August 2013, Vol 2, No 5

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Multiple Myeloma: Novel Agents Emerge in Initial Therapy, Refractory Setting

Wayne Kuznar

Uncategorized

Advances in the understanding of the biology of multiple myeloma (MM) and the identification of new drugs have resulted in improved management of MM, including patients who are refractory to proteasome inhibitors and immunomodulatory agents.
An update on initial therapy was offered by Donna E. Reece, MD, director, Program for Multiple Myeloma and Related Diseases, Princess Margaret Cancer Center, Toronto, Ontario, Canada.

Myeloma consists of at least 7 subtypes based on cytogenetics and molecular features. The highest-risk subtypes by fluorescence in situ hybridization are t(4;14), t(14;16), del(17p), and chromosome 1 abnormalities; all are recognized as adverse prognostic factors.

An evolving US treatment algorithm recommends treating younger patients, particularly those with standard-risk disease, with regimens based on novel agents such as thalidomide, bortezomib, and lenalidomide before autologous stem cell transplantation (ASCT).

After ASCT, bortezomib-based therapies have increased the median progression-free survival (PFS) to 3 years compared with 2 years achieved with older regimens such as VAD (vincristine, doxorubicin, and dexamethasone) or thalidomide plus dexamethasone induction, Reece said. Bortezomib-containing regimens as induction also yield better response rates and overall survival (OS) compared with these older regimens. The inclusion of bortezomib, particularly in a 3-drug regimen, seems important for high-risk disease, as indicated by the recent integrated analysis of the 4 phase 3 studies of bortezomib induction.

Thalidomide as a single agent or in conjunction with corticosteroids as post-ASCT maintenance improved both PFS and OS in a meta-analysis of 7 phase 3 clinical trials. Lenalidomide maintenance has been assessed in 2 phase 3 trials, demonstrating significant prolongation of PFS and time to progression.

“Advantages of consolidation [moderately intensive combination therapy given for several cycles after recovery from ASCT] compared with long-term maintenance therapy include a finite period of treatment and, potentially, a lower and more predictable cost,” said Reece. In the future, consolidation with a 3-drug combination would ideally be integrated into therapy, particularly in the high-risk setting.

In elderly patients, the addition of a novel agent (ie, thalidomide, bortezomib, or lenalidomide) to melphalan and prednisone results in a better antimyeloma effect, although the incidence of grade 3/4 toxicity is relatively high. Lenalidomide plus weekly dexamethasone is also a promising regimen in elderly patients.

Approaches to Double-Refractory MM
More frequent use of proteasome inhibitors and immunomodulatory agents as part of initial therapy and in the maintenance setting has contributed to drug resistance, which portends a poor prognosis. New therapeutic strategies are needed in this challenging population, said Robert Z. Orlowski, MD, PhD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX.

Carfilzomib, Pomalidomide
Potent analogues of existing MM drugs, such as carfilzomib and pomalidomide, have demonstrated clinical efficacy in the double-refractory setting, resulting in the recent approval of both drugs. Carfilzomib in patients with relapsed or refractory MM was associated with an overall response rate (ORR) of 15.4%, with a median duration of response of 7.8 months. Median OS was 15.6 months in the overall population and 11.9 months in the double-refractory subgroup.

Pomalidomide has been shown to be active against double-refractory MM in several phase 2 and phase 3 trials. The ORR was 31%, PFS was 3.8 months, and OS was 13.8 months in patients with relapsed/refractory MM who were randomized to pomalidomide with weekly dexamethasone.

In a phase 3 trial, patients were randomly assigned to either pomalidomide and low-dose dexamethasone or single-agent high-dose dexamethasone. In patients with double-refractory disease, median PFS in the pom?­alidomide arm was 3.2 months versus 1.7 months in the high-dose dexamethasone arm (P<.001); median OS was not reached in the pomalidomide arm, whereas median OS in the high-dose dexamethasone arm was 7.4 months (P<.001), said Orlowski.

KSP Inhibitor
A novel strategy targets kinesin-spindle protein (KSP), said Orlowski. ARRY-520 is a potent, highly selective KSP inhibitor that was studied in a phase 2 trial as both a single agent (cohort 1) and in combination with low-dose dexamethasone (cohort 2). After a median treatment time of 3.9 months, the ORR was 22%, and the median duration of response was 5.4 months. In cohort 1, 53% had disease refractory to bortezomib, and 75% had disease refractory to lenalidomide. Of 32 patients in cohort 1 with assessable response, ORR was 16% (5 partial responses).

Daratumumab
Daratumumab is an investigational human monoclonal antibody that has received breakthrough therapy designation from the FDA for the treatment of patients with MM who have received at least 3 prior lines of therapy or who are double refractory to a proteasome inhibitor and an immunomodulatory agent. A phase 1/2 dose escalation study in 32 patients with relapsed MM showed at least a minimal response in 8 of the 12 patients who received 4 mg/kg or higher of daratumumab, with no major safety issues.

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