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.

However, 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 should 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 IMW consensus statement in the journal Blood (abstract).

The morning presentations about therapies combining current myeloma drugs will be covered in this update.  Morning presentations about potential new myeloma therapies were covered in an update published earlier today, and presentations from the rest of the day will be covered in additional updates.

MPR-R Versus MPR Versus MP

Dr. Antonio Palumbo from the University of Torino in Italy presented the final results of a Phase 3 trial aimed at assessing whether Revlimid (lenalidomide) maintenance therapy is beneficial for newly diagnosed, older myeloma patients ineligible for a stem cell transplant (abstract).

The trial tested three treatment regimens.  Two groups of patients received induction (upfront) therapy consisting of melphalan (Alkeran), prednisone, and Revlimid. Then half of the patients were placed on maintenance therapy with Revlimid (MPR-R), while the other half of these patients received a placebo as “maintenance” therapy (MPR).  A third group received only melphalan and prednisone as induction therapy, then a placebo as “maintenance” therapy (MP).

The results of this trial showed that Revlimid maintenance significantly extends progression-free survival.  Median progression free survival was 31 months for the MPR-R group of patients, 14 months for the MPR patients, and 13 months for the MP patients.

However, Revlimid maintenance therapy has not yet impacted overall survival.  The percentage of patients still alive at the four-year mark was 59 percent for the MPR-R group, 58 percent for the MPR group, and 58 percent, as well, for the MP group.

The latest secondary cancer data from the trial indicated that Revlimid maintenance as well as Revlimid induction therapy noticeably increases a patient’s risk of developing a second cancer.  For instance, there were 12 cases of non-invasive second cancers out of 150 patients who received MPR-R, 10 cases out of 152 patients who received MPR, and 4 cases out of 153 patients who received MP.

Dr. Palumbo argued, however, that the increased risk of secondary cancer associated with Revlimid treatment is far outweighed by the drug’s benefits. Most myeloma specialists agree with this perspective, and it is also the conclusion that the European Medicines Agency reached when it reviewed Revlimid’s secondary cancer risk this past summer.

Dr. Palumbo said recent results, including those from his trial, are moving myeloma in the direction of continuous therapy rather than specific periods of therapy as has typically been the case in the past.

VMP Versus MP

The next presentation was by Dr. Jesús San Miguel from the University Hospital in Salamanca, Spain.  He presented updated results from a Phase 3 clinical trial comparing the three-drug regimen Velcade (bortezomib), melphalan, and prednisone (VMP) to melphalan and prednisone alone (MP) (abstract).

The goal was to determine if a previously reported overall survival benefit for the VMP regimen persisted after five years of follow-up. In addition, the researchers analyzed the risk of secondary cancers in both treatment groups.

The analysis included 655 patients who were previously untreated and also ineligible for stem cell transplants.  Half of the patients received VMP, and the other half received MP alone.

After about five years of follow up, the median overall survival was 56.4 months for VMP patients versus 43.1 months for MP.

The overall survival benefit of VMP versus MP was also observed for several patient subgroups, including patients 75 years old or older (50.7 months versus 32.9 months), patients with stage III multiple myeloma (42.1 months versus 30.5 months), and patients with kidney disease (56.8 months versus 36.7 months). However, no significant difference in overall survival was observed in patients with high-risk chromosomal abnormalities.

Dr. San Miguel concluded that VMP resulted in a substantial long-term overall survival benefit compared to MP across a range of key patient subgroups, and as was discussed in yesterday’s ASH daily update, the risk of increased secondary cancers associated with the treatment is negligible or non-existent.

VT Versus VP Maintenance Therapy

Dr. San Miguel’s colleague Dr. María-Victoria Mateos then presented results from a Spanish trial that was conducted with older, newly diagnosed multiple myeloma patients who were ineligible to receive a stem cell transplant (abstract).

Patients in this study first received induction therapy with either Velcade, melphalan, and prednisone (VMP) or Velcade, thalidomide (Thalomid), and prednisone (VTP).  They then received one of two possible maintenance regimens: Velcade plus thalidomide (VT) or Velcade plus prednisone (VP).  A total of 178 patients started one of those two maintenance therapies.

In this presentation, Dr. Mateos focused on comparing the results of the maintenance therapies, since she and her colleagues previously published results showing that the two induction treatments tested in this trial had very similar efficacy.

After a median follow-up of 34 months, the complete response rate increased from 24 percent after induction therapy to 42 percent after maintenance therapy.  The complete response rate was similar, but slightly higher for VT versus VP (46 percent versus 39 percent).

The median progression-free survival from the start of induction therapy was 35 months.  From the start of maintenance therapy, the median progression-free survival was 30 months for patients receiving VT and 24 months for patients receiving VP.

The median overall survival was 60 months and was similar for both maintenance regimens.

The VT maintenance regimen had slightly higher levels of side effects, but they were generally not an issue.

Dr. Mateos believed that the benefit in terms of progression-free survival seen for the VT regimen supports pursuing that combination as a preferred maintenance regimen.  However, she also believed side effects could be reduced and the regimen further improved if patients were put on a Velcade-Revlimid maintenance regimen.

VD Versus VTD Versus VMP

Dr. Ruben Niesvizky from the Weill Cornell Medical College in New York presented results from a Phase 3 trial involving older, newly diagnosed, transplant-ineligible multiple myeloma patients.

The 502 patients in the study received 24 weeks of induction therapy with one of three regimens: Velcade plus dexamethasone (Decadron) (VD), Velcade plus thalidomide and dexamethasone (VTD), or Velcade plus melphalan and prednisone (VMP).  All three regimens were followed by an extended 25-week Velcade consolidation therapy.

The three Velcade-based induction regimens were effective, with overall response rates of 73 percent, 80 percent, and 69 percent for VD, VTD, and VMP, respectively.

After a median follow-up of 22 months, the median-progression free survival rates were similar for each of the regimens: 13.8 months for VD, 14.7 months for VTD, and 17.3 months for VMP.

Overall survival rates one-year after the start of treatment were also similar: 87.4 percent for VD, 86.1 percent for VTD, and 88.9 percent for VMP.

Patients receiving VTD experienced the most side effects, while those taking VD had the least side effects.

Overall, Dr. Niesvizky concluded that the three regimens were relatively similar in efficacy but yielded encouraging results for the patient population targeted by the trial.

For more detailed coverage of yesterday’s myeloma-related presentations and research at the ASH meeting, see the ASH 2011 Day Three thread in The Myeloma Beacon discussion forum.

The Beacon is publishing updates from Day Four of ASH in the Beacon’s myeloma forums.  As always, the news from each day will also be summarized in daily updates like this one.

In fact, overall survival for patients in the trial who received thalidomide maintenance was slightly lower than overall survival for patients who did not receive maintenance therapy.  The difference, however, was not statistically significant.

In contrast, progression free survival was significantly longer for patients who received thalidomide maintenance compared to patients who were not on a maintenance regimen.

The study findings thereby highlight how progression free survival and overall survival do not always move in lockstep with one another.

The authors of the British study also found that the choice of relapse therapy had a significant impact on the survival of patients who received thalidomide maintenance therapy.  The impact was so significant that the authors believe thalidomide maintenance therapy would have shown a clear overall survival benefit if relapse therapies had been better selected.

Recent evidence suggests that thalidomide (Thalomid) maintenance therapy may work to reduce or suppress residual cancer that may exist in patients following induction therapy.

The goal of the British analysis was to determine whether the suppression of residual cancer by thalidomide maintenance provides a subsequent improvement in survival.

The researchers noted that, although there have been trials of thalidomide maintenance in the past, results regarding survival have been conflicting.  They pointed out that differences in results between trials may reflect differences in patient subgroups (chromosomal abnormalities, relapsed/refractory, etc.) and the type of relapse therapy given following disease progression.

To further confirm the effect of thalidomide maintenance therapy, the British researchers retrospectively analyzed data from patients who had participated in the Phase 3 MRC Myeloma IX trial.

The Myeloma IX trial included 1,970 newly diagnosed multiple myeloma patients, mostly in the United Kingdom.  The goal of the trial was to compare the efficacy of the bisphosphonates Zometa (zoledronic acid) and Bonefos (clodronic acid) in myeloma patients (see related Beacon news) while also exploring the efficacy and safety of several different myeloma treatment regimens.

Half of the Myeloma IX trial participants were randomly selected to receive maintenance treatment with thalidomide.  The other half of the trial participants received no maintenance therapy.  Patients who received thalidomide maintenance therapy did not necessarily receive thalidomide as part of their induction therapy.  The selection of patients for maintenance therapy was made without consideration of the patient’s induction therapy.

Patients received 50 mg of thalidomide during the first four weeks of maintenance therapy. The dose was then increased to 100 mg until disease progression if patients tolerated the higher dose.

When the researchers compared the progression-free survival of patients who had received thalidomide maintenance to those who had not, they found a significant improvement with thalidomide maintenance.  Specifically, the progression-free survival was 23 months for patients receiving thalidomide maintenance, compared to 15 months for patients not receiving maintenance.

The researchers also found that improvements to progression-free survival were observed whether or not patients had received thalidomide-based induction therapy.

The results were different, however, when the researchers turned their attention to overall survival.  Overall survival rates for the patients who received thalidomide maintenance were statistically no different from — and often lower than — the survival rates of patients who did not receive thalidomide maintenance.

The researchers therefore looked to see whether thalidomide maintenance had a different effect on patients with higher-risk chromosomal abnormalities compared to patients without such abnormalities.

And, in fact, there was a difference in outcomes.  Thalidomide maintenance had a significant negative impact on overall survival in patients with higher-risk chromosomal abnormalities.

In contrast, there was a trend — not yet statistically significant — to thalidomide maintenance having a positive impact on the overall survival of patients without higher-risk chromosomal abnormalities.

When the British researchers looked in greater depth into why some patients who had been on thalidomide maintenance therapy lived longer than others who had been on the same regimen, they found that the treatment patients received at relapse played a key role.  Patients who received either Revlimid (lenalido­mide) or Velcade (bortezomib) at relapse lived significantly longer than those who received other treat­ments.

Indeed, based on a mathematical model they developed, the authors of the current study believe that thalidomide maintenance would have demonstrated a significant positive impact on overall survival across all patients if the maintenance patients always received either Revlimid or Velcade at relapse.

Patients received thalidomide maintenance therapy for a median of seven months.  Fifty two percent of patients stopped therapy before disease progression due to the severity of side effects, the most common of which was peripheral neuropathy (nerve damage causing tingling in the hands and feet).

The study authors point out that greater differences in survival might have been observed between thalidomide and non-thalidomide maintenance groups if patients had been able to continue thalidomide therapy for longer periods of time.  They also suggest that drugs with fewer side effects, such as Revlimid, may produce better results.

For additional information, please see the study in the journal Blood (abstract).

“Our study showed that maintenance therapy with Velcade in relapsed / refractory multiple myeloma patients may improve the progression-free survival and overall survival of patients with a low grade of toxicity,” Dr. Giulia Benevolo, lead author of the study, told The Myeloma Beacon.

“[However], this is a Phase 2 trial, and the results must be confirmed in randomized trials,” Dr. Benevolo added.

Over the past decade, novel drugs such as Velcade (bortezomib), thalidomide (Thalomid), and Revlimid (lenalidomide) have increased the overall survival of multiple myeloma patients, but most patients eventually relapse and require rescue therapies to control or delay disease progression.

Patients who respond to rescue therapy often subsequently receive maintenance therapy with the aim of prolonging remission.

All three novel agents have been investigated and used as maintenance therapy. Results of past studies suggest that Revlimid maintenance increases the survival and time to disease progression for myeloma patients following stem cell transplantation. However, these studies have also raised concerns that Revlimid maintenance may increase the risk for developing secondary cancers (see related Beacon news).

Prior studies have also shown that thalidomide maintenance therapy improves overall survival, but thalidomide has not been widely adopted as maintenance therapy because of concerns about its side effects.

Results of a recent Phase 3 clinical trial involving newly diagnosed multiple myeloma patients indicate that more patients achieve a complete response with Velcade maintenance than thalidomide maintenance following Velcade-containing initial therapies and autologous stem cell transplantation.

Dr. Benevolo and her colleagues sought to assess whether Velcade in combination with dexamethasone (Decadron) is a safe and effective form of maintenance therapy in relapsed/refractory multiple myeloma patients who previously responded to Velcade-containing rescue therapies.

The study included 49 relapsed/refractory multiple myeloma patients with a median age of 71 years. The patients had received a median of two prior therapy regimens.

All patients had responded to Velcade-containing rescue therapies after having relapsed or been refractory to prior treatment. Patients who achieved a complete response after Velcade-containing rescue therapies were excluded because their disease was not measurable.

All patients received 1.3 mg/m² of Velcade on days 1 and 15 and 20 mg of oral dexamethasone on days 1-2 and 15-16 of successive 28-day cycles until relapse.

After a follow-up of 25 months, the researchers found that Velcade maintenance improved the quality of response after rescue therapy to a complete response in 8 percent of patients and to a very good partial response in 6 percent of patients.

The overall response rate was 35 percent, and the median time to progression was 17 months.

After one year, 79 percent of patients were still alive and 61 percent of patients had not progressed.

According to the researchers, side effects were generally mild.  The most common side effect was peripheral neuropathy, or treatable pain and tingling sensations in the extremities, which was experienced by 31 percent of the patients.  Other side effects included fatigue (16 percent), constipation or diarrhea (6 percent), shingles (4 percent), and pneumonia (2 percent).  Six percent of patients experienced peripheral neuropathy that was severe enough to require a reduction in their Velcade dose.

None of the patients experienced severe pain and tingling sensations or blood-related side effects, and none of the patients died from side effects.

For more information, please see the full article in the journal Cancer (abstract).

Results from a study conducted by the Cancer and Leukemia Group B (CALGB) showed that Revlimid (lenalidomide) maintenance therapy following stem cell transplantation significantly extends survival of myeloma patients.  Two other studies investigating Revlimid maintenance, the IFM 2005-02 and MM-015 studies, have not yet shown a survival benefit.

All three studies, however, have raised concerns that Revlimid maintenance may increase a myeloma patient’s risk of developing a second cancer.  Interim results presented in December as well as updated results from each of the trials presented today showed that more patients who received Revlimid maintenance reported second cancers as compared to patients who did not receive Revlimid.

The presentations of the trial results were followed by a panel discussion about Revlimid and second cancers.  Many of the panel participants were uncertain whether Revlimid increases the risk of developing a second cancer.

For more information on today’s IMW session on second cancers, see The Myeloma Beacon’s extensive coverage of each of the presentations in the Beacon forums.  The Beacon will also provide more details in a daily update about day three of the workshop.  For more related information, see the Beacon’s previous coverage of the Revlimid controversy.

Additionally, much awaited data about the safety and effectiveness of Revlimid (lenalidomide) maintenance therapy will be presented at the meeting.

The Myeloma Beacon will be covering the event, so readers can expect many articles during the meeting and in the weeks afterward about the key myeloma findings.

The International Myeloma Workshop (IMW) is a meeting organized by an international group of myeloma specialists and held every other year.

The first day of this year’s meeting will focus on the biology of multiple myeloma and bone involvement.

Some of the highlights from the second day will include sessions on high-risk myeloma, the continuum of care for myeloma patients, and treating younger newly diagnosed patients as well as a debate about whether to treat smoldering myeloma patients and a poster session on myeloma therapy.

The third day will feature sessions on treating older newly diagnosed patients, new drugs and therapeutic approaches, secondary cancers, and individualizing patient treatment.

The meeting will conclude on the fourth day with discussions about supportive care and a session on clinical trial results.

Abstracts for many of the presentations are now available on the IMW website.

The most recent data from the CALG-B study show that Revlimid maintenance extends survival compared to placebo.  As of February 2011, 91 percent of patients treated with Revlimid maintenance were still alive compared to 84 percent of patients who did not receive Revlimid.

These results are important as the debate continues about whether the benefits of Revlimid maintenance outweigh the risk that it may be linked to higher rates of patients developing a second cancer (see related Beacon news).  Updated data and more discussions about Revlimid and second cancers are expected at the meeting.

Additional information about the meeting, including details about registration, the meeting schedule, and abstracts, can be found at the IMW website.

Why is the FDA investigating the safety of Revlimid and thalidomide?

In December, intermediate results from three clinical trials studying long-term use of Revlimid (lenalidomide) showed that multiple myeloma patients who received Revlimid may be at an increased risk for developing a second cancer, as compared to patients who received a placebo.

In two of these studies, Revlimid was used as maintenance therapy after stem cell transplantation.  In the third study, Revlimid was used in combination with melphalan (Alkeran) and prednisone for elderly, newly diagnosed myeloma patients.  Neither of these uses is currently approved by the FDA, although they are still legal – and not uncommon – uses in the United States.

Revlimid is currently approved by the FDA for use with dexamethasone (Decadron) to treat multiple myeloma patients who have already received another treatment.  It is also approved to treat certain patients with a group of blood disorders known as myelodysplastic syndromes.  No evidence so far has suggested a connection between these approved uses of Revlimid and elevated rates of second cancers.

Given that recent studies have suggested Revlimid maintenance therapy may put patients at higher risk of developing second cancers, the FDA is reviewing all approved and investigational uses of Revlimid, including use in multiple myeloma and also myelodysplastic syndromes.

No studies have suggested that thalidomide may be linked to higher rates of second cancers.  However, since thalidomide (Thalomid) is chemically similar to Revlimid, the FDA is also reviewing the safety of thalidomide.  It is standard procedure for the FDA to investigate related compounds if the safety of one is in question.

Are reviews such as this one common?

Once a drug is approved by the FDA, safety reviews are not common.  However, the FDA continues to monitor all drugs after they are approved, and it will investigate the safety of a drug if any data emerge suggesting the drug may not be as safe as believed when it was first approved.

How long can the review be expected to take?

Reviews such as this typically take a few months.  The FDA may be waiting on data from some of the ongoing clinical trials to allow it to complete its review.

Who typically conducts these reviews?

Safety reviews are typically conducted by FDA staff, who may consult with temporary Special Government Employees, members of the Oncologic Drugs Advisory Committee (ODAC), and potentially other individuals without conflicts of interest if they are needed to understand the data and situation at hand.  The ODAC is the committee of outside scientific experts that advises the FDA in regard to the approval of new oncology drugs and changes to the approved use of already marketed oncology drugs.

What are the possible outcomes of this review?

According to the FDA, the agency may conclude that there is no safety problem, that further investigation is needed, or the agency can modify the prescribing information or the approved uses of Revlimid and thalidomide.

Although it is theoretically possible that the FDA could revoke its approval for the sale and use of Revlimid or thalidomide, these drugs have demonstrated clear benefits for multiple myeloma patients, so such an outcome is considered highly unlikely.

If a link is found between Revlimid or thalidomide and second cancers, a warning could be placed on their official prescribing information, their use as maintenance therapy might not be approved by the FDA, or a cap might be placed on the length of time they are recommended to be used.

Until the FDA review is complete, should patients continue taking Revlimid and thalidomide?

The FDA recommends at this time that patients taking Revlimid or thalidomide should continue to take their medications as prescribed by their physician.  The agency even went as far as to say that they believe the benefits of Revlimid outweigh the safety concerns.

Will this review have any impact on pomalidomide’s anticipated approval as a multiple myeloma treatment?

Pomalidomide (CC-4047) is also chemically related to Revlimid and thalidomide.  It is in Phase 3 clinical trials as a potential multiple myeloma treatment and is expected to be submitted to the FDA for approval in the near future.  The FDA, however, is prohibited from commenting on how its investigation into the safety of Revlimid and thalidomide may impact the application for approval of pomalidomide or any other drugs that may now, or in the future, be under review by the FDA.

For more information, see the Beacon’s announcement about the FDA investigation and the rest of the Beacon articles about the Revlimid controversy.

The investigation is being carried out due to clinical trial results that suggest Revlimid may increase the risk of secondary cancer in patients taking the drug for extended periods of time.

The announcement confirms a Beacon news update last week that reported evidence that an investigation of Revlimid was underway (see related Beacon news).

Today’s FDA statement says that the agency is “aware of results from clinical trials … that have found that patients treated with Revlimid (lenalidomide) may be at an increased risk of developing new types of cancer compared to patients who did not take the drug.”

For this reason, the FDA “is currently reviewing all available information on this potential risk and will communicate any new recommendations once it has completed its review.”

The announcement adds that the FDA recommends that patients now taking Revlimid should continue taking the drug as prescribed by their physician, and that the FDA currently believes “the benefits of Revlimid continue to outweigh the potential risks.”

One somewhat unexpected development found in the FDA announcement is news that the agency also is investigating thalidomide (Thalomid) and whether it, too, may be linked to increased rates of secondary cancer.  This investigation is being carried out, the FDA said in its statement, because Revlimid and thalidomide are chemically very similar to one another. 

The FDA did not report or suggest, however, that the agency has any evidence at this time that thalidomide may increase rates of secondary cancer in multiple myeloma patients.

In a statement to the Beacon regarding the FDA announcement, a spokesperson for Celgene, the company that markets both Revlimid and thalidomide, said that Celgene “will continue to provide any information needed to complete the [FDA's] review and, as before, will also look toward the presentation of further data at medical meetings this summer.”

More data on Revlimid and its potential link to increased rates of secondary cancer are expected to be presented at the upcoming International Myeloma Workshop in May and the American Society of Clinical Oncology meeting in June.

The full text of the FDA announcement is available at the FDA website. 

A complete compilation of Beacon articles with information on the Revlimid safety controversy is available here.

A group of myeloma researchers issued a joint statement on the issue; the European Medicines Agency has begun an investigation into Revlimid’s risks and benefits; and there are subtle signs – but no official confirmation – that the U.S. Food and Drug Administration may be conducting its own investigation into Revlimid and its safety.

As the Beacon announced last week, a group of myeloma researchers has issued a statement regarding the occurrence of secondary cancers after treatment with Revlimid (lenalidomide).  (See related Beacon news.)

The group of researchers was called together as an advisory board arranged by Celgene, the company that markets Revlimid.  The advisory board includes a number of leading European myeloma researchers as well as the lead investigators of all three clinical trials that have reported data showing higher rates of secondary cancer among patients receiving Revlimid maintenance therapy.

Members of company-sponsored advisory boards typically are reimbursed by the sponsor for their travel expenses and are paid an honorarium for their time.  Celgene has not yet responded to a Myeloma Beacon inquiry asking whether members of this advisory board were compensated by the company.

The advisory board’s statement says that the risk of developing a secondary cancer after exposure to Revlimid depends on whether the patient is newly diagnosed or relapsed / refractory, and on whether the patient has received certain types of chemotherapy.

The statement notes, for example, that an increased risk of secondary cancer has only been seen in newly diagnosed patients who are treated with DNA-damaging chemotherapy at the same time or prior to Revlimid therapy.  This will often be the case, however, as a number of chemotherapies commonly used to treat myeloma patients are known to damage DNA, including cyclophosphamide (Cytoxan), melphalan (Alkeran), busulfan (Myleran),  cisplatin (Platinol), and etoposide (VP-16).

“The missing bullet in the [advisory board’s statement] is that a significant increase in second cancers has been noted in patients receiving post-transplant lenalidomide [Revlimid] maintenance compared with those receiving placebo in both Phase 3 studies reported so far,” said Dr. S. Vincent Rajkumar from the Mayo Clinic in response to the board’s statement.  “This finding needs to be studied closely to determine whether 1) the risk is real, 2) there are confounders, and 3) the risk is related to duration of such therapy.”

Three studies have shown that Revlimid used as maintenance therapy after stem cell transplantation or in combination with melphalan and prednisone in newly diagnosed patients significantly increases progression-free survival.  However, the board notes that an increase in overall survival in these studies has not yet been shown.

The advisory board also states that results of 11 Celgene-sponsored clinical trials indicate that Revlimid does not appear to increase the risk of secondary cancers when it is used to treat relapsed / refractory patients, regardless of whether the patients have been treated with DNA-damaging chemotherapy.

The board’s statement concludes by saying that, until more follow-up data is available, Revlimid should be used in clinical trials studying the rate of secondary cancers and in “defined clinical indications.”  Dr. Philip McCarthy, one of the advisory board members and lead investigator of the U.S.-based trial studying Revlimid maintenance therapy, clarified that “defined clinical indications” should be interpreted as approved and commonly accepted uses of Revlimid.

In Europe, Revlimid is officially approved for use with dexamethasone (Decadron) in myeloma patients who have received at least one prior therapy.  It is uncommon for the drug to be used differently in Europe due to government and insurance restrictions.

In the United States, Revlimid’s officially-approved use is the same as in Europe.  However, it frequently is used in the U.S. as first-line therapy, and it also is used as single-agent maintenance therapy for select patients, particularly those who are at high risk of relapsing.

In a separate development, the European Medicines Agency on March 18 announced that it would begin reviewing the benefits and risks of Revlimid due to its potential link to secondary cancers.  The agency will assess whether current safety and efficacy data impact the balance between the benefits and risks of Revlimid’s approved use.

Such a review is uncommon but not unheard of.  Last year, the European Medicines Agency (EMA) – which acts as a kind of Europe-wide equivalent to the U.S. Food and Drug Administration – conducted similar reviews of about 5 percent of EMA-approved medicines.  Celgene representatives have told the Beacon that they expect the review will take 3 to 6 months to complete.

The Agency’s review could result in no changes for the use of Revlimid in Europe; changes to the drug’s official prescribing information, such as the addition of warnings or restrictions; or a suspension or revocation of Revlimid’s approval for use in Europe.  The most common result of such investigations is a change in the drug’s official prescribing information.

In the meantime, the Agency recommends that European physicians and patients continue to use Revlimid according to its approved use until the Agency’s review is complete.  It does not recommend delaying, modifying, or restricting use of Revlimid.  It also recommends that clinical trials studying other uses of Revlimid should continue enrollment and treatment of participants.

Finally, in a separate but related development, the Beacon has received subtle, and admittedly indirect, evidence that the U.S. Food and Drug Administration (FDA) may be carrying out an investigation similar to the one recently initiated by the EMA.

Specifically, when the Beacon recently inquired as to whether the FDA was conducting a similar investigation, a spokesperson responded that “there is nothing that [the FDA] can say publicly on this topic at this stage.”

In addition, Celgene’s press representatives have not responded to several email and phone requests for comment on whether there is an ongoing FDA investigation into Revlimid and its safety.

More data on the Revlimid maintenance studies are expected to be published at the upcoming International Myeloma Workshop in May and the American Society of Clinical Oncology meeting in June.  The International Myeloma Working Group will also meet in May and may issue recommendations related to the issue.

According to the statement, the group initially met in Paris on February 23, 2011 at a meeting arranged by Celgene, the company that developed and markets Revlimid (lenalidomide).

The group includes 12 well-known multiple myeloma researchers, almost entirely from Europe. Among the group’s members are investigators from the CALGB 100104, IFM 2005-02, and MM-015 clinical trials, which are the three trials that last December reported data suggesting a possible connection between Revlimid and increased rates of secondary cancer.

The group, it should be noted, is not an existing “consensus group” or “working group” of multiple myeloma researchers such as The International Myeloma Working Group.  Instead, it is an ad hoc group arranged by Celgene specifically to review and discuss the Revlimid-secondary cancer issue.

The group’s statement is reproduced in full below.  The Myeloma Beacon will have further information on the statement in a more detailed news article later today or over the weekend.

The researchers’ statement first appeared online at the website of the British charity Myeloma UK.

Statement of the Multiple Myeloma Researchers

An Advisory Board arranged by Celgene was held in Paris on 23rd February and a consensus view of European myeloma physicians, on the current position of the description and further investigation of second primary malignancies (SPM) after exposure to Lenalidomide, was reached.

1. It was noted that in order to interpret the meaning of an increased rate of SPM, that it is of crucial importance to distinguish clearly between relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM).  This distinction is important because of the nature of the prior treatment received, the age of the patient and the nature and duration of follow up in the study.
    
2. There was consensus that there is no apparent increased rate of SPM for patients treated with Lenalidomide/Dexamethasone in RRMM, the current licenced indication for Lenalidomide.  In a review of 11 Celgene-sponsored trials with Lenalidomide/Dexamethasone in relapse/refractory patients, 8.2% of the patients (311 cases) received treatment for >24m, and the incidence of SPM was not increased in this long-term-exposed population. In RRMM there is a clinically significant survival benefit for the use of Lenalidomide.
    
3. There was consensus that there is no apparent increased rate of SPM for NDMM patients treated with Lenalidomide/Dexamethasone, who have not had concurrent or prior exposure to chemotherapy.  For NDMM, there are 3 trials that have used Lenalidomide, in protocols, where there is concurrent or prior use of chemotherapeutic agents, which have reported data, MM-015, IFM-2005-02 and CALGB-100104.  There were apparent increased rates of SPM cases in each of these studies.  A fourth study, MM020, has yet to report.
    
   It is known that there are increased rates of SPM following exposure to DNA damaging chemotherapies.  Thus, it is important to distinguish clearly between the different clinical settings in these NDMM studies where the patients are of different ages, exposed to different induction chemotherapies and have different durations of exposure to Lenalidomide.
    
   Recognising that Lenalidomide as a maintenance treatment in the IFM-2005-02 study has been discontinued.  There was consensus that the MM-015 & MM-020 in NDMM and other co-operative studies in NDMM can continue to completion based on current available data, with appropriate amendments to retrospectively and prospectively capture SPM data.
    
   In the 3 NDMM trials that have reported, there is a highly significant increase in progression free survival (PFS), compatible with an approximate 50-60% decrease in the hazard ratio of disease progression.  This is likely to be of clinical significance, but as yet, has not been associated with an overall survival (OS) benefit.
    
   There was consensus that it would be interesting to see Event Free Survival analyses for IFM-2005-02 & CALGB 100104, where SPM is included as an event (in addition to progression or death), similar to the analysis already conducted for MM-015, in order to further characterize the risk/benefit profile for the agent in these settings.
    
   There was consensus that no additional actions were required by Celgene with regard to ongoing MM-015 and MM-020 studies, above those currently being taken in response to Afssaps (France) Clinical Trial Unit request.
    
4. There was consensus that there is no apparent increased rate of SPM for patients treated with Lenalidomide in Chronic Lymphocytic Leukaemia, lymphomas or solid tumour studies.
    
5. There is a consensus, that going forward there is a need for caution and close follow-up of trials incorporating Lenalidomide.  Until there is more follow up data available Lenalidomide should be used in defined clinical indications and in trials with ongoing data collection on rates of SPM.

Group Members: Michel Attal (France), Michele Cavo (Italy), Bertrand Coiffier (France), Faith Davies (UK), Meletios A. Dimopoulos (Greece), Thierry Facon (France), Heinz Ludwig (Austria), Phillip McCarthy (USA), Gareth Morgan (UK), Jesus F. San Miguel (Spain), Antonio Palumbo (Italy), Pieter Sonneveld (Netherlands).