Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Noopur Raje, MD, has disclosed that she has received consulting fees from Amgen, Celgene, Millennium, and Onyx.
One of the major advances in our treatment of multiple myeloma (MM) has been the development and FDA approvals of proteasome inhibitors (PIs) targeting the ubiquitin–proteasome pathway, a tightly regulated degradation process. Proteasome inhibition leads to apoptosis in MM because cancerous cells often have greater proteasome activity and are more susceptible to the proapoptotic consequences of proteasome inhibition. Currently, we can choose among 3 FDA-approved PIs for our patients with MM: bortezomib, ixazomib, and carfilzomib. Given that all 3 PIs are active in MM, how can we decide which one best suits a patient’s medical needs and personal preferences? The decision often comes down to differences in dosing, safety profile, and efficacy in risk-defined subgroups.
Patients With Comorbidities and/or Toxicity Concerns
Bortezomib and ixazomib are both reversible PIs suitable for patients with comorbidities or concerns about specific toxicities. Bortezomib can be administered either intravenously or subcutaneously. It combines well with immunomodulatory drugs (IMiDs), such as lenalidomide and thalidomide, and is active both in combination and as monotherapy in first-line and relapsed/refractory settings. Because its pharmacokinetics are not affected by renal impairment, bortezomib should be preferentially used in patients with renal dysfunction. However, it is associated with sensory peripheral neuropathy and worsening symptoms in those with preexisting peripheral neuropathy.
Ixazomib is an oral PI, making it more convenient than intravenous or subcutaneous dosing. It is well tolerated with lower rates of neuropathy than bortezomib, making it an ideal PI for older patients with comorbidities. It also combines well with IMiDs. In the phase III TOURMALINE-MM1 trial, which led to the FDA approval of ixazomib, patients with relapsed/refractory MM demonstrated a significantly prolonged median PFS with ixazomib plus lenalidomide/dexamethasone vs placebo plus lenalidomide/dexamethasone (20.6 vs 14.7 months, respectively; P = .01).
Patients With High-Risk Disease
In contrast to bortezomib and ixazomib, carfilzomib is an irreversible PI given intravenously and is highly active in MM. The new dosing schedule of weekly carfilzomib as shown in the ARROW study at ASCO 2018 is more convenient, and dose escalation has demonstrated a dose response to carfilzomib. It has been studied in combination with monoclonal antibodies such as daratumumab and elotuzumab as well as with IMiDs. Notably, carfilzomib is very effective in patients with high-risk disease. For example, in a phase II trial of carfilzomib, thalidomide, and dexamethasone as induction and consolidation therapy for newly diagnosed MM, the subgroup with high-risk disease (defined as adverse cytogenetics and/or International Staging System stage 3) had a CR rate comparable to those with standard-risk disease (66% vs 58%, respectively). However, carfilzomib should be used with caution in patients with a history of cardiac disease because new and worsening cardiac events have been observed with carfilzomib.
How do you choose among the PIs for your patients with MM? Please share your insights in the comments box!
To see what 4 other experts and I would recommend for patients with MM in different clinical scenarios, visit the Interactive Decision Support Tool: Therapy Selection for MM.