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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.
Cell cycle inhibitors for the treatment of acute myeloid leukemia: a review of phase 2 & 3 clinical trials
Published in Expert Opinion on Emerging Drugs, 2020
Nadya Jammal, Caitlin R. Rausch, Tapan M. Kadia, Naveen Pemmaraju
Dinaciclib is a CDK1, 2, 5, and 9 inhibitor that has shown activity in inducing apoptosis and growth inhibition in preclinical studies of leukemia cells [47–49]. In a phase II cross-over multi-center study in patients with R/R AML, dinaciclib was compared to gemtuzumab ozogamicin [49,50]. Of the 13 patients enrolled, activity was seen in 60% of patients. Overall with a transient reduction in circulating blasts was seen within a week of administration of dinaciclib, however, no complete remissions were achieved. Gastrointestinal toxicity, liver test abnormalities, and hypotension were the most common toxicities reported. Electrolyte abnormalities and TLS was observed, with one patient requiring emergent dialysis. With the high incidence of TLS seen with the use of various CDK inhibitors in treating CLL, monitoring during initial administration of CDK inhibitors is suggested.
New drugs in early development for treating multiple myeloma: all that glitters is not gold
Published in Expert Opinion on Investigational Drugs, 2020
Luca Bertamini, Francesca Bonello, Mario Boccadoro, Sara Bringhen
Dinaciclib is a selective inhibitor of cyclin-dependent kinases (CDK) 1/2/5/9, a family of proteins involved in the regulation of the cell cycle and in DNA repair. In MM, CDK activity is often dysregulated, and loss of CDK inhibitors has been demonstrated in MM cells. In particular, the inhibition of CDK5 enhances MM cell sensitivity to PIs, making this mechanism of action a target of interest [77]. Dinaciclib was initially tested as monotherapy in a phase I/II trial on RRMM patients. ORR was modest (11%) and median PFS and OS were 3.5 and 18.8 months, respectively. Main toxicities were hematologic, gastrointestinal (nausea and diarrhea) and fatigue, although G3-4 AEs were rare, with the exception of neutropenia [78]. A phase I trial with dinaciclib-Vd is currently ongoing (NCT01711528).
Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach
Published in Expert Opinion on Investigational Drugs, 2019
Daniel J. Lee, Joshua F. Zeidner
A randomized phase II study of dinaciclib versus gemtuzumab ozogamicin, a CD33 antibody-drug conjugate, in relapsed/refractory AML was conducted, and the experience with dinaciclib was reported [71]. Dinaciclib was given at 50 mg/m2 IV over 2 hours on day 1 of cycle 1, and intra-patient dose escalation was permitted to 70 mg/m2 IV over 2 hours on day 1 of each subsequent 21-day cycle based on an earlier phase I dose-escalation study in multiple advanced cancers [72]. Fourteen patients with AML received dinaciclib on this study. Toxicities were frequent, including diarrhea and grade 3 or higher fatigue. Half of the participants developed tumor lysis syndrome, and one subject died of hyperacute tumor lysis that led to acute renal failure. No objective responses were observed. Pharmacodynamic studies from 1 AML and 3 ALL patients treated with dinaciclib showed decreases in MCL-1 in all specimens at 4 hours post-treatment, but these decreases were short-lived, and MCL-1 expression returned to baseline by 24 hours. Decreased phosphorylated Rb protein was also observed in 1 participant, but 2 subjects had nearly undetectable phosphorylated Rb pre-treatment. Additional in vitro studies demonstrated improved MCL-1 downregulation and apoptosis of primary AML samples with prolonged dinaciclib exposure [71].