China
Africa
Explore chapters and articles related to this topic
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Onyx Pharmaceuticals has also developed a second-generation, orally available proteasome inhibitor, oprozomib (ONX 0912), which selectively inhibits the chymotrypsin-like activity of both the constitutive proteasome (PSMB5) and the immunoproteasome (LMP7). It was granted orphan drug status by the FDA for the treatment of Waldenström’s macroglobulinaemia and multiple myeloma in 2014 and has been in a number of hematological clinical trials, although it has not yet reached the approval stage.
Plasma Cell Neoplasms
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
There literally appears to be no shortage of new investigational agents for patients with relapsed-and-refractory MM (Figure 12.12). Some of the candidate agents that are now either in early phase trials or moving on to phase I–II studies, include next-generation proteasome inhibitors, such as marizomib and oprozomib, a kinesin spindle protein inhibitor, filanesib, a cyclin dependent kinase inhibitor, dinaciclib, a selective BCL2 inhibitor, venetoclax (ABT-199), a pan-PIM kinase inhibitor, LGH-447, and a selective nuclear export inhibitor, KPT-276. Marizomib appears to have activity in patients who are refractory to bortezomib and carfilzomib, and further studies are in progress. There is also interest, and now some clinical evidence supporting a role for T-cell mediated immunity in myeloma. A phase II study of 48 patients with relapsed myeloma following multiple prior therapies, including proteasome inhibitors and IMiDs and auto-SCT, demonstrating durable clinical responses in about 60%, and very good partial responses in 27%, following treatment with pembrolizumib combined with pomalidomide and dexamethasone. Good results have also been observed following combinations of other immune checkpoint inhibitors, such as ipilimumab, a CTLA-4 inhibitor, several PD-1 antibodies, nivolumab, pidiluzumab and PDL-1 antibodies, such as durvalumab. Interestingly, anti-CD19 CAR T-cells have also demonstrated activity in targeting B-cell maturation antigen (BCMA) in relapsed-and-refractory myeloma patients. BCMA is expressed on myeloma cells and has been implicated in the disease pathogenesis. It is conceivable that CAR T-cell could also be developed against other myeloma antigens, such as CD38 and CD44v6. Novel approaches to target patients with MM and dysregulated MYC, by inhibiting the micro-RNA 17-92 (miR-17-92) cluster through degradation of its precursor RNA, by MIR17PT inhibitor, has now been tested successfully in myeloma cell lines. If these in vitro findings of MIR1PT in combination with bortezomib, dexamethasone and melphalan, are confirmed, then early-phase clinical trails should follow to target MYC, historically a difficult target.
Risk adapted post-transplant maintenance in multiple myeloma
Published in Expert Review of Hematology, 2019
In the next five years, we anticipate that more data will accumulate on maintenance in NDMM after ASCT, establishing the preferred maintenance for each risk group. We anticipate increasing use of combination treatment as maintenance and new data regarding the monoclonal antibodies. These may turn out to be preferred treatments for high risk patients. Trials are under development that will randomize patients that achieve minimal residual disease negativity to limited duration therapy and continuous duration therapy to progression in an attempt to answer the question whether patients who have no detectable disease benefit from ongoing therapy exposure. Just as the treatment of multiple myeloma has grown from doublet therapy to triplet therapy and now four drug induction, we believe maintenance therapy will follow suit. In the United States the current standard of care is lenalidomide maintenance however we anticipate combination maintenance therapy including combination such as lenalidomide ixazomib, lenalidomide daratumumab and ixazomib daratumumab will be explored. Other antibodies including elotuzumab and isatuximab will move into the maintenance space given their low toxicities. The ongoing development of the other proteasome inhibitor oprozomib will also be evaluated in the maintenance of patients achieving a response. Ongoing research into the role of minimal residual disease and research into the optimal ways of measuring this endpoint are ongoing.
Ixazomib: a novel drug for multiple myeloma
Published in Expert Review of Hematology, 2018
Saurabh Zanwar, Jithma Prasad Abeykoon, Prashant Kapoor
Marizomib, is another investigational unique PI that irreversibly inhibits all three catalytic subunits (β1, β2, and β5) of 20S, thereby potentially conferring superior efficacy and lacking cross-resistance with other PIs [84,85]. Although single agent studies have shown rather modest responses, marizomib in combination with pomalidomide and dexamethasone shows robust responses in relapsed/refractory MM and owing to its good penetrability across the blood–brain barrier, it has been found to be effective in patients with CNS myeloma [86–88]. Oprozomib is another oral PI belonging to the epoxyketone group that selectively and irreversibly inhibits the chymotrypsin-like 20S proteasome subunit [22]. In a phase 1/2 study of oprozomib that enrolled 87 patients with MM among other relapsed hematological malignancies, the most common grade ≥3 AEs on the phase 1b dose were GI, including diarrhea seen in approximately one-third of the patients, followed by nausea and vomiting. The ORR with the phase 2 dose was promising at 27% (3/11 all PR) in carfilzomib-refractory patients and 33% (4/12; 2 PR and 2 VGPR) in carfilzomib-sensitive patients with MM [89]. These newer PIs represent exciting options in the treatment of relapsed MM.
Proteasome inhibitors for the treatment of multiple myeloma
Published in Expert Opinion on Pharmacotherapy, 2018
Emilia Scalzulli, Sara Grammatico, Federico Vozella, Maria Teresa Petrucci
Oprozomib induces apoptosis in MM cells resistant to bortezomib-based therapies. It also seems to enhance the antimyeloma activity of bortezomib, lenalidomide–dexamethasone and a pan-histone deacetylase inhibitor. A phase Ib/II single-agent open-label study [59] was conducted in 106 patients to determine its MTD and safety profile. Oprozomib was administered following two schedules: once daily on days 1, 2, 8, and 9 of a 14-day cycle (schedule 1) or on days 1–5 of a 14-day cycle (schedule 2) at the initial dose of 150 mg per day and escalated in 30 mg increments to a maximum of 330 mg per day. The MTD of oprozomib was determined as 300 mg per day in the first schedule and 240 mg per day in the second schedule. Preliminary data suggests that step-up dosing is associated with improved tolerability and fewer adverse events. Single-agent oprozomib has promising antitumor activity.