Treating Newly Diagnosed Multiple Myeloma in Transplant-Eligible Patients

San Francisco, CA—Recent advances in the treatment of patients with multiple myeloma have dramatically altered the trajectory of the disease, as providers now have several efficacious agents in various drug classes at their disposal. At the 2017 NCCN Hematologic Malignancies Congress, Shaji K. Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, MN, provided management strategies for newly diagnosed multiple myeloma, including the role of autologous stem-cell transplant (ASCT) and posttransplant maintenance therapy.

Newly Diagnosed Disease

According to Dr Kumar, the ideal initial therapy for patients with newly diagnosed multiple myeloma should rapidly and effectively control the disease, reverse disease-related complications, reduce the risk for early death, be easily tolerated with minimal or manageable toxicity, and not interfere with stem-cell collection when needed.

The current standard of care is based on the results of the phase 3 clinical trial SWOG S0777, which showed that the addition of the proteasome inhibitor bortezomib (Velcade) to lenalidomide (Revli­mid) plus dexamethasone significantly improved progression-free survival (PFS) and overall survival (OS), with acceptable toxicity. As reflected by the proportion of patients with very good partial response or better, the triplet combination also yielded a deeper response, reported Dr Kumar.

“Based on these data, we strongly believe that the combination of a proteasome inhibitor and an immunomodulatory drug should be the standard-of-care therapy for patients with myeloma,” said Dr Kumar. “Nevertheless, not everyone in the world can use lenalidomide and bortezomib,” he added.

A randomized clinical trial comparing the combination of bortez­omib, thalidomide, and dexa­methasone versus bortezomib, cyclophosphamide, and dexamethasone as induction therapy before high-dose therapy and ASCT demonstrated better overall response and deeper response with the thalidomide regimen than the cyclophosphamide regimen. Although the incidence rate of 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, adding 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 clinical trials at the University of Chicago showed that the addition of carfilzomib (Kyprolis) to lenalidomide plus dexamethasone yielded significantly better responses than historically seen with other combination regimens. However, before this combination becomes the standard of care, data from ongoing phase 3 clinical trials are needed, Dr Kumar acknowledged.

Duration of Induction Therapy and the Role for Transplant

Determining when to stop induction therapy is another challenge for providers. Based on the paucity of data, it is unclear whether patients with poor response to initial therapy benefit from additional alternative therapy before ASCT. Retrospective analysis of 539 patients with multiple myeloma who had an ASCT after having achieved less than a partial response to first-line induction chemotherapy showed no difference in PFS or OS between patients who moved directly to transplant and those who switched therapy before transplantation.

However, the impact of ASCT has been more conclusively demonstrated. A recent study by Attal and colleagues showed that patients undergoing ASCT had a much deeper response, with nearly 14% higher minimal residual disease negativity compared with those receiving consolidation therapy with lenalidomide, bortezomib, and dexamethasone (Attal M, et al. N Engl J Med. 2017;376:1311-1320).

“Stem-cell transplantation continues to have a very important role and should be considered early in all eligible patients,” said Dr Kumar.

After transplantation, clinical trials have increasingly shown the benefit of maintenance therapy in this patient population. A meta-analysis showed that patients who received lenalidomide maintenance therapy had better PFS and OS than those who did not receive lenalidomide maintenance therapy. However, patients with advanced and/or high-risk disease did not benefit from lenalidomide maintenance therapy, Dr Kumar said.

“In our practice, we tend to use bortezomib maintenance for these high-risk patients, but the role of double transplant is also being explored,” said Dr Kumar.

A meta-analysis of phase 3 studies in Europe showed better outcomes with tandem ASCT, especially in patients with deletion 17p and t(4;14) 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. Because nearly 30% of patients with multiple myeloma have some degree of renal deficiency, reversing renal dysfunction should be a priority for providers.

In patients with light chain–induced acute renal failure, bortezomib plus doxorubicin and dexamethasone therapy induces a high rate of renal responses in patients with multiple myeloma, he said.

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, in addition to the management of infections and toxicity, said Dr Kumar.

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