Lenalidomide Maintenance for Multiple Myeloma Improves Survival

Three studies published this week show that lenalidomide improves progression-free and overall survival as a maintenance therapy in multiple myeloma, despite its link to other primary cancers.

The results of a phase III randomized, global trial (MM-015) of melphalan–prednisone–lenalidomide (MPR) followed by lenalidomide maintenance therapy in multiple myeloma show the regimen significantly improves progression-free survival in newly diagnosed patients who are ineligible for an autologous stem cell transplant. The greatest benefit was seen among patients who were between 65 and 75 years of age. The trial results are published in the New England Journal of Medicine.[1]

Shown is a drawing of a myeloma cell (abnormal plasma cell) making M proteins

Compared to MPR alone, MPR plus lenalidomide maintenance therapy (MPR-R) increased progression-free survival by 17 months. Patients in the MPR-R arm had a median progression-free survival of 31 months compared to 14 months for those in the MPR arm (P < .001). Response rates were better for those in the lenalidomide maintenance arm-77% compared to 68% for MPR alone (P < .001). The benefit was best among those patients between 65 and 75 years of age, but not for those who were older than 75 (P = .001). The study showed a 66% reduction in rate of progression when lenalidomide was added after induction, compared to patients who were treated with MPR alone (P < .001). The melphalan–prednisone (MP) arm had a median progression-free survival of 13 months-not different from the MPR arm result. The benefit of adding lenalidomide maintenance was seen for all subgroups of patients, other than those over 75 years of age.

The 3-year overall survival rate was 70% in the MPR-R group, 62% in the MPR group and 66% with MP. Toxicity included grade 4 neutropenia and thrombocytopenia. Approximately 16% of patients had to discontinue treatment in the MPR-R group, compared to 14% in the MPR, and 5% in the MP group. Secondary cancers were seen in 7% of MPR-R patients, 7% of MPR patients, and 3% of MP patients after a 3-year analysis. Four deaths in the MPR-R and MPR groups were attributed to lenalidomide.

Lenalidomide Maintenance in Patients After Stem-Cell Transplant

A second and third study, also published in the New England Journal of Medicine compared lenalidomide maintenance therapy to placebo in multiple myeloma patients after a stem cell transplant.

The second study, the Cancer and Leukemia Group B (CALGB) 100104 phase III study from Philip L. McCarthy and colleagues, shows that lenalidomide given as a maintenance therapy for multiple myeloma patients younger than 71 after a stem cell transplant results in longer time to disease progression and significantly improves overall survival in patients with myeloma.[2] Of patients who received lenalidomide, 20% had progressive disease, compared to 44% of those who received a placebo (P < .001). Median time to progression was 46 months for patients on the maintenance therapy compared to 27 months for those in the placebo group (P < .001). However, prolonged lenalidomide exposure was associated with a high level of toxicity and secondary cancers-18 patients (8%) who received lenalidomide were diagnosed with secondary primary cancers compared to 6 patients (3%) who were in the placebo group.

The third study randomized patients younger than 65 years of age after a first-line transplant to either maintenance or placebo until relapse.[3] Lenalidomide improved patient progression-free survival by 18 months (41 months compared to 23 months for the placebo group, P < .001). Overall survival after 4 years was the same in both study arms. As with the McCarthy et al study, patients taking lenalidomide experienced secondary cancers and higher toxicity compared to those on placebo.

Multiple myeloma is a plasma-cell cancer. Plasma cells are white blood cells that produce antibodies-the neoplastic cells accumulate in the bone marrow where they interfere with normal blood cell production. The cancer accounts for about 13% of all blood cancers. The median age at diagnosis is typically 70 years. New agents such as lenalidomide, thalidomide, and bortezomib, as well as the recently available autologous stem-cell transplantation technique have improved survival for those multiple myeloma patients younger than 60 years of age.

Lenalidomide as Standard of Care for Multiple Myeloma?

Lenalidomide (Revlimid) is an analog of thalidomide but more potent-able to inhibit tumor necrosis factor-alpha with a much higher potency and less severe side effects. The drug was first approved for multiple myeloma patients by the US Food and Drug Administration (FDA) in 2006 in combination with dexamethasone for those patients who have received at least one prior therapy. The drug is not without issues however. The FDA has an ongoing safety review of lenalidomide due to its role in causing new primary cancers in patients.

The primary tumors observed with lenalidomide exposure are generally acute myeloid leukemia and other myelodysplastic syndromes. Lenalidomide is an alkylating agents and the “leukemogenic potential” of these types of agents-usually observed after at least 3 years of follow-up has been well-established according to the MM-015 study authors.

The current debate, according to Ashraf Z. Badros, of the University of Maryland School of Medicine, and author of an editorial in the New England Journal of Medicine, is whether therapy should be of fixed duration or include maintenance of a remission state.[4] Badros also highlights that a progression-free survival end point may not be an appropriate end point for a longer maintenance therapy. However, he points out that “overall survival in myeloma is a complex topic that depends on disease biology and on the success of post-relapse therapy.”

Badros states that all myeloma patients eventually receive lenalidomide. The question is whether patients should be receiving the drug early in their treatment to improve survival. The field is currently divided on whether there is enough evidence to say lenalidomide is a standard of care. Thus far, these current studies-both for stem cell transplant patients and those ineligible for a transplant-support lenalidomide maintenance therapy after a careful assessment of both risk and benefits. The choice lies with patient and physician.

“These findings fill a gap that existed previously in terms of data on whether maintenance therapy with lenalidomide prolongs the time to disease progression after initial therapy,” said Dr. McCarthy in a statement. “We now have evidence that it does, in this and the two other lenalidomide studies that are presented in this issue of the Journal. This shows that patients with multiple myeloma now have options for prolonging the response to initial therapy. The next steps will be trying to improve on these responses by adding new agents that may prove even more effective in combination with lenalidomide following transplant.”

Other promising treatments for multiple myeloma include pomalidomide, carfilzomib, a proteasome inhibitor. “There are a lot of details and questions that need to be highlighted and addressed so we can improve future clinical trials,” Badros said.

Reference

1. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.

2. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781.

3. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

4. Badros AZ. Lenalidomide in myeloma--a high-maintenance friend. N Engl J Med. 2012;366:1836-1838