Developments in Induction Therapy for Multiple Myeloma

Drs. Jasielec and Jakubowiak review the state of the art in selecting an optimal induction therapy regimen for patients with multiple myeloma.

In a recent review article, Drs Jasielec and Jakubowiak of the Department of Medicine & Comprehensive Cancer Center at The University of Chicago summarized the role of proteasome inhibitors and immunomodulatory drugs in treatment of new cases of multiple myeloma (MM).

Oncologists continually monitor but do not treat patients with asymptomatic or smoldering MM. Monitoring is important because symptoms of MM, such as bony disease, hypercalcemia, renal dysfunction, or anemia, signal the need to begin treatment with induction therapy.

A course of induction therapy followed by a hematopoietic stem cell transplant is not an option for all patients, but most patients younger than 65 years without major comorbidities are eligible. To decide which induction regimen to use, physicians may classify patients by genetic risk factors. Patients at higher risk may have genetic abnormalities associated with diminished survival, including t(4;14), t(14;16), 1q21, del17p, and chromosome 13 deletions.

For induction therapy, 2-drug combination treatments are used in standard-risk patients and 3-drug combination treatments that include bortezomib are used in high-risk patients. Jasielec and Jakubowiak speculate that, in the future, virtually all eligible patients, including standard-risk patients, will receive 3-drug combination therapies for MM as induction therapy before stem cell transplant.

According to Jasielec and Jakubowiak, combination therapy with (1) lenalidomide, bortezomib, and dexamethasone (RVD) or (2) cyclophosphamide, bortezomib, and dexamethasone (CVD) is currently in favor, “… owing to good tolerability and consistently high response rates.” Three- and 4-drug combinations with the new-generation proteasome inhibitor carfilzomib have been evaluated, although Jasielec and Jakubowiak state that data are not yet sufficient to recommend carfilzomib in initial therapy.

The results of continuing clinical trials may change the preferred treatment strategy. For instance, lenalidomide, bortezomib, and dexamethasone with a fourth agent—pegylated liposomal doxorubicin—shows superior efficacy to historical results with the 3-drug combination.

In a phase-2 trial, a 3-drug regimen of bortezomib, thalidomide, and dexamethasone (VTD) showed superiority to thalidomide and dexamethasone (TD) in terms of pretransplant complete response rates.

More research is required to develop evidence-based conclusions on the optimal regimen for each patient. Although treatment algorithms have been proposed for treatment of patients with poor prognostic factors, such as the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART), treatment algorithms have not yet been validated in prospective studies.

The newest agents, carfilzomib, ixizomib, and elotuzmab, will further expand treatment options for patients with MM. Identifying the optimal regimen for the majority of patients remains a challenge for oncologists faced with a variety of emerging therapies to treat this complex disease.