Currently, there are three major controversies in multiple myeloma patient management: early versus late transplant, treat or observe ‘high-risk’ smoldering myeloma, and whether to use maintenance therapy. The latter is predominantly an issue following autologous stem cell transplantation.

In May, one of the world’s premier medical journals, the New England Journal of Medicine, published three articles about clinical trials comparing Revlimid ^[1] (lenalidomide) maintenance versus observation.  In two of the studies, Revlimid maintenance was given following autologous stem cell transplantation.  In the third study, Revlimid maintenance was given following conventional therapy in patients not considered candidates for transplants.  For all three studies, a computer selected which patients received Revlimid maintenance and which were only observed.

These articles are briefly summarized as follows:

• Dr. Michel Attal and his colleagues from the French Myeloma Group reported on 614 patients with a median follow up of 45 months. The median event-free survival (time to progressive disease) was 40 months in the Revlimid maintenance group versus 23 months for the observation group. However, there was no improvement in the overall survival of the patients (abstract ^[2]).
• Dr. Philip McCarthy  and his colleagues from the U.S. Intergroup reported on 460 patients with a median follow up of 34 months. The median event-free survival was 46 months in the Revlimid maintenance group versus 27 months in the observation group. With multiple analyses in a subgroup of patients, an overall survival benefit was observed (abstract ^[3]).
• Dr. Antonio Palumbo from Italy, along with his colleagues, reported on 459 patients with a median follow up of 30 months. This study was a non-transplant study with three treatment groups: melphalan ^[4] (Alkeran) plus prednisone ^[5]; melphalan plus prednisone and Revlimid; and melphalan plus prednisone and Revlimid followed by Revlimid maintenance. They observed a median event-free survival of 13 months, 14 months, and 31 months, respectively. No improvement in survival was demonstrated at the time of the study analysis (abstract ^[6]).

So, it appears there are three studies, all confirming the improvement in the time to progression, with one showing (in subgroup analysis) an improvement in survival.

Yet, there are disadvantages to maintenance therapy as well:

• Nine percent to 27 percent of the patients discontinued Revlimid maintenance due to side effects.
• The risk of developing a second cancer increased from 1 percent to 3 percent in the observation groups to 5 percent to 7 percent in the Revlimid maintenance groups.
• Only one study demonstrated an improvement in survival.
• It is unknown if re-treatment with the standard 25 mg dose of Revlimid will induce responses when the 10 mg dose used for maintenance is no longer effective (e.g. will the sub-therapeutic Revlimid dose drive the development of a resistant clone).
• Revlimid maintenance places a financial burden on society with a cost of approximately $165,000 per year.
• Finally, none of these studies included a quality of life assessment to gauge the patients’ perceptions of the consequences of chronic therapeutic administration of Revlimid.

Maintenance therapy with other anti-myeloma agents has also been reported.

Thalidomide ^[7] (Thalomid) post-transplant has shown improved event-free survival in some studies. Unfortunately, long-term thalidomide use is associated with significant side effects, minimizing its potential use in this setting.

Preliminary data on Velcade ^[8] (bortezomib) maintenance have been reported.  After conventional therapy, Velcade appears to be effective as a maintenance therapy in combination with other agents. Velcade maintenance after autologous transplant also appears promising, but these trials are not yet mature enough to completely evaluate.

Given this controversy, the International Myeloma Working Group, an international group of over 150 myeloma experts, wrote, “Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.”

Therefore, the question of “To maintain, or not to maintain?” has not clearly been answered.  Each patient should discuss the aforementioned controversies with their treating physician before deriving a final decision.

For more information, see related Beacon news about the Revlimid maintenance studies ^[9] and the IMWG consensus statement ^[10] about maintenance therapy.

Dr. David H. Vesole is Co-Chief of the Myeloma Division and Director of Myeloma Research at The John Theurer Cancer Center at Hackensack University Medical Center. Dr. Vesole writes a quarterly column for The Myeloma Beacon.