Proteasome inhibitors in multiple myeloma: 10 years later Philippe Moreau, Paul G. Richardson, Michele Cavo, Robert Z. Orlowski, Jesu´s F. San Miguel, Antonio Palumbo, and Jean-Luc Harousseau Blood. 2012;120(5): R3 김승민 /Prof 윤휘중

Introduction ubiquitin-proteasome pathway is responsible for degradation of the majority of regulatory proteins in eukaryotic cells Ex: cell-cycle progression, apoptosis, and DNA repair (26S proteasome)

Introduction Disruption of proteasome activity results in growth arrest and cell death because of induction of an apoptotic cascade Cancer cells have higher levels of proteasome activity compared with normal cells and, moreover Cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells Proteasome inhibition has been extensively explored as a therapeutic strategy in multiple myeloma (MM) Pis can be classified into 3 groups: boronates, epoxyketones, and salinosporamides.

Introduction β-1 (caspase-like activity) β-2 (trypsin-like activity) β-5 (chymotrypsin-like activity))

Bortezomib initial studies of single-agent bortezomib (10 yeasr ago) manageable toxicity antineoplastic activity in patients with relapsed/refractory MM intravenously (IV) on a twice-weekly schedule the maximum tolerated dose (MTD) was determined to be 1.3 mg/m2, dose-limiting adverse events (AEs): diarrhea and peripheral neuropathy Bortezomib  treatment of relapsed and refractory MM

Bortezomib APEX trial (bortezomib VS high-dose dexamethasone) bortezomib  the treatments of choice for relapsed MM bortezomib-associated toxicities gastrointestinal symptoms, anemia, thrombocytopenia, fatigue, and PN PN  bortezomib mainly causes direct dorsal root ganglion toxicity Bortezomib-induced PN (weekly dosing & SC administration) hematologic toxicity (transient thrombocytopenia)

Bortezomib initial studies of single-agent bortezomib (10 yeasr ago) no significant differences in TTP and 1-year OS with SC versus IV SC VS IV administration. PN of any grade (38% vs 53%; P =.04) grade more than or equal to 2 (24% vs 41%; P =.01), grade more than or equal to 3 (6% vs 16%; P =003)

bortezomib plus cyclophosphamide and dexamethasone (VCD) bortezomib plus cyclophosphamide and prednisone (VCP) Bortezomib plus lenalidomide and dexamethasone (VRD). Response rates range from 60% to 90%, median PFS of approximately 7 to 15 months median OS of 16 to 37 months Bortezomib-based combinations in refractory MM

Bortezomib in front-line MM median TTP was 24.0 versus 16.6 months with VMP vs MP ORR was 71% versus 35% CR rates were 30% and 4 hazard ratio for OS was 0.61 in favor of VMP, median follow-up of 16.3 months. These results led to the approval of VMP induction therapy in patients ineligible for ASCT in the United States and European Union

Bortezomib in front-line MM weekly schedule resulted in a substantial improvement in safety and did not impact efficacy. UPFRONT study have also introduced the concept of bortezomib-based maintenance in elderly patients

Bortezomib-based induction before ASCT. The IFM phase 3 study  pre-ASCT induction in previously untreated patients Bortezomib dexamethasone vs vincristine-doxorubicin-dexamethasone (VAD) Post-induction response rates were significantly higher with bortezomib- dexamethasone After first transplantation, CR/nCR and more than or equal to VGPR rates remained significantly higher with bortezomib-dexamethasone There was a trend for improved PFS in bortezomib +dexamethasone group but 3-year survival rates were not different

Bortezomib-based induction before ASCT. The IFM phase 3 study Bortezomib dexamethasone with VAD as pre-ASCT induction in previously untreated patients Postinduction response rates were significantly higher with bortezomib-dexamethasone, regardless of disease stage or adverse cytogenetic abnormalities. After first transplantation, CR/nCR and more than or equal to VGPR rates remained significantly higher with bortezomib-dexamethasone (Table 3). There was a trend for improved PFS with bortezomibdexamethasone versus VAD (P.06), but 3-year survival rates were not different

Bortezomib-based induction before ASCT. In the IFM trial standard” bortezomib+ dexamethasone induction VS VTD VTD  using lower bortezomib and thalidomide doses to reduce the neuropathy rate. VTD was again found to result in superior response rates before and after ASCT, VTD  reduced neurotoxicity. superiority of a 3-drug over a 2-drug combination for tumor burden reduction as pre-ASCT induction. the HOVON group VAD versus PAD as pre-ASCT induction, followed by thalidomide and bortezomib maintenance superiority of the bortezomib-based triplet over VAD in terms of postinduction and post-ASCT response rates; and OS was also superior after PAD plus bortezomib maintenance. No data are available to draw conclusions regarding the superiority of one bortezomib-based combination over another. Thus, based on response rates and depth of response as surrogate markers for outcome, 3-drug combinations are, in 2012, the standard of care before ASCT

Result imatinib interruption after 1 or 3 years of imatinib treatment  increased risk relapse was observed even in patients who achieved complete response (CR) before randomization Preliminary results of continuous versus interrupted imatinib after 5 years of therapy were reported at the 2010 ASCO A total of 21 patients with tumor response or stable disease (SD) after 5 years of imatinib treatment were randomized 5 of 11 patients in the interruption arm relapsed after a median follow-up of 12 months from randomization compared with no relapse among the 10 patients in the continuation arm (P = 0.035).

Carfilzomib Interruption of therapy after 1 year in responding patients resulted in rapid PD. 58 randomized patients Imatinib interruption (32) + imatinib continuation arm (26) 26 of 32 (81%) patients in the treatment interruption arm experienced PD after treatment interruption 8 of 26 patients (31%) in the imatinib continuation arm, at the time of data cut-off Median PFS after randomization was 6.1 months in the interruption arm and 18 months in the continuation arm.

Marizomib, MLN9708

Conclusions Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy

Conclusions bortezomib is an established componentof induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. a new route of bortezomib administration, subcutaneous infusion has recently been approved carfilzomib, marizomib, and MLN9708, Secondgeneration PIs in patients with relapsed/ refractory MMs have demonstrated positive results