Novel Therapeutics Have Revolutionized Multiple Myeloma Treatment

Jean-Luc Harousseau, MD

Novel therapeutics, including thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade), have revolutionized the treatment of multiple myeloma. At the John Theurer Cancer Center’s New Frontiers in the Management of Solid and Liquid Tumors conference, held in Hackensack, New Jersey, Jean-Luc Harousseau, MD, head of the Department of Clinical Hematology, and director of the CentreRené Gauducheau, Saint-Herblain, France, discussed how these novel agents have advanced treatment in both elderly and younger patients.

Elderly Patients

Harousseau discussed frontline treatments for multiple myeloma patients aged >65 years, in whom outcomes have improved through the addition of novel agents to the previous standard treatments (eg, melphalan plus prednisone (MP) or high-dose dexamethasone plus chemotherapy). Harousseau highlighted key findings from ongoing research in the frontline clinical management of multiple myeloma:

• Combination melphalan, prednisone, and thalidomide (MPT) significantly improves response rate and progression- free survival (PFS) versus MP, but only marginally improves overall survival (OS). Harousseau said it is significant to note that OS benefits with MPT have been found in multiple myeloma patients aged >75 years.
• The VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial demonstrated the superiority of melphalan, prednisone, and bortezomib (MPV) over MP in response rate, PFS, and OS.
• Combining lenalidomide with low-dose dexamethasone is associated with improved survival over lenalidomide plus high-dose dexamethasone.
• A phase III international trial at the International Myeloma Foundation is now examining whether it is better to use MP- or dexamethasone-based combinations in elderly patients.

Harousseau also discussed how maintenance therapy has improved outcomes in elderly patients with multiple myeloma:

• Induction treatment with bortezomib, melphalan, prednisone, and thalidomide, followed by maintenance with bortezomib and thalidomide (VMPT-VT), has superior response rates and PFS versus bortezomib, melphalan, and prednisone (VMP) without maintenance.
• Initial treatment with melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance (MPR-R) significantly improved PFS versus either MP or MPR without maintenance.

Despite these promising results, questions remain regarding the use of maintenance therapy in elderly patients with multiple myeloma. Harousseau indicated that future research needs to determine the optimal duration of therapy; examine whether promising PFS results will translate into improved OS; and explore whether maintenance is required after all induction regimens.

Younger Patients

Harousseau also discussed how novel therapeutics have improved upon the current standard of care in multiple myeloma patients aged <65 years.

Adding combination treatment with novel agents, such as VTD (bortezomib, thalidomide, and dexamethasone), to standard treatment before and after autologous stem cell transplantation (ASCT) significantly improves the rate of complete response (CR) plus very good partial response (VGPR). This should translate into improved PFS, according to Harousseau. One explanation for the improved results, according to Harousseau, is that some novel agents work more effectively in patients with a poorer prognosis, such as bortezomib’s efficacy in patients with a t(4;14) translocation.

In the maintenance setting, Harousseau said thalidomide has shown benefits in younger patients. However, the optimal dose and treatment duration is unknown. Treatment for >1 year has produced serious adverse events, and there is no consensus regarding which patients will benefit from using the drug.

The International Myeloma Foundation 2005-02 trial found that maintenance with long-term, low-dose lenalidomide demonstrated a significant PFS benefit in almost all subgroups of patients with multiple myeloma. However, patients receiving lenalidomide maintenance were shown to have a higher risk of secondary malignancies, usually occurring >2 years after treatment.

In the future, researchers hope to be able to identify subgroups of patients in which the use of novel agents can eliminate the need for ASCT with initial treatment, delaying its use until salvage therapy. Nevertheless, Harousseau was optimistic about the near-term future of multiple myeloma treatment, pointing to several experimental therapies, including pomalidomide, carfilzomib, and elotuzumab, already being evaluated in clinical trials.