Proteasome Inhibitors in High-Risk Multiple Myeloma

Ravi Vij, MD, MBA:The fact is that patients who have high-risk features seem to have a better outcome when a proteasome inhibitor is used as part of their treatment. And in that regard, patients who have a (4;14) translocation, or 17p deletion especially, there are data that suggest the use of a proteasome inhibitor in combination improves progression-free survival. So that is one thing we keep in mind when we decide on a long-term strategy for patients with high-risk disease.

For patients who have symptomatic, aggressive relapse, we do certainly use 3-drug regimens over 2-drug regimens unless a patient has a performance status that does not permit us to deliver a 3-drug regimen. Regimens employing daratumumab and Kyprolis are the popular 3-drug regimens that people have used in recent years. Depending on what they have had in their prior line of therapy, there are a number of 3-drug regimens that can be employed, and daratumumab can be paired with pomalidomide, lenalidomide, or bortezomib. Likewise, Kyprolis can be paired with Revlimid, Cytoxan, or pomalidomide as well. These are popular regimens that are used depending on the given situation.

In regard to ixazomib, lenalidomide, and dexamethasone, that is a regimen that is now FDA approved for the treatment of patients with relapsed and refractory multiple myeloma. The use of ixazomib has been shown to improve progression-free survival and depth of response compared with lenalidomide and dexamethasone alone. Also, with the use of ixazomib, it has been shown that patients have deeper responses the longer they are on therapy. Ixazomib is a convenient once-a-week drug that is well tolerated. It has few adverse effects. Some patients complain of neuropathy. Some patients have some GI [gastrointestinal] intolerance to the drug. It is rare to cause rashes. Generally, the 3-drug regimen of ixazomib, lenalidomide, and dexamethasone is not much more toxic than lenalidomide and dexamethasone alone.

So the 3-drug regimen does offer benefit for patients who desire an oral treatment. Not only in patients who are older where transportation may be an issue, but even in patients who are young and are employed, it is very disruptive to their schedule often to have to take off work to come to a doctor’s office to get treatment. And I think in that scenario, the 3-drug regimen of ixazomib, lenalidomide, and dexamethasone, again, offers a convenient option.

Because proteasome inhibitors are thought to be the treatment of choice for patients with high-risk disease, such as those who have a translocation (4;14) or deletion 17p, the oral regimen of ixazomib, lenalidomide, and dexamethasone certainly offers an attractive proposition as well.

Transcript edited for clarity.

Case: 75-Year-Old Man With Symptomatic R/R Multiple Myeloma

January 2015

• A 75-year-old man was diagnosed with multiple myeloma; R-ISS stage I
• PMH: hypertension; coronary artery disease post stent placement
• Patient was treated with lenalidomide + dexamethasone for 9 months; transplant-ineligible due to age and performance status
• Patient achieved a VGPR, discontinued treatment thereafter due to patient request

September 2018

• On routine follow-up 3 years later, patient presents with new-onset back pain and generalized fatigue
• Imaging: multiple new lytic lesions with compression fractures
• Laboratory results:
  • Hb, 10.7 g/dL
  • Ca²⁺, 9.3 mg/dL
  • Creatinine, 1.1 mg/dL
  • M-protein, 3.2 g/dL
• Cytogenetics/FISH: del (17p) discovered at relapse
• ECOG PS: 2