Dr. Michel Attal from the Purpan Hospital in Toulouse, France, presented a review of current maintenance therapies for multiple myeloma during the American Society of Clinical Oncology (ASCO) annual meeting last month.

The focus of Dr. Attal’s presentation was on whether there is evidence to support the use of the novel anti-myeloma agents thalidomide ^[1] (Thalo­mid), Revlimid ^[2] (lenalidomide), and Velcade ^[3] (bortezomib) as mainte­nance therapy after initial therapy and stem cell transplantation.

Maintenance therapy refers to 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.

According to Dr. Attal, a drug should be recommended for maintenance therapy if it is able to improve patients’ overall survival.

He added that a drug should still be considered for maintenance therapy even if it does not improve overall survival as long as it significantly improves progression-free survival without increased toxicity.

Based on available data from several clinical trials, Dr. Attal came to the following conclusions about the use of novel agents in maintenance strategies for myeloma:

Thalidomide and Velcade have been shown to increase response rates and prolong progression-free survival, but the frequency of neurological side effects associated with these drugs may make them more useful as short-course consolidation agents rather than long-term maintenance drugs.

Revlimid prolongs the duration of response and decreases the risk of relapse in patients, irrespective of age. However, concerns remain regarding the risk of secondary cancers and about the overall survival benefit associated with Revlimid maintenance. Current data support the use of Revlimid maintenance in elderly patients despite the potential risk of secondary cancers, but more mature data are needed before recommendations for younger patients can be made.

Overall, Dr. Attal feels that the objectives of maintenance therapy have not been met yet and therefore maintenance therapy cannot be considered as standard of care.

“I think that maintenance therapy cannot [currently] be considered as a standard practice. [In order to] con­sider maintenance therapy as a standard practice, it should delay relapse but also improve overall survival with an acceptable toxicity. Today, we see that none of the currently evaluated drugs have reached all these objectives.” said Dr. Attal.

“Currently, Revlimid is the most promising candidate [for maintenance therapy]. However, we still need to confirm the survival benefit, and we still need to better define the duration of Revlimid maintenance,” he added.

Detailed findings from clinical trials regarding the use of thalidomide, Revlimid, and Velcade as mainte­nance therapy included in Dr. Attal’s review are summarized below.

Thalidomide

Thalidomide Maintenance After Stem Cell Transplantation

Data from available clinical trials indicate that thalidomide maintenance therapy following high-dose initial therapy is associated with a longer progression-free survival in younger myeloma patients. However, the benefit regarding overall survival is more variable.

Results of the French IFM 9902 trial showed that thalidomide maintenance after stem cell transplantation, compared to no maintenance, led to a better complete response/very good partial response rate (67 percent versus 55 percent), a better three-year progression-free survival rate (52 percent versus 36 percent), and a better four-year overall survival rate (87 percent versus 77 percent).

An Australian study also showed that maintenance therapy involving thalidomide plus prednisone ^[4] resulted in a higher very good partial response rate, progression-free survival, and overall survival compared to prednisone alone.

In another study conducted at the University of Arkansas, patients who received thalidomide as maintenance therapy had better complete response (62 percent versus 43 percent) and five-year progression-free survival rates (56 percent versus 44 percent) than patients who did not receive thalidomide.

Initial results of the study showed no improvement in overall survival in patients who received thalidomide maintenance. Survival was also shorter after relapse in patients who had been exposed to thalidomide. However, after a median follow-up of 72 months, researchers confirmed a longer overall survival in patients who received thalidomide maintenance.

A meta-analysis of five transplant studies also showed a significant improvement in both progression-free survival and overall survival with thalidomide maintenance therapy.

Although these studies indicate an overall survival benefit in patients treated with maintenance therapy, results of other studies suggest that long-term thalidomide use may induce more resistant disease at relapse and therefore provide no overall survival benefit (see related Beacon ^[5] news).

The benefits of thalidomide maintenance may also be limited to patients with favorable chromosomal abnormalities, or cytogenetics.

For instance, in the IFM 9902 study, only patients who lacked the chromosomal abnormality del13q and who did not achieve a very good partial response after initial therapy benefited from thalidomide maintenance.

In the British MRC Myeloma IX trial, thalidomide maintenance did not improve progression-free survival in patients with adverse chromosomal abnormalities such as t(4;14), t(14;16), del17p, or gain (1q21). These patients also had a worse overall survival.

“Thalidomide maintenance is not effective in patients with poor cytogenetics or in patients already in complete response after transplantation. Thus, in my opinion, thalidomide could be proposed for a limited duration of time at a low dose for patients failing to achieve a complete response after transplantation and without poor cytogenetics,” said Dr. Attal.

Notably, however, an Australian trial showed that thalidomide maintenance improved progression-free survival regardless of the presence of chromosomal abnormalities.

Thalidomide Maintenance In Elderly, Transplant-Ineligible Patients

Limited data are available concerning thalidomide maintenance in elderly patients and patients ineligible for stem cell transplantation.

In the MRC Myeloma IX trial, researchers found that thalidomide had a limited effect in improving progression-free survival in patients ineligible for stem cell transplantation (see related Beacon ^[5] news).

Three other studies involving elderly myeloma patients compared the combination of melphalan ^[6] (Alkeran), prednisone, and thalidomide – known as MPT – as initial therapy, followed by thalidomide maintenance, to melphalan and prednisone alone as initial therapy without thalidomide maintenance. In two out of three studies, the progression-free survival was higher in patients who received MPT plus thalidomide mainte­nance, but the overall survival was the same.

However, Dr. Attal noted that these studies were designed to evaluate the entire treatment program and not thalidomide main­te­nance specifically, which makes it difficult to determine the value of thalidomide maintenance itself from these studies.

Safety

According to Dr. Attal, the major problem associated with thalidomide maintenance is the frequency of side effects. Peripheral neuropathy (tingling and pain in the extremities due to nerve damage), sedation, and constipation are common problems associated with thalidomide maintenance and can either reduce patient quality of life or lead to premature discontinuation of therapy.

Dr. Attal pointed out that the optimal dose of thalidomide should be the smallest dose that is effective and tolerable. In most patients, the appropriate thalidomide dose and duration may be 50 mg per day for less than one year.

Revlimid

Revlimid Maintenance After Stem Cell Transplantation        

Results from two large, Phase 3 clinical trials indicate that Revlimid maintenance cuts the risk of relapse in myeloma patients after stem cell transplantation (for in-depth coverage of all Revlimid maintenance studies, please see the Beacon ^[7] article published this May).

In the IFM 2005-02 trial, 614 patients who had recently undergone stem cell transplantation received con­solidation therapy with Revlimid and then were randomly selected to receive long-term Revlimid mainte­nance therapy or a placebo until relapse.

After a median follow-up of 45 months, the median progression-free survival was 40 months for patients who received Revlimid maintenance versus 23 months for patients who received a placebo. After three years, 61 percent of patients who received Revlimid remained disease-free, compared to 34 percent who received a placebo.

However, the four-year overall survival rates were similar between patients who received Revlimid and patients who received a placebo (73 percent versus 75 percent).

In the CALGB study, 568 patients were randomly selected to receive either Revlimid maintenance therapy or a placebo following stem cell transplantation.

After a median follow-up of 34 months, the total time to progression was 46 months in patients who received Revlimid, compared to 27 months in patients who received a placebo.

A subgroup analysis showed that patients treated with Revlimid initial therapy had significantly longer survival if they received Revlimid maintenance, compared to those who received a placebo.

Current evidence shows that Revlimid maintenance can be beneficial for patients regardless of initial prognostic factors, such as response to initial therapy or adverse chromosomal abnormalities.

In the IFM 2005-02 trial, the three-year progression-free survival among all subgroups of patients who received Revlimid maintenance was higher compared to patients who received placebo. This included patients who had achieved a very good partial response after initial therapy as well as patients who had the chromosomal abnormality del13q.

Revlimid Maintenance In Elderly, Transplant-Ineligible Patients

According to Dr. Attal, current data indicate that prolonged treatment with Revlimid has a clear benefit in elderly, transplant-ineligible myeloma patients and is therefore a good choice for long-term maintenance.

In the MM-015 Phase 3 clinical trial, 459 myeloma patients who were at least 65 years of age received initial therapy with either melphalan and prednisone, abbreviated as MP, or melphalan, prednisone, and Revlimid, a combination known as MPR. Patients in the MPR treatment group then received maintenance therapy with either Revlimid or a placebo until disease progression. Patients receiving melphalan and prednisone received maintenance therapy with a placebo.

Analysis of the study showed that the addition of Revlimid maintenance to MPR initial therapy significantly improved the median progression-free survival compared to initial therapy alone (31 months for MPR-R versus 14 months for MPR and 13 months for MP).

The analysis also showed that Revlimid maintenance benefited patients regardless of disease stage, response to initial therapy, and age.

However, the three-year overall survival rate was similar between patients who received Revlimid main­tenance and those who did not.

Safety

According to Dr. Attal, Revlimid may be a good alternative to thalidomide as maintenance therapy because of its safer side effect profile.

Dr. Attal pointed out that side effects were acceptable across all Phase 3 clinical trials investigating Revlimid maintenance.

However, he pointed out that concerns over the increased risk of secondary cancers in patients receiving long-term treatment with Revlimid have generated controversy over the use of Revlimid as maintenance therapy (see related Beacon ^[8] news).

In the IFM 2005-02, CALGB, and MM-015 clinical trials, myeloma patients who received Revlimid mainte­nance experienced higher rates of second cancer than patients not receiving Revlimid maintenance.

At the 2011 American Society of Hematology meeting this past December, Dr. Antonio Palumbo of the University of Torino in Italy summarized results of a retrospective analysis of the risk of secondary cancers associated with Revlimid maintenance in 2,283 myeloma patients across nine different European clinical trials (see related Beacon ^[9] news).

Results of the analysis suggest that the benefits of Revlimid maintenance outweigh its risks. However, according to Dr. Attal, longer follow-up is needed to confirm this finding.

Velcade

Velcade Maintenance After Stem Cell Transplantation

To date, only two Phase 3 clinical trials of Velcade ^[3] (bortezomib) maintenance following stem cell trans­plantation have been conducted.

In the HOVON 65 trial, patients who received Velcade maintenance following initial therapy with Velcade-doxorubicin ^[10] (Adriamycin)-dexamethasone ^[11] (Decadron) had a better three-year progression-free survival rate (48 percent versus 42 percent) and overall survival rate (78 percent versus 71 percent) than patients who received low-dose thalidomide maintenance following initial therapy with vincristine ^[12] (Oncovin)-doxorubicin-dexamethasone.

Since the two patient groups were treated with different initial therapies as well as different maintenance therapies, Dr. Attal said that researchers are unable to clearly define the role of Velcade maintenance.

“According to the design of this trial, it’s impossible to know whether the progression-free survival benefit is due to the induction [initial] regimen or to the maintenance regimen used,” said Dr. Attal.

In the Spanish PETHEMA/GEM trial, patients received main­te­nance therapy with Velcade plus thalidomide, thalidomide alone, or interferon alpha 2b.

However, like the HOVON trial, patients also received different initial treatment regimens prior to main­te­nance therapy. These included thalidomide-dexamethasone, Velcade-thalidomide-dexamethasone, or a poly-chemotherapy regimen known as VBMCP/VBAD/B.

Velcade-thalidomide, thalidomide alone, and interferon alpha maintenance improved patients’ complete response rates by 23 percent, 11 percent, and 19 percent, respectively post transplant.

After a median follow-up of 24 months, the two-year progression-free survival rate was significantly higher in patients who received Velcade-thalidomide maintenance than in patients who received thalidomide or interferon alpha (78 percent versus 63 percent versus 49 percent, respectively).

The overall survival rates were similar across all three treatment groups.

Dr. Attal noted that the variation in initial treatment regimens among participants in both the HOVON and PETHEMA trials makes it unclear whether Velcade maintenance itself is responsible for increasing progression-free survival.

“Today, the role of maintenance treatment with Velcade is unclear. We have no study comparing Velcade versus placebo after the same induction [initial] regimen,” said Dr. Attal.

Velcade Maintenance In Elderly, Transplant-Ineligible Patients

Three large Phase 3 clinical trials have investigated the role of Velcade maintenance alone or in com­bi­nation with thalidomide or prednisone in elderly, transplant-ineligible myeloma patients.

However, similar to the Velcade maintenance after transplantation studies, two of three of transplant-ineligible studies did not directly compare Velcade maintenance to placebo, so it is difficult to draw any conclusions on the role of Velcade maintenance.

In the UPFRONT Phase 3 trial, elderly patients received single-agent Velcade as maintenance therapy following initial therapy with Velcade-dexamethasone (VD), Velcade-thalidomide-dexamethasone (VTD), or Velcade-melphalan-prednisone (VMP).

After a median follow-up of 26 months, the one-year progression-free survival rates for patients who received VD, VTD, and VMP were 57 percent, 64 percent, and 67 percent, respectively. Moreover, the two-year overall survival rates were 74 percent, 74 percent, and 78 percent, respectively.

In a Spanish trial, researchers assessed a three-year maintenance regimen involving Velcade plus thalidomide (VT) or Velcade plus prednisone (VP).

After a median follow-up of 46 months, patients who received VT had a similar progression-free survival as patients who received VP (39 months versus 32 months).

The overall survival was also similar between patients who received VT and VP (not reached versus 60 months).

In an Italian study, patients who received VT maintenance therapy following initial therapy with Velcade-melphalan-prednisone-thalidomide had a longer progression-free survival than patients who did not receive maintenance therapy following initial therapy with VMP (not reached versus 27 months).

Safety

Like thalidomide, Velcade has shown unfavorable neurotoxic effects when used as mainte­nance therapy in myeloma patients. According to Dr. Attal, Velcade’s neurotoxicity profile limits its use in myeloma mainte­nance regimens, and dose adjustments should be made accordingly.

In the HOVON-65 trial, 27 percent of patients receiving Velcade maintenance required dose reductions and 9 percent discontinued Velcade altogether because of toxicity, primarily peripheral neuropathy. Less than half of the patients in the trial were able to receive two years of Velcade maintenance as planned.

In the UPFRONT trial, 13 percent to 25 percent of elderly patients receiving Velcade maintenance required dose reductions.

For more information, please see the review article ^[13] (pdf) Dr. Attal wrote to accompany his presentation.