Sagar Lonial

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

PurposeCharacterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.MethodsForty-two patients were randomized to receive bortezomib 1.0 or 1.3xa0mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (nxa0=xa021, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.ResultsTwelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112xa0L/h for first dose; 15–32xa0L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0xa0mg/m2 group.ConclusionsBortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3xa0mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

New Targets and New Agents in High-Risk Multiple Myeloma.

Advances in the treatment of multiple myeloma have resulted in dramatic improvements in outcomes for patients. The newly emerging profiling of mutations emerging as a consequence of large prospective sequencing studies such as the CoMMpass Study or other efforts from European investigators are not further helping to define the place and role for personalized medicine in myeloma. While mutations such as NRAS, KRAS, and BRAF do occur in myeloma, it is not clear that targeting them as a single drug strategy will result in meaningful responses or durations of response. Personalized medicine in multiple myeloma at this time likely entails the use of risk-based approaches for maintenance therapy, the use of current biology-based treatments such as proteasome inhibitors, and immunomodulatory agents, with an eye towards the use of mutation-specific treatments in the setting of minimal residual disease or in concert with biology-based treatments overall.

Plerixafor in combination with granulocyte-colony-stimulating factor after chemotherapy increases mobilization efficiency in patients with lymphoma or myeloma: results of a Phase II clinical trial.

We tested whether adding plerixafor to G‐CSF mobilization after chemotherapy would increase the proportion of patients collecting the target number of CD34+ cells/kg in 1 day of apheresis to >75%.

Clinical potential of carfilzomib in the treatment of relapsed and refractory multiple myeloma

Treatment of refractory and/or relapsed multiple myeloma has been a challenging problem for over 20 years. However, we have made significant progress addressing this disease with the use of bortezomib, the first in class proteasome inhibitor, and the immunomodulatory agents, thalidomide and lenalidomide. Carfilzomib, the second-generation proteasome inhibitor, has also been approved for treatment of relapsed/refractory multiple myeloma. Carfilzomib is a highly selective and potent inhibitor of proteasome chymotrypsin-like activity. Phase I and II clinical trials have reported an acceptable toxicity profile, with manageable thrombocytopenia and anemia being the most common side effects. Peripheral neuropathy, a frequent dose-limiting side effect of bortezomib, was rare. Further, carfilzomib demonstrated encouraging single- agent activity and appeared to be effective even in patients refractory to bortezomib. Based on these promising data, carfilzomib is moving forward into Phase III trials for relapsed multiple myeloma and is also being investigated as front-line combination therapy for patients with newly diagnosed myeloma.