Revlimid And Secondary Cancers: An Update
There have been several additional developments in the past few weeks related to concerns about a potential link between Revlimid and secondary cancers.
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.
Related Articles:
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
- Dr. Christoph Driessen On Nelfinavir In The Treatment Of Multiple Myeloma
Why in the world would FDA need to do anything when there is 180,000 people on Revlimid with a unbeleivably low 0.4% secondary malignancy rate vs 5-6% norm and with no SM link in the 11 trials for people on Revlmid more than 24 months.
Its clear as stated in the UK piece that came out that they beleive problem is melphalan - and the fact that 21% of IFM patients had DOUBLE stem cell transplants. Both melphalan and SC transplants are known to increase secondary malignancy. Revlimid has also shown it does not incr SM in CLL and NHL trials as well.
There is no problem with Revlimid - dex which is what is used in US. In fact it appears to DECREASE SM rate. The problem is with melphalan and Stem Cell trans.
It's interesting, Steven, that all the data you quote on this subject are data that have been cited primarily by Celgene spokesmen. Is there any particular reason for this bias?
The arguments that "it's the melphalan" or "it's the stem cell transplant" or "it's the weird French regimen" are all bogus.
Look, let's say you split 200 people into two groups of 100 people each. You ask the people in Group A to walk across a sheet of ice, and 10 percent of them slip. You also ask the people in Group B to walk across the same sheet of ice, but, before they go out on the ice, you have each of them drink two shots of whiskey. Among the people in Group B, 25 percent slip when they walk across the ice.
Saying "it's the melphalan" in the Revlimid trials is like saying "it's the ice" that made more of the people in Group B slip than in Group A. It's not the ice; it's the whiskey. And it's not the melphalan; it's the Revlimid.
In all three of the Revlimid maintenance trials, the patients within each trial were exposed to basically the same treatment regimen, except some patients were given longer-term Revlimid treatment. And, in all three trials, the patients who got longer-term Revlimid had higher rates of secondary cancer.
Yes, the patients in the CALGB trial, for example, were given melphalan before their stem cell transplants. But ALL the patients in the trial were given melphalan, not just the patients who were given Revlimid maintenance therapy. So it wasn't the melphalan that caused more than twice the number of patients in the Revlimid arm to get secondary cancer.
It also wasn't the "weird French regimens" in the IFM trial that caused the Revlimid patients to have more than SIX times the number of secondary cancers as the placebo patients.
Of course its a combination of heavily chemo pretreated patients adn in the case of IFM a VERY difficult patient population including heavily pretreted chemo and including 21% who had DOUBLE stem cell transplants (note the 3 lead investigtors on the French trial were all part of the positive release last week from the EU. The UK companian release was even stronger - "Is the apparent increased risk of second cancers seen in these clinical studies due to Revlimid? NO" & "it is likely that Revlimid will eventually become a standard front-line treatment in myeloma."
There is also observational bias - its clear the placebo patients are not followed as closely once they move on. CALGB trial will show Overall Survival benefit in May per Ken Anderson from Harvard/Dana Farber the lead investigator. I would not be shocked if IFM does also.
And oh EVEN with the non-statistically significant small imbalance - the risk benefit is largely in the favor of the Revlimid maintenance regimen (which in practice will end up being Rev-Dex avoiding the known SPM enhancer melphalan anyway). The PFS benefit is STUNNING. And CALGB will show overall survival benefit which is the gold standard of medicine. Rituxan maintenance was approved on PFS benefit alonein the EU for Follicular Lymphoma Pts - EMEA approved Rituxan in maintenance therapy without showing overall survival,"PFS remains the only realistic efficacy endpoint.”
o EMEA Statement:"PFS represents an accepted intermediate efficacy endpoint. Considering the very long natural history for patients with newly diagnosed follicular lymphoma with a median survival of about 10 years, PFS remains the only realistic efficacy endpoint."
There are also drugs on the market in the EU like Gleevac and others with a much higher rate of SM than Revlimid with melphalan. Because the risk benefit and PFS benefit is so amazing. And most Drs will end up using Rev-Dex imo which has a very very very low 0.4% rate in SM in 180k patients.
IMO - the imbalance in the IFM study is related to the aggressive way in which patients are treated in France and the IFM protocol, with the imbalance unlikely to materialize consistently or as strongly in the other studies of Revlimid maintenance. Key factors factors, such as the length and aggressiveness of pre-transplant chemotherapy and the use of double transplants in 21% of the patients in the IFM study, as likely contributors to the IFM signal.
There is also NO signal in any of the CLL or NHL trials using Revlimid Dex.
The key point of my comments is IN THE US - Revlimid-Dex is used - melphalan is not. And in 180,000 patients THERE IS NO SM signal - you ignore that. 0.4% SM rate in 180,000 patients. That is much lower than the minimum "norm" or background rate of at least 5-6%. There is no problem with Rev-Dex - in fact it appears IMO to DECREASE the risk of SM. 0.4% vs 5-6%.
And the 'new" data that came from the EU group last week answers a lot of questions positively imo with respect to Rev-dex:
"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."
Rev-Dex is what is approved in the US. There is no problem with Rev-Dex. IT appears to DECREASE SM rates. Period.
Many of the analysts who cover are doctors..
Citi covered the different trials in detail and came away with the facts that lead them to think the French trial was different..
Some had DOUBLE STEM CELL transplants..known to increase risk of SPMs..
Mephalan has an 8 fold increase in risk..
The French trial had patients that were treated with Velcade before and were moved over..thus very sick..heavily pretreated people..BUT watch..even in this trial you will most likely see Overall Survival..showing Revlimid is keeping people alive..
The data will speak for itself at the two upcoming conferences..
When I said melphalan was not used in the US - I meant in combination with Revlimid. It is of course used before SC trans - but not with Revlimid
Revlimid-Dex is used and again - the 180,000 patients on it have a very very low 0.4% SM rate vs minimum 5-6% norm.
Also remember Dr Palumbo says the norm for Multiple Myeloma patients is that 2% a yr get SM - every yr and its cumulative - so you should expect a MM population on drug for 36 months to have at least a 6% SM rate. This is normal background rate.
Revlimid is a miracle drug - it will also work in CLL and NHL. Rev-Dex has about the least side effects of an effective cancer drug ever.
Some day Revlimid will eclipse Avastin as the largest selling Oncology drug in the world. I thank God it is available for patients.
Melphan is used in the US, regularly in the SCT process and it is used sometimes in HR cases in the maintenance therapy regimen.
Maintenance therapy in the treatment of all cancers is a relatively NEW theory being used in the US. And as with all medical theories as what is now done comes with new information over time on whether it is the proper thing to do. With the recent articles on cancer survival rates increasing, maintenance therapy will probably be here to stay for awhile and over time we will discover whether it is viable in its risks vs. benefit scenarios.
It is unrealistic to me, that anytime you continue to take drugs, long term, there will be no risk. My husband is on a Revlimid/Velcade maintenance therapy after tandem transplants. I have not felt confident about it and it is understood now that a 3 year maintenance is a target stated, but they will attempt to keep him on the regimen for as long as he can tolerate it. Viewing it like taking blood pressure medicine. I would like him to stop, but I will support his decision one way or the other, but not without serious reservations and concerns. When we signed the stream of paper at the time treatment began, ALL the chemotherapy drugs had secondary cancers as a primary risk factor.
Thanks for the conversation guys, it is one that is needed.
Steven, I think you're still missing the point. I don't think anyone is questioning the benefits of Revlimid/dexamethasone, which is typically used soon after diagnosis or at relapse. You're also right that Revlimid is rarely given in combination with melphalan in the U.S. -- but the main concern is about melphalan (given before a stem cell transplant) followed by long-term Revlimid maintenance therapy after stem cell transplantation (no dexamethasone). Melphalan can damage the DNA, potentially making people susceptible to another cancer when treated somewhat later with the immunomodulator Revlimid. The two drugs don't have to be given at the same time.
The trials are showing that Revlimid maintenance certainly delays progression, significantly. But does it also extend survival? It's not clear yet. If it doesn't increase survival, then is it really beneficial? Why take a drug for a couple of years (keep in mind there are substantial costs, side effects, and inconveniences of taking these drugs) if it doesn't increase survival? Instead, enjoy the drug-free year or two and start treatment again at relapse. In the meantime, maybe more effective drugs with fewer side effects will be available.
The principal investigator of the CALG-B trial said we will see an Overall Survival benefit in May data. This is amazing because this trial allowed CROSSOVER. And still the PFS benefit is huge and it likely will still show Overall Survival. And of course the EMEA says we dont need OS if there is a dramatic PFS benefit.
o EMEA Statement:”PFS represents an accepted intermediate efficacy endpoint. Considering the very long natural history for patients with newly diagnosed follicular lymphoma with a median survival of about 10 years, PFS remains the only realistic efficacy endpoint.”
The benefit of Revlimid in maintenance is significant. Once the OS benefit is revealed in a few weeks - even with crossover allowed - the debate will end. Revlimid will become the largest selling oncology drug in history imo once approved in NHL.
Melphalan WITH Rev/Dex is absolutely used in maintenance therapy in the US for High Risk Myeloma patients. I would agree it is not common, but would disagree that it is not used in this manner. It most definitely is in certain situations.
Wow, I guess if you work for Celgene, or if you own Celgene stock, you can get really sensitive about anything critical of the company's main source of revenue -- Revlimid.
Where should I start? Well, how about suggesting that we should all agree to drop this 180,000 patient number and the secondary cancer rates observed among those patients.
First of all, according to the Celgene CEO in the company's last quarterly earnings call, the number is actually 170,000 patients.
Second, it's not patients who have been treated with only Revlimid and dexamethasone, and it's not just patients from the U.S. It's the total number of patients anywhere in the world who have ever been treated with Revlimid, regardless of how long they received the drug and regardless of what drug (if any) they received it with.
Now, given that long-term treatment with Revlimid is still relatively new, and given that it's not very common outside the U.S., we can guess that most of those 170,000 patients didn't get the drug for a particularly long time. So the rate of secondary cancer among those 170,000 patients tells us basically bupkis about the safety of Revlimid as a long-term myeloma treatment.
But let's accept the rest of the arguments made by the Celgene/Revlimid fanboys. Let's accept that the problems with Revlimid really only occur in patients who have had stem cell transplants and/or who have received DNA-damaging chemotherapy like melphalan at some point prior to potential treatment with Revlimid.
So who are you going to give Revlimid to?
Well, following the fanboy logic, you won't give it to young patients who have opted for a stem cell transplant up front.
You also won't give it to patients who have opted for UAMS-type regimens involving two transplants and treatment with multiple chemotherapy agents, such as VDT-PACE.
And you won't give Revlimid to all those older patients who, if they're not healthy enough to do a stem cell transplant, thought leaders like Dr. Kyle say should be treated first with melphalan in combination with prednisone and/or thalidomide.
So following the fanboy logic, we really only should be giving Revlimid to patients who don't opt for, or who can't have, stem cell therapy, and who also decide to go against the recommendation of many myeloma experts and not have upfront therapy with any chemotherapeutic agent such as melphalan.
This is the logical conclusion to statements like "the problem is stem cell transplants" and "the problem is melphalan and other DNA-damaging agents". And it's a conclusion that, I think, would lead to Revlimid being used in a rather limited number of myeloma patients.
• Source: Leukemia & Lymphoma - Incidence of Second Malignancies in 589 Myeloma Patients was 6.6%."
• SEER database shows 6.1% SM risk based upon 28,838 MM patients. Increased risk of developing a second malignancy was associated with pts diagnosed with MM at ages younger than 70 years.
• IFM 2005-01 (Velcade + Dex) Study – 43% of Pts Rolled Into IFM 2005-02 . DCEP Consolidation rate 39%. Higher Risk of Secondary Malignancies Stem Cell Transplant Followed by DCEP Consolidation
• Celgene has conducted an analysis of 15 Revlimid trials and finds no increase in tumors and an overall rate lower than expected in this population.
• The Company analyzed standardized incidence ratios, which take time into consideration. The company reviewed data from myeloma regulatory trials, MM-009 and MM-010 (relapsed refractory studies), and MM-015 and MM-020 (the newly diagnosed myeloma trials), and compared this to the U.S. SEER cancer registry, which showed a very low incidence rate of secondary primary malignancies. The company has also stated there was no significantly increased risk of AML MDS and no significant increased risk of solid tumors.
• The number of reported observations of “B-cell malignancies” at this time is so low that comparisons to registry data are not meaningful.
• Celgene analyzed its pharmaco-vigilance database and found the incidence of second primary malignancies among more than 170,000 patients is less than one half of 1%.(sunsequently updated to 180,000 and 0.4% in a recent webcast)
• The MM-015 study there were eight malignancies in the induction arm (MP-R) but five malignancies in the maintenance arm (MPR-R). While both were higher than control (two), if the drug was causing tumors, one would expect more tumors in the maintenance arm than the induction arm.
• Celgene also believes that there was an imbalance of patients with high-risk cytogenetics in the Revlimid arms versus control in MM-015. Specifically, there were nine patients who had a rare “triple mutation” that confers higher risk to AML and all were in the Revlimid arm. Of the five cases of AML, cytogenetics was available for three, and all three had the triple mutation.
the risk benefit is largely in the favor of the Revlimid maintenance regimen (which in practice will end up being Rev-Dex avoiding the known SPM enhancer melphalan anyway). The PFS benefit is STUNNING.