Novel Agents Emerge in Initial Therapy, Refractory Setting

TON - September 2013 Vol 6 No 8 published on September 23, 2013 in Hematologic Cancers
Wayne Kuznar

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 of the Program for Multiple Myeloma and Related Diseases, Princess Margaret Cancer Centre, Toronto, Ontario, Canada, at the 2013 American Society of Clinical Oncology Annual Meeting.

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 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 transplant (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 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.

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 population, said Robert Z. Orlowski, PhD, MD, professor in the Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, Texas.

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 pomalidomide arm was 3.2 months versus 1.7 months in the high-dose dexamethasone arm (P <.001), and 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 rate 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 US Food and Drug Administration 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.

Related Items
High Tumor Microsatellite Instability a Marker for Lynch Syndrome, More Common Condition Than Generally Expected
Wayne Kuznar
TOP - November 2018, Vol 11, No 3 published on November 21, 2018 in Lynch Syndrome
Pomalidomide Added to the Regimen in First Relapse Extends PFS in Multiple Myeloma
Wayne Kuznar
TOP Web Exclusives published on October 9, 2018 in Multiple Myeloma
High Tumor Microsatellite Instability a Marker for Lynch Syndrome, More Common Condition Than Generally Expected
Wayne Kuznar
TON - September 2018, Vol 11, No 4 published on September 19, 2018 in Lynch Syndrome
A Dynamic FDA Has Led to More Rapid Cancer Drug Development
Wayne Kuznar
TOP Web Exclusives published on September 11, 2018 in FDA Approvals, News & Updates
NCCN Issues First Guideline for Immunotherapy-Related Adverse Events
Wayne Kuznar
TOP Web Exclusives published on September 11, 2018 in Side-Effects Management
NCCN Updated Guideline Adds Treatment Options for HER2-Positive Breast Cancer, Emphasizing CDK4/CDK6 Inhibition in Hormone-Sensitive Disease
Wayne Kuznar
TOP Web Exclusives published on August 15, 2018 in NCCN News
NCCN Issues First Guideline for Immunotherapy-Related Adverse Events
Wayne Kuznar
JHOP Web Exclusives published on August 10, 2018 in Immunotherapy
Regorafenib Dose-Escalation Strategy Potentially a New Standard in Metastatic Colorectal Cancer
Wayne Kuznar
TOP - August 2018, Vol 11, No 2 published on August 3, 2018 in Colorectal Cancer
Immunotherapy Combination Shows Durable Responses in Mismatch Repair–Deficient Metastatic Colorectal Cancer
Wayne Kuznar
TOP - August 2018, Vol 11, No 2 published on August 3, 2018 in Immunotherapy
Palliative Care Use Dismal Among Patients with Hematologic Malignancies
TON - March 2018, Vol 11, No 1 published on March 9, 2018 in Conference Correspondent, ASH, Palliative Care, Hematologic Cancers
Last modified: May 21, 2015