- The Myeloma Beacon - https://myelomabeacon.org -

Revlimid Maintenance Therapy: Three Major Studies Clarify The Benefits And Risks

By: The Myeloma Beacon Staff; Published: May 11, 2012 @ 2:49 pm | Comments Disabled

The results of the three major clinical trials investigating Revlimid maintenance therapy were published yesterday in three separate articles in the New England Journal of Medicine.

The articles were accompanied by an editorial summarizing the study findings and discussing their significance for the treatment of multiple myeloma patients.

All three clinical trials involved newly diagnosed multiple myeloma patients.  The patients in the trials first underwent initial treatment that in some cases included Revlimid [1] (lenalidomide).  In two of the three trials, the initial treatment also included a stem cell transplant.

After the initial treatment, patients were randomly assigned to take either Revlimid or a placebo on a regular basis until they relapsed.  This kind of extended treatment, given after a more intensive initial course of therapy, is known as maintenance therapy.

MORE INFORMATION

News articles about:
- maintenance therapy [2]
- Revlimid [3]
- second cancers [4]
- prognosis and survival [5]

Forum discussions about:

- maintenance therapy [6]

- Revlimid [7]

- second cancers [8]

- prognosis and survival [9]

All three trials found that Revlimid maintenance therapy significantly delays the progression of multiple myeloma.  In younger newly diagnosed myeloma patients who had undergone a stem cell transplant, for example, Revlimid maintenance therapy nearly doubled the time to relapse.

Only one of the three trials, however, found that Revlimid maintenance therapy improved the overall survival of patients. In the other two trials, patients who were on Revlimid maintenance therapy typically lived no longer than those who took the placebo.

In addition, all three trials revealed that the patients taking Revlimid were significantly more likely to experience a second cancer than those who took a placebo.

Prior to the publication of yesterday’s articles, findings from the three trials already had been presented and discussed at several conferences in recent years.  The findings are therefore well known among myeloma specialists (and long-time Beacon readers).

Nevertheless, publication of the results in a major peer-reviewed medical journal is a clear signal that the medical community views the findings as significant and relevant to the treatment of myeloma patients.

At the same time, the publication of the articles in unlikely to settle the important questions many physicians and patients still have about the value of maintenance therapy with Revlimid.

Among those questions, perhaps the most important is whether delaying disease progression is worthwhile when it requires long-term treatment, often with side effects, with an uncertain benefit in terms of overall survival.

Details Of The Three Trials

The trial results that were published yesterday were from three multi-center Phase 3 clinical trials being carried out in the United States and in Europe.

Two of the trials, known as the CALGB and IFM trials, were carried out with younger newly diagnosed multiple myeloma patients who also underwent a stem cell transplant as part of their initial myeloma therapy.

Patients in the third trial, known as the MM-015 study, were newly diagnosed myeloma patients as well.  However, they were at least 65 years of age and not eligible for a transplant.

CALGB Study

The CALGB trial registered patients between April 2005 and July 2009 at centers across the United States.  Patients had to be newly diagnosed and under the age of 70 years.  A specific induction treatment was not required for the trial.  All patients had to undergo a stem cell transplant after their initial treatment.

After their transplants, patients in the trial were randomly assigned to receive either 10 mg of Revlimid (231 patients) or a placebo (229 patients) as daily maintenance therapy.  The study was “double blind,” meaning that neither patients nor their physicians knew which patients were receiving Revlimid and which were receiving a placebo.

In December 2009, an interim analysis of the trial results showed a statistically significant difference in the rate of disease progression between the two patients groups.  The study was therefore unblinded, and patients who had been receiving the placebo were given the option to start taking Revlimid.  Of 128 patients eligible to make this switch, 86 chose to do so.

Patients who received Revlimid maintenance therapy during the study stayed on the maintenance regimen until their disease progressed.

IFM Study

The IFM trial was conducted in France, Switzerland, and Belgium, registering patients between July 2006 and August 2008.  Participants in the trial had to be newly diagnosed myeloma patients under the age of 65.

Most of the participants were initially treated with one of two treatment regimens: Velcade [10] (bortezomib) and dexamethasone [11] (Decadron), or vincristine [12] (Oncovin), doxorubicin [13] (Adriamycin), and dexamethasone.  About a quarter of the patients also had their initial treatment augmented with additional combination therapy involving the DCEP regimen: dexamethasone, cyclophosphamide [14] (Cytoxan), etoposide [15], and cisplatin.

After their initial therapy, patients underwent a stem cell transplant.  One fifth of the patients also went on to receive a second transplant.

After patients had completed their transplants, they received two 28-day cycles of treatment consisting of 25 mg of Revlimid, administered on days 1 to 21 of each cycle.  Then, patients were randomly selected to receive either 10 mg Revlimid daily (307 patients) or a placebo (307 patients) until disease relapse.  As in the CALGB trial, the administration of Revlimid and the placebo was double blind, and was intended to continue until disease relapse.

In July 2010, the study was unblinded after a data analysis showed a statistically significant benefit to Revlimid treatment in terms of delaying disease progression.  However, no patients were switched from the placebo-treated group to the Revlimid treated group.

In January 2011, an interim analysis of the trial data revealed a significant difference in the rates of second cancer between the two patient groups.  The researchers leading the study therefore decided to halt all further dosing of Revlimid during the trial.

MM-015 Study

The third and final trial, the MM-015 study, was conducted in Europe, Australia, and Israel.  Patients were recruited from February 2007 until September 2008, and they had to be 65 years of age or older and transplant ineligible.

Each MM-015 trial participant was randomly assigned to one of three treatment groups.

The first group (154 patients) – denoted “MP” – received nine 4-week cycles of treatment with melphalan [16] (Alkeran), prednisone [17], and a placebo as initial therapy, followed by “maintenance” therapy with a placebo.

The second group (153 patients) – denoted “MPR” – received nine 4-week cycles of treatment with melphalan, prednisone, and Revlimid (10 mg on days 1 to 21 of the cycle), followed by “maintenance” therapy with a placebo.

The third group (152 patients) – denoted “MPR-R” – received the same upfront treatment as the second group (melphalan, prednisone, and Revlimid), but received Revlimid as maintenance therapy.  The Revlimid maintenance dose was 10 mg on days 1 to 21 of a 28 day cycle.

As in the CALGB and IFM trials, the dosing of Revlimid and a placebo in the MM-015 also was double blind.  The trial was unblinded in May 2010 after a data analysis showed patients receiving Revlimid maintenance therapy had a longer time to disease progression than patients on placebo.  As in the IFM trial, however, no patients were switched during the trial from the placebo group to the Revlimid group.

Progression-Free Survival

Patients receiving Revlimid maintenance in all three studies experienced significantly longer progression-free survival times than patients who did not receive Revlimid maintenance therapy.

CALGB Study

CALGB Progression-Free Survival [18]In the CALGB-study, patients on Revlimid maintenance had longer progression-free survival times and rates, even after the study was unblinded in December 2009 and patients in the placebo group were allowed to begin Revlimid maintenance.

(Click here [18] or on the image to the right to see a graph of the key CALGB progression-free survival results.)

At a median follow-up time of 34 months, 37 percent of patients receiving Revlimid maintenance had progressed or died, compared to 58 percent of patients who did not receive Revlimid maintenance.

The three-year progression-free survival rate was 66 percent among patients receiving Revlimid maintenance, compared to 39 percent among patients not receiving Revlimid maintenance.

The median time to disease progression was 46 months for patients on Revlimid maintenance, compared to 27 months for patients not receiving Revlimid maintenance.

IFM Study

When the study was unblinded at a median follow-up time of 30 months, the median time to disease progression was almost double (41 months) for patients on Revlimid maintenance, compared to patients not receiving Revlimid maintenance (23 months).

The three-year progression-free survival rate was 59 percent among patients receiving Revlimid maintenance, compared to 35 percent among patients not receiving Revlimid maintenance.

At a median follow-up time of 45 months, the four-year progression-free survival rate was still significantly higher for patients receiving Revlimid maintenance (43 percent) than for patients who did not receive Revlimid maintenance (22 percent).

MM-015 Study

As previously reported for the MM-015 study, the median progression-free survival time from the start of the trial was significantly longer for patients receiving Revlimid maintenance (MPR-R, 31 months) than for patients receiving MPR (14 months) or MP (13 months).

When the researchers compared progression-free survival times from the start of maintenance therapy, they found that the median was 26 months with Revlimid maintenance, compared to 7 months without maintenance.

The progression-free survival benefit associated with Revlimid maintenance, however, was not found to be statistically significant in patients over the age of 75 years: median progression-free survival times in this patient population were 19 months with MPR-R, 12 months with MPR, and 15 months with MP.

Overall Survival

The CALGB study showed an overall survival benefit for patients treated with Revlimid maintenance, but the other two studies did not.

CALGB Study

CALGB Overall Survival [19]After a median follow-up time of 34 months, 85 percent of the patients receiving Revlimid maintenance and 77 percent of the patients in the placebo group were still alive.

(Click here [19] or on the image to the right to see a graph of the key CALGB overall survival results.)

The estimated three-year overall survival rate was higher for the Revlimid group (88 percent) than the placebo group (80 percent), even though most of the placebo group began Revlimid maintenance when the study was unblinded.

A subgroup analysis showed that patients treated with Revlimid induction therapy had significantly longer survival if they received Revlimid maintenance, compared to those who received a placebo.  The same analysis also showed that Revlimid maintenance did not provide a survival advantage for: patients who were treated with thalidomide induction therapy; patients who had elevated beta-2 microglobulin levels; or patients who achieved a complete response prior to the start of maintenance therapy or placebo.

IFM Study

IFM Overall Survival [20]Unlike the CALGB study, the estimated four-year overall survival rate was similar for the Revlimid maintenance (73 percent) and placebo (75 percent) groups.  The study investigators pointed out that these rates are high and could be due to the use of intensive treatment as well as effective therapies at relapse.

(Click here [20] or on the image to the right to see a graph of the key IFM overall survival results.)

The researchers also stated that a longer follow-up is needed to fully assess the effect of Revlimid maintenance on overall survival.

The investigators of the CALGB study wrote in their article that the difference in survival results between the CALGB and IFM trials may be due to differences in induction and consolidation therapies, the use of one versus two transplants, and the discontinuation of maintenance therapy.  They suggested that longer follow-up and additional studies might clarify the difference in results.

MM-015 Study

As was the case with the IFM study, Revlimid maintenance did not extend overall survival in the MM-015 study.

After a median follow-up time of 30 months, the estimated overall survival time was 42.5 months for the MPR-R group and was not yet reached for the MPR and MP groups.

The three-year overall survival rate was similar for all three treatment groups.  Specifically, the survival rates were 70 percent for the MPR-R group, 62 percent for the MPR group, and 66 percent for the MP group.

Second Cancers

In all three studies, patients receiving Revlimid maintenance experienced higher rates of second cancer than patients not receiving Revlimid maintenance.

The rate of second cancer in these studies is a key reason U.S., Canadian, and European authorities recently added warnings to Revlimid’s prescribing information about the risk of second cancer associated with the drug (see related Beacon [4] news articles).

In the CALGB study, 8 percent of patients receiving Revlimid maintenance experienced secondary cancers, compared to 3 percent of patients who did not receive Revlimid maintenance. Of the 8 percent in the Revlimid maintenance group, 4 percent were blood-related cancers and 4 percent were solid tumors (excluding non-melanoma skin cancers).

In the IFM study, the researchers observed 32 cases of second cancers in 26 patients receiving Revlimid maintenance and 12 cases in 11 patients not receiving Revlimid maintenance. Based on these cases, they calculated that 3.1 percent of patients receiving Revlimid maintenance developed a second cancer each year and 1.2 percent of patients not receiving Revlimid maintenance developed a second cancer each year.

In the MM-015 study, the rate of second cancers at three years was reported to be 7 percent for patients receiving MPR-R, 7 percent for patients receiving MPR, and 3 percent for patients receiving MP.

Implications Of The Three Studies

As one might expect, the authors of the three studies are relatively positive, overall, about the benefits of Revlimid maintenance therapy.

The MM-015 investigators, for example, write in their conclusion that “MPR-R is an effective treatment for patients with newly diagnosed multiple myeloma who are ineligible for transplantation.

Similarly, the authors of the IFM article believe that their data, along with the CALGB data, “support the use of [Revlimid] maintenance therapy” after stem cell transplantation in patients with myeloma.

The IFM investigators also add, however, that the “impressive benefits” of Revlimid maintenance therapy “must be weighed against the increased risk” associated with that therapy.

An independent perspective on the three articles that were published yesterday is available in the form of an editorial that accompanied the articles. The editorial was written by Professor Ashraf Badros of the University of Maryland’s Greenbaum Cancer Center.

Prof. Badros notes in his editorial that the three studies provide “compelling evidence” that Revlimid maintenance therapy delays relapse. He adds, however, that there still are important questions relevant to this therapy that need to be answered.

For example, is delaying disease relapse actually what is important when testing a maintenance therapy?

With maintenance therapy, delaying relapse is achieved by continuously treating patients with a drug that, for some patients, will involve frequent side effects. Thus, even if the therapy results in some additional overall survival, will it be enough to be worthwhile given the side effects patients experience during the maintenance therapy?

Similarly, can physicians be certain there actually is a survival benefit to maintenance therapy? Is it possible that, by treating a patient continuously with low-dose Revlimid, the patient’s myeloma evolves such that, when relapse occurs, the disease is more resistant to treatment and there is no net survival benefit to the maintenance therapy?

Prof. Badros finds it difficult to come to a clear conclusion at the end of his editorial. “Whether these data establish a new standard of care for myeloma may be debatable,” he writes. He then starts a concluding sentence that sounds like a strong endorsement of Revlimid maintenance therapy … until one gets to a key qualifying statement at the end.

“The data on progression-free survival,” he said, “provide support for the use of [Revlimid] maintenance therapy after careful assessment of the risks and benefits.”

For more information, see the studies (CALGB [21], IFM [22], and MM-015 [23]) and the accompanying editorial [24] in the New England Journal of Medicine (abstracts).

Note: The graphs that are included with this article are from the original journal articles and are copyrighted property of the Massachusetts Medical Society. For copyright reasons, only a limited number of graphs have been included. The ones that have been selected were chosen because they more fully describe important data, and because they permit more complete comparisons of important results from the different trials.


Article printed from The Myeloma Beacon: https://myelomabeacon.org

URL to article: https://myelomabeacon.org/news/2012/05/11/revlimid-lenalidomide-maintenance-therapy-studies-clarify-benefits-and-risks/

URLs in this post:

[1] Revlimid: https://myelomabeacon.org/resources/2008/10/15/revlimid/

[2] maintenance therapy: https://myelomabeacon.org/tag/maintenance-therapy/

[3] Revlimid: https://myelomabeacon.org/tag/Revlimid/

[4] second cancers: https://myelomabeacon.org/tag/secondary-cancer/

[5] prognosis and survival: https://myelomabeacon.org/search/prognosis+survival/

[6] maintenance therapy: https://myelomabeacon.org/forum/search.php?keywords=maintenance&terms=any&author=&sc=1&sf=titleonly&sr=topics&sk=t&sd=d&st=0&ch=300&t=0&submit=Search

[7] Revlimid: https://myelomabeacon.org/forum/search.php?keywords=Revlimid&terms=any&author=&sc=1&sf=titleonly&sr=topics&sk=t&sd=d&st=0&ch=300&t=0&submit=Search

[8] second cancers: https://myelomabeacon.org/forum/search.php?keywords=secondary&terms=any&author=&sc=1&sf=titleonly&sr=topics&sk=t&sd=d&st=0&ch=300&t=0&submit=Search

[9] prognosis and survival: https://myelomabeacon.org/forum/search.php?keywords=prognosis+survival+expectancy&terms=any&author=&sc=1&sf=titleonly&sr=topics&sk=t&sd=d&st=0&ch=300&t=0&submit=Search

[10] Velcade: https://myelomabeacon.org/resources/2008/10/15/velcade/

[11] dexamethasone: https://myelomabeacon.org/resources/2008/10/15/dexamethasone/

[12] vincristine: https://myelomabeacon.org/resources/2008/10/15/vincristine/

[13] doxorubicin: https://myelomabeacon.org/resources/2008/10/15/doxorubicin/

[14] cyclophosphamide: https://myelomabeacon.org/resources/2008/10/15/cyclophosphamide/

[15] etoposide: https://myelomabeacon.org/tag/etoposide/

[16] melphalan: https://myelomabeacon.org/resources/2008/10/15/melphalan/

[17] prednisone: https://myelomabeacon.org/resources/2008/10/15/prednisone/

[18] Image: http://static9.light-kr.com/images/original/research/RevMaintPFS-CALGB.PNG

[19] Image: http://static9.light-kr.com/images/original/research/RevMaintOS-CALGB.PNG

[20] Image: http://static9.light-kr.com/images/original/research/RevMaintOS-IFM.PNG

[21] CALGB: http://www.nejm.org/doi/full/10.1056/NEJMoa1114083

[22] IFM: http://www.nejm.org/doi/full/10.1056/NEJMoa1114138

[23] MM-015: http://www.nejm.org/doi/full/10.1056/NEJMoa1112704

[24] editorial: http://www.nejm.org/doi/full/10.1056/NEJMe1202819

Copyright © The Beacon Foundation for Health. All rights reserved.