway | ||||
Alsina et al. [50] | Tipifarnib | Phase II | 64% stable disease, 0% ≥ PR | r/r MM |
Heuck et al. [56] | Trametinib | Retrospective cohort | 10% ≥ PR | Mutations in NRAS, KRAS, BRAF, MAPK-activation in GEP |
Hyman D.M. et al. [38] | Vemurafenib | Phase II Basket-trial | No responses in the 5 MM patients | BRAFV600 mutated |
NCI-MATCH [65] | Dabrafenib + Trametinib | Phase II Basket-trial | No response in myeloma patients | BRAF V600E/R/K/D mutated |
BIRMA-Study [67] | Encorafenib + Binimetinib | Phase II | ORR (≥PR) 82% | BRAFV600-mutated |
NCT03091257 | Dabrafenib and/or Trametinib | Phase I | Ongoing | BRAF/KRAS/NRAS mutated |
NCT03312530 [68] | Cobimetinib + Venetoclax ± Atezolizumab | Phase I/II | ORR (≥PR) 27%/29% in the combination arms | - |
Guo et al. [66] | CH5126766 (VS-6766/ RO5126766) | Phase I | PR in 1/7 myeloma patients | Solid tumors and myeloma with RAS/RAF/MEK pathway mutations |
MyDRUG-trial (NCT03732703) | Cobimetinib + Dexamethasone + Ixazomib/Pomalidomide | Phase I/II Umbrella-trial | Ongoing | RAF/RAS-mutation |
TAPUR (NCT02693535) | Vemurafenib + Cobimetinib | Phase II Basket-trial | Ongoing | BRAFV600 E/D/K/R mutated |
CAPTUR (NCT03297606) | Vemurafenib + Cobimetinib | Phase II < Basket-trial | Ongoing | BRAF V600 mutated |
AKT-pathway | ||||
Richardson et al. [78] | Perifosine (+ Dexamethasone) | Phase II | 38% PR + MR after addition of dexamethasone | r/r MM |
Jakubowiak et al. [79] | Perifosine + Lenalidomide + Dexamethasone | Phase I | ORR (≥PR) 50% | r/r MM, no previous therapy with lenalidomide required |
Richardson et al. [80] | Perifosine + Bortezomib + Dexamethasone | Phase I/II | ORR (≥MR) 41%, 32% in bortezomib-refractory patients | r/r MM |
Richardson et al. [81] | Perifosine + Bortezomib + Dexamethasone | Phase III | ORR (≥PR) 20% vs. 27% in the placebo arm) | Phase III |
Spencer et al. [82] | Afuresertib | Phase I | ORR (≥PR) 8%, long median PFS in responding patients (319 days) | r/r MM |
Voorhees et al. [84] | Afuresertib + Bortezomib + Dexamethasone | Phase I/II | Preliminary data: ORR (≥PR) 41% in phase I part | r/r MM |
Tolcher et al. [88] | Trametinib + Afuresertib | Phase I/II | Discontinued due to toxicity | r/r MM, relapsed triple negative breast or endometrial cancer |
NCT01989598 | GSK2141795 + Trametinib | Phase II | Ongoing | r/r MM |
NCI MATCH | Capivasertib | Phase II | Ongoing | AKT-mutated |
Günther et al. [90] | Everolimus | Phase I | ORR (≥PR) 7% (1/15, maximum PFS 3 (months) | r/r MM |
Farag et al. [91] | Temsirolimus | Phase II | ORR (≥PR) 6% (1/16) | r/r MM |
Yee et al. [93] | Everolimus + Lenalidomide | Phase I | ORR (≥MR) 65% | r/r MM, no previous lenalidomide required |
Ghobrial et al. [92] | Temsirolimus + Bortezomib | Phase I/II | ≥PR 33% | r/r MM, no previous bortezomib required |
Ghobrial et al. [94] | Sapanisertip (TAK228) | Phase I | 1/31 myeloma patients with MR | r/r MM |
PIM-kinase pathway | ||||
Raab et al. [105] | PIM 447(LGH447) | Phase I | ORR (≥PR) 9%, disease control rate 72%, median PFS 10.9 months | r/r MM |
NCT02144038 | PIM 447(LGH447) + BYL719 | Phase I/II | Discontinued due to toxicity | r/r MM |
c-MYC pathway | ||||
Amorim et al. [118] | OTX015 | Phase I | No activity in the myeloma group | r/r MM, lymphoma |
NCT02157636 | CPI-0610 | Phase I | Ongoing | r/r MM |
NCT03068351 [119] | RO6870810 + Daratumumab | Phase I | ORR (≥PR) 16.7% | r/r MM, no previous daratumumab required |
Tolcher et al. [128] | DCR-MYC | Phase I | No published results available | r/r MM, advanced solid tumors, lymphoma |
p53 pathway | ||||
NCT02633059 | Idasanutlin + Ixazomib + Dexamethasone | Phase I/II | No published results available | r/r MM with del17p |
NCT03031730 | KRT-232 (AMG232) + Carfilzomib + Lenalidomide + Dexamethasone | Phase I | ongoing | r/r MM |
Strassz et al. [150] | HDP-101 | Phase I/II | Due to start Q1/2021 | r/r MM |
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John, L.; Krauth, M.T.; Podar, K.; Raab, M.-S. Pathway-Directed Therapy in Multiple Myeloma. Cancers 2021, 13, 1668. https://doi.org/10.3390/cancers13071668
John L, Krauth MT, Podar K, Raab M-S. Pathway-Directed Therapy in Multiple Myeloma. Cancers. 2021; 13(7):1668. https://doi.org/10.3390/cancers13071668
Chicago/Turabian StyleJohn, Lukas, Maria Theresa Krauth, Klaus Podar, and Marc-Steffen Raab. 2021. "Pathway-Directed Therapy in Multiple Myeloma" Cancers 13, no. 7: 1668. https://doi.org/10.3390/cancers13071668