Management of High-Risk Multiple Myeloma

Sagar Lonial, MD: This is a young gentleman, 54 years old, who presented with symptomatic myeloma and had a constellation abnormalities at his initial presentation, that included translocation 11;14, which we know often times can be a good risk prognostic finding; had deletion of chromosome 13, which we now know is neutral; as well as deletion of 17p, which we now think is a high-risk genetic abnormality. And so, this is a patient who clearly needed initial induction therapy and presented with what I would consider a high-risk phenotype at the time of initial diagnosis.

Prognosis in the context of abnormal cytogenetics is really a moving target in myeloma, and the reason I say that is that we have patients with deletion of 17p, who actually do quite well for a long period of time with aggressive induction, consolidation, and then maintenance therapy. And that has been published by Ajay Nooka from our group in leukemia a couple of years ago. There are other patients who, despite our best efforts and aggressive induction, consolidation, and maintenance, have very, very rapid progression and early death often within 2 years. And so, this is a patient who I would think about who has high-risk disease with deletion of 17p, but I think we can offer them a pretty reasonable progression-free and overall survival with aggressive therapy. If that patient reacts differently, then we would obviously change our therapy to try and mitigate some of that. But I think with the new agents that we have across the board, including second-generation proteasome inhibitors and now monoclonal antibodies, the outcomes for high-risk patients are actually better than they’ve ever been before.

When considering management of patients who present with high-risk disease, there is a little bit of controversy here about what the optimal induction regimen would be. At our center, this patient would have received a bortezomib/lenalidomide/dexamethasone or VRd-based induction. We have over 700 patients worth of data on this, about one-quarter of this were high-risk, and we think our outcomes certainly with that regimen are very reasonable. I think there’s almost nobody who would try and use a doublet for the management of a patient with high-risk disease at this time point. The alternative that one could consider to use would be KRd, or carfilzomib in combination with lenalidomide and dexamethasone. There are emerging data from a couple of small phase II clinical trials suggesting that carfilzomib with lenalidomide/dexamethasone is actually superior to bortezomib based on historical controls. But, again, there may be some adverse events associated with the use of carfilzomib that are not seen when bortezomib is used. And so, I think that’s an area that is open for discussion.

At our center, similar to what this patient received, we would have used VRd as the initial induction therapy. We would have collected stem cells after 4 cycles of therapy and would have taken this patient to a single cycle of high-dose therapy and autologous transplant. The role of tandem transplant is also being explored, predominantly by the Europeans. And there are 2 data sets around this question about single versus tandem transplant. In the European trial, patients who had high-risk disease, who received a tandem auto transplant, seemed to have better progression-free survival than the patients with high-risk disease that received a single transplant. However, in the United States trial where that exact same question was evaluated, there was no difference in progression-free survival and no difference in overall survival.

And I think the reason that we see this discrepancy between the European and the United States trial is access to drugs. More patients in the United States trial got VRd as part of their initial induction therapy, whereas in Europe more patients got VCd, or bortezomib with cyclophosphamide and dexamethasone. And I think that really impacted the long-term outcomes for both of those trials.

Finally, as we talk about maintenance, the use of bortezomib maintenance does clearly have an impact in the context of high-risk disease. That’s what this patient received and in our case here, our center would have used a VRd maintenance and consolidation that has a much better track record, maybe more challenging to give. But if you can give it, the outcomes are superior to even what we see with single-agent bortezomib in the maintenance setting.

Transcript edited for clarity.

Multiple Myeloma With High-Risk Features

July 2017

• A 54-year-old Caucasian male presented to his physician with anemia
• Bone marrow biopsy showed 43% plasma cells
• FISH t(11:14), deletion 13, deletion 17p
• Diagnosis: multiple myeloma with high-risk features
• The patient was treated with lenalidomide, bortezomib, and dexamethasone (VRD) followed by autologous stem cell transplant, and bortezomib maintenance