Recent advances in the treatment of multiple myeloma have dramatically altered the trajectory of disease, as providers now have several efficacious agents in various drug classes at their disposal. At the National Comprehensive Cancer Network 12th Annual Congress: Hematologic Malignancies, Shaji K. Kumar, MD, Mayo Clinic, Rochester, MN, discussed evidence-based management strategies for patients with newly diagnosed multiple myeloma, including the role of autologous stem cell transplantation and posttransplant maintenance therapy.
Therapeutic Agents for Newly Diagnosed Multiple Myeloma
According to Dr Kumar, the ideal initial therapy for newly diagnosed multiple myeloma should rapidly and effectively control disease, reverse disease-related complications, decrease the risk of early death, be easily tolerated with minimal/manageable toxicity, and not interfere with stem cell collection if needed. The current standard of care is based on the results from the randomized, open-label, phase 3 SWOG S0777 trial, which showed that the addition of the proteasome inhibitor bortezomib to the reference treatment lenalidomide plus dexamethasone significantly improved progression-free survival (PFS) and overall survival (OS), with acceptable toxicity. As indicated by the proportion of patients with a very good partial response or better, the triplet combination also yielded a deeper response, Dr Kumar reported.
“Based on these data, we strongly believe that the combination of proteasome inhibitor and immunomodulatory drug should be the standard-of-care therapy for myeloma patients,” he said. “Nevertheless, not everyone in the world can use lenalidomide and bortezomib.”
A randomized trial comparing the combination of bortezomib-thalidomide-dexamethasone with bortezomib-cyclophosphamide-dexamethasone as induction before high-dose therapy and autologous stem cell transplantation demonstrated improved overall response—and deeper response—with the thalidomide regimen. Although peripheral neuropathy was higher in the thalidomide arm, hematologic toxicity was significantly reduced.
“Clearly, there’s a balance between efficacy and toxicity that clinicians must consider when treating this disease,” said Dr Kumar, who noted that changing drugs within the proteasome inhibitor combination to achieve better outcomes may also help reduce toxicity.
Although not designed for a formal comparison, 2 phase 2 trials at the University of Chicago showed that the addition of carfilzomib to lenalidomide-dexamethasone yielded significantly better responses than historically seen with other combination regimens. Before the combination becomes standard of care, however, data from ongoing phase 3 trials are needed, Dr Kumar acknowledged.
Duration of Induction Therapy and the Role for Transplantation
Determining when to stop induction therapy is another challenge for providers. Based on the paucity of data, said Dr Kumar, it’s not clear whether patients with poor response to initial therapy benefit from additional alternative therapy prior to stem cell transplantation. A retrospective analysis of myeloma patients (N = 539) who underwent an autologous stem cell transplantation after having achieved less than a partial response to first-line induction chemotherapy showed no difference in PFS or OS between people who went directly to transplant and those who switched therapy prior to transplant.
The impact of autologous stem cell transplantation, however, has been more conclusively demonstrated. A recent study by Attal and colleagues found that patients undergoing transplantation had a much deeper response, with almost 14% higher minimal residual disease negativity compared with those receiving consolidation therapy with lenalidomide, bortezomib, and dexamethasone.
“Stem cell transplantation continues to have a very important role and should be considered early in all eligible patients,” said Dr Kumar.
Following transplantation, trials have increasingly shown the benefit of maintenance therapy in this population. A meta-analysis found that patients who received lenalidomide maintenance therapy had better PFS and OS compared with those who did not. According to Dr Kumar, however, patients with advanced and/or high-risk disease did not benefit from lenalidomide maintenance.
“In our practice, we tend to use bortezomib maintenance for these high-risk patients,” he said, “but the role of double transplant is also being explored.”
Meta-analysis of phase 3 studies in Europe showed better outcomes with tandem autologous stem cell transplantation, especially in patients with del(17p) and t(4;14) genetic mutations.
“These data are still early, but they suggest the need for a discussion with patients about tandem transplant, particularly in high-risk disease,” said Dr Kumar.
Supportive Care Approaches
Finally, Dr Kumar highlighted the role of supportive care. As nearly 30% of patients with myeloma present with some degree of renal deficiency, reversing renal dysfunction should be a priority for providers. In patients with light chain–induced acute renal failure, he reported, bortezomib-doxorubicin-dexamethasone therapy induces a high rate of myeloma and renal responses. According to Dr Kumar, bisphosphonates, which have been shown to prevent skeletal-related events and improve OS in the first 4 months of treatment, are also an integral part of supportive care, along with management of infections and toxicity.