A group of myeloma experts from the International Myeloma Working Group recently published a consensus statement on maintenance therapies for myeloma patients.

In their statement, the experts reviewed the main findings from previous clinical trials that investigated the impact of maintenance therapies containing the novel agents thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib).

Maintenance therapy is a prolonged, and often low-dose, form of treatment given to myeloma patients after their initial therapy. The goal of maintenance therapy is to prevent disease progression for as long as possible while maintaining a favorable quality of life. Maintenance therapy is different from consolidation therapy, which usually involves a shorter course of treatment with the goal of deepening patients’ responses to the initial therapy.

Based on these results, the experts came to the following conclusions for myeloma patients considering maintenance therapy:

The experts did not come to a consensus on the use of Revlimid as maintenance therapy. Revlimid maintenance increased progression-free survival in younger patients, which according to some experts speaks in favor of using Revlimid maintenance. However, Revlimid maintenance was also associated with an increased risk of secondary cancers, which according to some experts cannot be neglected when deciding whether to use Revlimid maintenance. The experts, therefore, said that longer-term survival data is needed before they can make a recommendation in favor, or against, Revlimid maintenance.

The experts stated that thalidomide maintenance is a treatment option for younger patients after stem cell transplantation, since thalidomide maintenance is associated with an increase in progression-free survival. For older patients who are not candidates for stem cell transplantation, the use of thalidomide maintenance is less clear because trial results were mixed in this patient population.

According to the experts, there is currently insufficient evidence available to make specific recommendations for, or against, Velcade maintenance therapy.

Additionally, the experts did not recommend maintenance therapy with interferons or corticosteroids alone.

Revlimid

Summary:

The experts found that Revlimid maintenance is associated with a significant increase in progression-free survival in both younger patients undergoing stem cell transplantation as well as older patients receiving conventional chemotherapy. Results of one study also showed a significant survival benefit with Revlimid maintenance therapy. However, the experts acknowledged that myeloma patients with high-risk chromosomal abnormalities do not benefit from Revlimid maintenance.

In addition, the experts pointed out that Revlimid maintenance therapy may be associated with an increased risk of secondary cancers (see related Beacon news), which they recommended physicians bear in mind when deciding whether to prescribe Revlimid maintenance.

If the decision is made to use Revlimid maintenance therapy, the experts recommended a starting dose of 10 mg per day for both younger and elderly standard-risk patients. They added that both continuous therapy, as well as a “three weeks on, one week off” approach, may be effective.

Additional Information:

Results of two clinical trials, the United States CALGB 100104 trial and the French IFM 2005-02 trial, suggest that Revlimid maintenance may be effective in younger, standard-risk myeloma patients who received a stem cell transplant (see related Beacon news).

Results of the CALGB 100104 trial showed that after a median follow-up of 28 months, the median time to disease progression was significantly longer for patients who received Revlimid maintenance than for patients who received a placebo (48 months versus 31 months).

Patients who received Revlimid maintenance also had a significantly longer event-free survival than patients who received a placebo (42 months versus 22 months).

However, they also experienced more cases of low white blood cell counts, low red blood cell counts, low platelet counts, and infections.

Results of the IFM 2005-02 trial showed that after a median follow-up of 36 months, the median progression-free survival was significantly longer in patients who received Revlimid maintenance (41 months versus 24 months). However, the progression-free survival and overall survival were shorter in patients who had high-risk chromosomal abnormalities.

According to the authors of the review, a notable result of both the CALGB 100104 and IFM 2005-02 trials was the increased occurrence of secondary cancers among patients who received Revlimid maintenance.

Last year, after months of controversy over the apparent increase of secondary cancers among myeloma patients receiving Revlimid maintenance, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) began safety reviews of Revlimid. The EMA concluded that the benefits of Revlimid continue to outweigh its risks. However, the agency also recommended that the prescribing information for Revlimid be updated with a warning about the risk of new cancers (see related Beacon news).  The FDA investigation is still ongoing.

The experts commented that further studies are needed to evaluate the true risk of secondary cancers to identify risk factors and to develop strategies for their prevention in myeloma patients. According to the experts, “physicians and patients must weigh the benefits of Revlimid maintenance therapy against the low but relevant risk of secondary cancers.”

In addition to the CALGB 100104 and IFM 2005-02 trials, results of an Italian study indicated that Revlimid maintenance also prolongs the progression-free survival of elderly myeloma patients treated with conventional chemotherapy (31 months versus 13 months).

Thalidomide

Summary:

The experts found that thalidomide maintenance after stem cell transplantation may increase progression-free survival and, to a lesser degree, overall survival. However, they pointed out that patients with high-risk chromosomal abnormalities did not benefit from thalidomide maintenance.

The experts added that the lowest active dose of thalidomide is 50 mg per day and that the duration of thalidomide therapy should be limited to one year in order the limit the risk of severe side effects.

For older patients who are not candidates for stem cell transplantation, the experts pointed out that the use of thalidomide maintenance is less clear because trial results were mixed in this patient population.

Additional Information:

Studies of thalidomide maintenance therapy have been primarily in younger patients receiving a stem cell transplant.

In a small number of clinical trials investigating the impact of thalidomide maintenance in elderly patients, roughly half of the patients had been exposed to thalidomide during initial therapy. Results of these trials showed a significant increase in progression-free survival, but not overall survival, in elderly patients treated with thalidomide maintenance (see related Beacon news).

However, the experts were unable to confirm whether elderly patients who had not received thalidomide during initial therapy would benefit more from thalidomide maintenance than patients who had previously received thalidomide.

They indicated that thalidomide maintenance may be a valuable option in standard-risk elderly patients, although elderly patients may not tolerate thalidomide as well as younger patients.

According to the experts, most clinical trials have shown that thalidomide maintenance increases the quality of response and prolongs the progression-free survival of younger myeloma patients (see related Beacon news 1, 2, and 3). Additionally, these trials indicate that the risk for disease progression is similar in patients who received thalidomide during both their maintenance and initial phases and in patients who received thalidomide during their maintenance phase only.

However, the impact of thalidomide maintenance on overall survival rates is not as clear. While some studies indicate that thalidomide maintenance increases overall survival, other studies have shown that thalidomide maintenance fails to provide an overall survival benefit (see related Beacon news).

Therefore, the experts stated that the improved overall survival associated with thalidomide maintenance, as demonstrated in some studies, must be interpreted with caution.

They speculated that the most common explanation for the difference in overall survival rates across studies is the inclusion of elderly patients in some of the thalidomide maintenance trials that showed no improvement in overall survival. Moreover, they commented that differences in the availability of novel agents at relapse across studies may have also contributed to the different overall survival rates of myeloma patients receiving thalidomide maintenance.

In addition, the results of several clinical trials suggest that patients without high-risk chromosomal abnormalities are more likely to benefit from thalidomide maintenance than patients with high-risk factors.

For instance, in the MRC Myeloma IX trial, myeloma patients receiving thalidomide maintenance who did not have high-risk chromosomal abnormalities had a significantly better overall survival than patients who had chromosomal abnormalities.

Velcade

Summary:

The experts acknowledged that specific recommendations cannot be made for Velcade maintenance therapy at the present time because more information is needed regarding the optimal scheduling, dosing, and duration of Velcade maintenance.

They proposed further studies involving patients not previously exposed to Velcade in order to address these issues.

Additional Information:

According to the experts, single-agent Velcade maintenance therapies have only been investigated in myeloma patients who had already received Velcade during initial therapy.

For instance, the HOVON/GMMG clinical trial compared the effectiveness of a Velcade-doxorubicin (Adriamycin)-dexamethasone (Decadron) initial therapy followed by Velcade maintenance (PAD/Velcade) with a vincristine-doxorubicin-dexamethasone initial therapy followed by thalidomide maintenance (VAD/thalidomide).

After 36 months, patients who received PAD/Velcade had significantly better progression-free survival (78 percent versus 48 percent) and overall survival (71 percent versus 42 percent) rates compared to patients who received VAD/thalidomide.

Although the results of the HOVON/GMMG trial showed that Velcade maintenance therapy can be tolerated for up to two years, the experts claimed that the design of the study does not allow for a clear interpretation of the role of Velcade maintenance therapy because patients received different initial therapies.

Other studies have assessed the impact of Velcade maintenance in combination with thalidomide. Two of these studies indicated that Velcade plus thalidomide increases progression-free survival when administered as maintenance therapy.

Chemotherapy, Interferon, And Corticosteroids

Summary:

The results of previous clinical trials have suggested that conventional chemotherapy – melphalan (Alkeran) or BCNU (carmustine) typically used in combination with prednisone – prolongs the duration of remission in myeloma patients initially treated with melphalan plus prednisone. However, the experts pointed out that the use of chemotherapy in maintenance strategies was not pursued further when it was determined that chemotherapy failed to improve overall survival.

Interferon has also been shown to increase the duration of remission in myeloma patients, although results across studies have been mixed. According to the experts, physicians have abandoned the use of interferon in maintenance therapies because of toxicities and the inability to adequately select patients who are likely to benefit from interferon therapy.

Corticosteroids such as prednisone and dexamethasone have also yielded mixed results across studies. While prednisone has been shown to increase remission duration and survival, dexamethasone has been shown to lack benefit in myeloma patients. Taken together, the experts stated that the current data is insufficient to recommend corticosteroid maintenance therapy in myeloma patients.

For more information, please see the IMWG consensus statement in the journal Blood (full text, pdf).