“We are largely agreed that for patients in the newly-diagnosed setting, combination 3-drug regimens are better than 2,” added Dr Lonial. “You try to address clonal heterogeneity by hitting multiple targets with multiple agents.”

In the relapse setting, however, the benefits of combination therapy are less clear, Dr Lonial acknowledged. And for subsequent steps of treatment, there is more variation in how different centers approach therapy.

“The debate regarding the role of maintenance or the optimal duration of therapy continues, but the ability to reach a minimal residual disease-negative state appears to translate to a better outcome for all patients, especially those with high-risk disease,” noted Dr Kumar.

Biomarkers are not yet used in myeloma treatment planning to the same extent that they are in other cancer types, like HER2-positive breast cancer or epidermal growth factor receptor mutations in lung cancer. “But what we do know is that genetic markers predict for short vs long durations of remission,” noted Dr Lonial. “If we see high-risk genetics, we tailor a more-intense maintenance therapy.”

For Dr Lonial’s high-risk patients, that means attenuated dose-schedule RVD for posttransplant maintenance therapy.2

There is some evidence that a separate three-drug regimen KRD (carfilzomib, lenalidomide, and dexamethasone), may also be an effective initial therapy for high-risk myeloma, in lieu of VRD—but cardiotoxicity is a concern, noted Dr Kumar and others.3

Dr Lonial’s group has found VRD so effective that they rarely deviate from its administration as an initial therapy, he told Cancer Therapy Advisor.

Dr Kumar’s approach to posttransplantation consolidation and maintenance therapy includes lenalidomide maintenance or bortezomib-based maintenance for standard- and intermediate-risk patients, respectively, or carfilzomib or bortezomib-based maintenance for high-risk patients.3

Increasing Number of Options for Myeloma Relapse

Most patients eventually experience relapse, making long-term management of myeloma as a chronic disease, rather than “cure,” the realistic goal of treatment.

However, an increasing number of options exist for patients who have experienced relapse, including new classes of drugs, Drs Lonial and Kumar emphasized.

“I think what is really exciting right now is that we have not one but two monoclonal antibodies; they will help revolutionize treating patients at every phase of their disease,” Dr Lonial told Cancer Therapy Advisor.

“My guess is that we’re going to bring monoclonal antibodies into the newly diagnosed myeloma setting and really get patients into good responses very quickly following their initial induction therapy—even better than we are getting now. And then the question is going to be, do we incorporate antibodies as part of maintenance therapy? To me, that’s a really important part. We don’t have data for this now, but I think you’ll see data in the next 6 to 12 months that we’re starting to use antibodies in all phases of disease treatment, not just at the end phase.”

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He anticipates that checkpoint inhibitors are poised to play an important role in combination therapy, as well.

“Checkpoint inhibitors as a single agent don’t have a lot of activity in myeloma, but there are 2 datasets now looking at checkpoint inhibitors in combination with IMiDs, both with lenalidomide and pomalidomide, that suggest drug resistance can be overcome and you get responses where you didn’t with a single agent. I think incorporating checkpoint inhibitors into our current treatment paradigm, to induce long-term anti-tumor immunity, is going to be a really important part of what the next few years is going to be about,” Dr Lonial said.

Dr Kumar agreed that the monoclonal antibodies and the immune therapies appear particularly promising.

“The increasing numbers of treatment options and the increased understanding of the genetic heterogeneity of myeloma also has opened the doors for personalized medicine in myeloma, and many trials are planned to evaluate the possibility of developing targeted therapies for different types of myeloma,” he said.

“It’s a rapidly evolving time,” Dr Lonial said. “It’s going to be hard to say what the standard of care will be, because it keeps moving—and that’s a good thing for patients.”

References

  1. Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity [published online ahead of print January 4, 2016]. Bone Marrow Transplant. doi:10.1038/bmt.2015.307.
  2. Lonial S, Boise LH, Kaufman J. How I treat high-risk myeloma. Blood. 2015;126(13):1536-1543.
  3. Rajkumar SV, Kumar Shaji. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proceedings. 2016;91(1):101-119.