Challenges Associated with Multiple Myeloma and Myelofibrosis

San Francisco—As rare diseases, multiple myeloma and myelofibrosis, are difficult to manage and associated with high costs. Due to new therapies and evolving strategies that are effective but complex, the challenges are increasing.

At the AMCP meeting, a pharmacist and 3 physicians addressed these issues during a satellite symposium titled Myelofibrosis and Multiple Myeloma: Strategies for Effective Decision-Making.

Gary M. Owens, MD, president of Gary Owens Associates, said multiple myeloma is the second most prevalent hematologic malignancy behind non-Hodgkin’s lymphoma. Dr. Owens cited data from the American Cancer Society that in 2012, an estimated 21,700 new cases of multiple myeloma would be diagnosed and 10,710 deaths would occur due to multiple myeloma.

The disease, which is treatable but incurable, mostly affects older adults, with 75% of cases found in people ≥60 years of age, according to information from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database. Researchers from SEER concluded the incidence of multiple myeloma is highest in African Americans.

Based on patients diagnosed with multiple myeloma between 2001 and 2007, the 5-year survival rate associated with multiple myeloma was approximately 41%. Dr. Owens said that in recent years, the prognosis for people diagnosed with multiple myeloma has improved due to new FDA-approved therapies such as pulse corticosteroids, immunomodulators (thalidomide and lenalidomide), and a protease inhibitor (bortezomib).

JAK2 Inhibitors

Martha L. Arellano, MD, assistant professor of hematology and oncology at Emory University in Atlanta, Georgia, said myelofibrosis is among the myeloproliferative neoplasms, which are clonal disorders originating in pluripotent stem cells. Characteristics of myelofibrosis include clonal myeloid proliferation, dysregulation of kinase signaling, abnormal cytokine expression, and shortened survival.

According to Dr. Arellano, between 16,000 and 18,000 people have myelofibrosis, and the average age of diagnosis is between 60 and 65 years of age. The median survival of the disease is 6 years. The most frequent symptoms are fatigue, worsened quality of life, inactivity, early satiety, insomnia, concentration problems, and abdominal discomfort.

When treating myeloproliferative neoplasms, there are several goals, including managing symptoms, preventing thromboembolic complications, reducing malignant clone size, and replacing malignant stem cells through allogeneic transplantation. Dr. Arellano said healthcare professionals commonly use prognostic scoring systems to help select patients who could undergo allogeneic transplantation or take experimental therapies. Allogeneic transplantation is limited to younger, higher risk patients, according to Dr. Arellano.

Patients diagnosed with myelofibrosis often take immunomodulators such as thalidomide and lenalidomide and combination therapies such as thalidomide plus prednisone and lenalidomide plus prednisone. A new drug class, janus kinase 2 (JAK2) inhibitors, will likely play a major role in treating the disease, according to Dr. Arellano.

In November 2011, the FDA approved ruxolitinib (a JAK2 inhibitor) as the first drug specifically intended to treat myelofibrosis. The FDA approved ruxolitinib based on the results of the COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment) I and II trials. Other JAK2 inhibitors are in phase 2 development, including SAR302503, pacritinib, CYT387, lestaurtinib, givinostat, and LBH539.

Dr. Arellano said the results of trials involving JAK2 inhibitors have shown they are effective at decreasing splenomegaly and improving quality of life, and also have acceptable tolerability.

Multiple Myeloma Challenges

Jonathan L. Kaufman, MD, assistant professor of hematology/oncology at Emory University in Atlanta, Georgia, provided an overview of multiple myeloma treatments, including the combination of thalidomide plus dexamethasone, bortezomib plus dexamethasone, lenalidomide plus dexamethasone, lenalidomide plus low-dose dexamethasone, and bortezomib plus thalidomide plus dexamethasone.

Dr. Kaufman cited trials that found bortezomib plus thalidomide plus dexamethasone resulted in an increase in response to induction therapy, with 31% to 35% of patients having a complete response or near complete response and 50% to 62% having ≥ a very good partial response.

Dr. Kaufman said meta-analyses concluded that 3-drug therapies were superior to 2-drug therapies in terms of significantly higher response rates and progression-free survival. In addition, bortezomib-containing regimens provided a survival advantage when used as part of induction therapy.

However, there have been no randomized trials comparing bortezomib plus thalidomide plus dexamethasone with bortezomib plus dexamethasone or lenalidomide plus dexamethasone. There are also proteasome inhibitors being developed in combination with lenalidomide and dexamethasone that Dr. Kaufman said may be effective at treating multiple myeloma. He cited studies indicating carfilzomib was safe and effective as a second- or third-line therapy, while elotuzumab plus lenalidomide was another potential treatment option.

Of the FDA-approved therapies, Dr. Kaufman was especially intrigued with bortezomib. In patients with previously untreated multiple myeloma, a phase 3 trial found that adding bortezomib to melphalan and prednisone proved superior to treating them with melphalan plus prednisone, according to Dr. Kaufman. After 5 years of follow up, there was a median overall survival benefit of 13.3 months (56.4 months vs 43.1 months; P=.0004). Other studies concluded that there was no significant difference in administering bortezomib therapy once weekly versus twice weekly in terms of progression-free survival (P=1.00) or overall survival (P=.54).

In January 2012, the FDA approved subcutaneous bortezomib for all of the indications the drug had been approved to treat intravenously, including multiple myeloma and mantle cell lymphoma after ≥1 prior therapy.

Future Treatments

James T. Kenney, Jr, RPh, MBA, pharmacy operations manager at Harvard Pilgrim Health Care in Boston, Massachusetts, cited a report from the Pharmaceutical Manufacturers Association that found there were 49 medicines and vaccines in development for multiple myeloma in 2011.

From a managed care perspective, Mr. Kenney said multiple myeloma is difficult to manage because there are few FDA-approved therapies and a need to manage adverse events. However, he suggested a few options such as applying appropriate utilization management criteria, including step edits, quantity limits, tiered formularies, and prior authorization.

The biggest challenge for formulary managers when it comes to multiple myeloma, according to Mr. Kenney, is managing the pipeline and understanding what drugs may become approved. He said newer drugs are becoming more complex, making it more difficult to achieve patient adherence and compliance. Managers must also be aware of cost trends, off-label drug use, timeliness of drug delivery, and transitioning patients from retail to specialty pharmacy.

To determine the value of medications, Mr. Kenney recommended that pharmacy and therapeutics committees analyze clinical trials and their end points, with the following being especially useful: overall survival, complete response, progression-free survival, objective response rate, disease-free survival, and time to progression.