What Are the Best Ways to Use New Proteasome Inhibitors and IMiDs in Myeloma?

First-line treatment options and new therapies for the treatment of multiple myeloma were recently examined at the 17th International Congress on Hematologic Malignancies in NYC.

Historically, chemotherapy and immunomodulators (IMiDs) were first-line treatment options for patients with multiple myeloma. The challenge with traditional chemotherapy does not specifically target malignant cells and as a result, normal, healthy cells are damaged. The older IMiDs, thalidomide and lenalidomide, usually produced toxic adverse effects because high doses were required. The advent of a new class of drugs, the proteasome inhibitors (PSIs), and a newer IMiD expanded the list of active, efficacious drugs available for the treatment of multiple myeloma. This article, based on a lecture presented at the 17th International Congress on Hematologic Malignancies, focuses on appropriate use and strategies with the next-generation proteasome inhibitors and IMiDs.

The National Comprehensive Cancer Network (NCCN) multiple myeloma guidelines suggest a preferred primary regimen with bortezomib or lenalidomide plus a(n) additional agent(s). If the patient relapses or fails initial therapy, NCCN guidelines recommend repeating primary treatment or initiating bortezomib, bortezomib plus corticosteroid or chemotherapy, using a multi-agent chemotherapy regimen, or initiating treatment with the the newest addition to the guidelines — carfilzomib.² The FDA approved 2 novel agents within the last year. These includean IMiD, Pomalyst (pomalidomide), and a second generation PSI, Kyprolis (carfilzomib),for the treatment of relapsed or refractory multiple myeloma in patients who received at least 2 prior treatments, including bortezomib and lenalidomide, with progressive disease within 60 days of last treatment. NCCN does not currently include pomalidomide in its guidelines, but various clinical trials justify its use in clinical practice. In patients with relapsed or refractory multiple myeloma, treatment options are limited and novel agents or combinations can become life-saving strategies.

Pomalidomide is a thalidomide—analogue like lenalidomide and has a similar structure. However, it is more potent than earlier agents and functions differently. Protein degradation is inhibited by a combination of immunomodulators and proteasome inhibitors. A Phase II trial assessed patients randomized to receive pomalidomide (POM) or POM plus low-dose dexamethasone (LoDEX) until discontinuation. Overall response rate and progression-free survival was superior in the combination group, with a 3 month average extended survival, yet median duration of response was the same between treatment arms. The data suggests that POM had an adequate duration of response but efficacy is improved with the addition of an adjunct agent. Disadvantages of adding a corticosteroid were the higher rates of neutropenia (in patients 65 years and older) and pneumonia. The next question then became,“what is the appropriate dose of the adjunct agent for superior results?”

A similar study was conducted using LoDEX and high dose dexamethasone (HiDEX). Clinicians found that in patients with renal dysfunction, POM plus LoDEX yielded longer progression-free and overall survival compared with POM plus HiDEX. Two additional combination regimens were studied to determine clinical use. POM plus cyclophosphamide and prednisone only yielded a 6% complete response in patients refractory or relapsed with lenalidomide or refractory to the lenalidomide-bortezomib combination. Patients that were refractory to the combination group had a 12% complete response with POM combination, which is in accordance with pomalidomide’s indication.

Another trial aiming for improved results studied combination regimen with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma. The regimen was well tolerated with rapid responses and ORR of 73%. Efficacy data from this trial was encouraging and suggests that newer agents, pomalidomide and bortezomib, are superior to older chemotherapy agents in refractory or relapsed multiple myeloma.

The next generation proteasome inhibitors are the newest options for the treatment of myeloma. Carfilzomib was the first out of the group of new agents to be approved and has the same indication as pomalidomide. Several other next generation proteasome inhibitors are in the pharmaceutical pipeline:ixazomib, oprozomib, and marizomib. Carfilzomib is one of the irreversible proteasome inhibitors that may be clinically superior as a result of its mechanism .The most common adverse effects upon starting carfilzomib is fatigue and shortness of breath, and over time, ejection fraction of the heart may decrease.

In a single agent study, carfilzomib yielded excellent ORR of 78% in 266 relapsed or refractory patients and was well tolerated with potential for prolonged administration. Extensive cardiac and pulmonary safety monitoring was conducted and the most common adverse events were dyspnea (42%), cough (26%), pneumonia (13%), and cardiac failure grade > 3 (6%).

An additional study with carfilzomib in combination with POM and LoDEX also provided adequate response in relapsed or refractory patients. A high overall response rate of 50% was observed with this regimen, however, only 32 patients were enrolled in this trial. Carfilzomib may be useful in clinical practice to overcome the challenges of resistant myelomas that often lead therapy failures. Next generation PSIs are beneficial not only because they are available orally, but also because they are linked with less peripheral neuropathy. Novel PSIs are undergoing clinical trials and “place in therapy” for these agents has not been established.

Treatment of multiple myeloma has evolved over the past decade. The first generation PSIs and original IMiDs opened many doors for patients with failed chemotherapy regimens and poor outcomes. Despite their efficacy, these agents have many disadvantages, such as adverse effects, risk of secondary malignancies, and inconvenient administration. The newest IMiD is significantly more potent than its precursors, enabling clinicians to administer a lower dose, better control toxicity and adverse effects, and also help patients achieve improved outcomes. The newer PSIs fulfill the unmet need of administration convenience — they are available orally, which may lead to better patient compliance and outcomes. Clinical consensus has established that pomalidomide and carfilzomib are effective and extend life expectancy in refractory patients and are easily combined with other agents to form new regimens. Additional agents in the pipeline should further expand the scope of agents available for multiple myeloma patients and positively influence clinical outcomes.

References:

• Medina PJ, Shord SS. Chapter 135. Cancer Treatment and Chemotherapy. In: Talbert RL, DiPiro JT, Matzke GR et al. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011.
• National Comprehensive Cancer Network. Multiple Myeloma Guidelines. Version 1.2013. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf