Proteasome Inhibitors Show Promise as Treatment for Multiple Myeloma

January 31, 2020

Three proteasome inhibitors (PIs) are approved for patients with multiple myeloma (MM): Bortezomib, a first-in class PI, fights both newly diagnosed and relapsed/refractory MM (RRMM); carfilzomib, a next-generation PI, treats RRMM as both a monotherapy and in combination; and ixazomib, the first oral PI, treats RRMM in combination. PIs work by preventing the proteasomes in cancerous plasma cells from “recycling” what is essentially garbage protein.

Three proteasome inhibitors (PIs) are approved for patients with multiple myeloma (MM): Bortezomib, a first-in class PI, fights both newly diagnosed and relapsed/refractory MM (RRMM); carfilzomib, a next-generation PI, treats RRMM as both a monotherapy and in combination; and ixazomib, the first oral PI, treats RRMM in combination.

PIs work by preventing the proteasomes in cancerous plasma cells from “recycling” what is essentially garbage protein,1 misfolded or unfolded protein with no discernible function, leading to accumulation of that protein in the endoplasmic reticulum (ER), which itself leads to cell death and a condition called ER stress.2 Typically, proteasomes process the good proteins by using those that have been broken down to make new proteins.1

A recent review in Cancers detailed numerous clinical trials that have tested PIs as monotherapy and in combination with alkylators, immunomodulatory drugs, and monoclonal antibodies. The results show the superior efficacy of PIs in treating MM and RRMM. Below is a selection of some of the most promising results. To read about the rest, go here.

Bortezomib

Transplant-eligible patients. Phase 2 studies of bortezomib and dexamethasone (BD) induction demonstrated response rates of 66% to 90%, with a complete response (CR) rate of 15% to 21% and a very good partial response (VGPR) rate of 31.5% to 70.0%. The phase 3 Intergroupe Francophone du Myélome 2005‐01 phase 3 study went a step further, comparing BD with vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) as induction prior to autologous stem cell transplantation (ASCT) in previously untreated patients. The response rates were 78.5% and 62.8%, respectively, with BD also besting VAD in CR/near CR and VGPR or better rates: 35.0% versus 18.4% and 54.3% versus 37.2%. The progression-free survival (PFS) was 36.0 compared with 20.7 months (P = .06), respectively.2

Another phase 3 trial, CASSIOPEIA, tested daratumumab plus VTD (D-VTD) against VTD, as consolidation. After 4 cycles of induction and 2 posttransplant consolidation cycles of D-VTD or VTD, the stringent CR (sCR) and CR or better were 29% and 39%, respectively, compared with 20% and 26%. In addition, the level of minimal residual disease negativity was 64% for D-VTD versus 44% (P <.0001) for VTD alone.2

Transplant-ineligible patients. The phase 3 VISTA trial compared bortezomib (Velcade), melphalan, and prednisone (VMP) with MP for previously untreated MM. The median time to disease progression was 24.0 months for VMP but just 16.6 months for MP (hazard ratio [HR], 0.48; P = <.001). Both the overall response rate (ORR) and CR, too, were higher for VMP than MP: 71% versus 35% (P <.001) and 30% versus 4% (P <.001), respectively.2

The phase 3 SWOG study S0777 compared bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) with Rd in newly diagnosed MM “without intention for immediate ASCT.” The median follow-up was 55 months, after which the median PFS was 43 months for VRd compared with 30 months for Rd (HR, 0.712; P = .0037). The ORRs were 82% and 72%, respectively, and the CR rates, 16% and 8%.2

Carfilzomib

The phase 3 ENDEAVOR trial looked at carfilzomib (Kyprolis) and dexamethasone (Kd) versus BD for RRMM. The median PFS was almost twice as long with Kd than it was for BD: 18.7 versus 9.4 months (HR, 0.53; P <.0001). As well, the ORR was higher for Kd (77%) than BD (63%; P <.0001). OS was also higher for Kd compared with BD (47.6 vs 40.0 months; P = .010).2

ASPIRE investigated KRd and RD for use in RRMM. The results were higher for KRd across the board2:

  • ORR: 87.1% versus 66.7% (P <.001)
  • CR rate or better: 31.8% versus 9.3%
  • sCR rate: 14.1% versus 4.3%
  • Median OS: 48.3 versus 40.4 months (HR, 0.79; P .0045)

Ixazomib

A phase 3 TOURMALINE-MM1 study examined ixazomib, lenalidomide, and dexamethasone (IRd) against placebo, lenalidomide, and dexamethasone (placebo-Rd) in RRMM previously treated with 1 to 3 lines. The median PFS was 20.6 versus 14.7 months (HR, 0.74; P = .01) for IRd compared with placebo-Rd. Where high-risk cytogenetics were concerned, the median PF remained higher for IRd: 21.4 and 20.6 months. The ORRs were 78.3% and 72.0% (P = .04), respectively, and the CR rate plus VGPR, 48% versus 39%.2

TOURMALINE-MM3 studied ixazomib maintenance versus placebo following ASCT. After a median follow-up of 31 months, ixazomib produced a superior median PFS compared with placebo: 26.5 months versus 21.3 months (HR, 0.72; P .0023). Depth of response was also greater for the ixazomib group (46%) than the placebo group (32%).2

“PIs are an indispensable agent for increasing PFS and quality of life, and are achieving a deeper response, especially in subgroups of patients with poor prognosis,” the authors concluded. “These results will contribute to better understanding and decision making of the optimal maintenance therapy in MM.”

Several clinical studies are currently underway evaluating various combinations of PIs and other novel agents for safety and efficacy.

References

1. Omel J. How proteasome inhibitors work. CrowdCare Foundation website. myelomacrowd.org/myeloma-101-proteasome-inhibitors-work/. Published June 30, 2016. Accessed January 30, 2020.

2. Ito S. Proteasome inhibitors for the treatment of multiple myeloma. Cancers (Basel). 2020;12(2). doi: 10.3390/cancers12020265.