Table 1.
Overview on pathway directed therapies in multiple myeloma.
| 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 |
Abbreviations: MM: Multiple Myeloma, ORR: overall response rate, PR: partial remission, MR: minor remission.