Home » News

Revlimid And Secondary Cancers: Melphalan May Be The Culprit

8 Comments By and
Published: Mar 7, 2014 5:04 pm

The findings of a recent retrospective study may alleviate some of the concerns patients and physicians have had about Revlimid and the risk of secondary cancers.

The study found that the risk of developing a secondary cancer as a result of treatment with Revlimid occurred mainly when a patient had been treated with oral melphalan at the same time as Revlimid.

Revlimid (lenalidomide) did not appear to be associated with an in­creased risk of secondary cancers when administered together with dexamethasone or cyclophosphamide.

In addition, although treatment with Revlimid before or after high-dose melphalan – which is typically used as part of the stem cell transplant process – also appeared to increase the risk of developing secondary cancers, the increase was not statistically signifi­cant,­ and the increase in risk was not as much as occurred with Revlimid plus oral melphalan (Alkeran).

The study investigators found that patients who received Revlimid in com­bi­na­tion with low-dose oral mel­phalan were near­ly five times as likely to develop a second blood cancer compared to patients who received melphalan alone.

Based on these results, the investigators suggest cyclophosphamide or drugs that work differently than melphalan be used in combination with Revlimid, rather than oral melphalan, for the treatment of multiple myeloma.

They do not make any specific recommendations regarding the use of Revlimid before or after stem cell transplantation in current clinical practice.  Instead, they suggest further studies to confirm whether longer exposure to Revlimid increases the risk of secondary cancers and to establish the optimal duration of main­tenance therapy.

Background

Over the last decade, significant advances have been made in the treat­ment of multiple myeloma due to the introduction of the novel agents thalidomide (Thalomid), Revlimid, Velcade (bortezomib), and most recently Kyprolis (carfilzomib) and Pomalyst (pomalidomide, Imnovid).

As myeloma patients live longer because of these improved treatments, the development of secondary can­cers has become a greater concern.

Many factors affect a person’s risk of developing cancer, including age (the risk of developing cancer in­creases with age), pre-existing conditions (myeloma patients are more likely than the general population to develop another cancer), and treatments the person receives (several myeloma treatments are known to increase a person’s risk of developing a secondary cancer).

Previous studies have shown that long-term exposure to melphalan increases a myeloma patient’s risk of developing a second cancer.

Recent studies have also shown that newly diagnosed patients who receive Revlimid maintenance therapy following melphalan-based treatment are more likely to develop secondary cancers than patients who do not receive Revlimid maintenance therapy (see related Beacon news articles).

At the same time, another study showed that Revlimid plus dexamethasone therapy did not increase the risk of developing secondary cancers in relapsed myeloma patients.

Thus, the investigators of the current study were interested in assessing the relationship between Revlimid, melphalan, and secondary cancers in newly diagnosed myeloma patients.

Study Design

An international group of researchers retrospectively analyzed the results from seven Phase 3 clinical trials that investigated Revlimid therapy in newly diagnosed myeloma patients.

The studies included 3,218 newly diagnosed myeloma patients who underwent treatment; 81 percent of the patients received Revlimid and 19 percent did not.

The patients were recruited for trial participation between January 2000 and December 2012.

The median age of all the patients was between 65 years and 74 years old.

Across the seven studies, patients were treated with Revlimid plus low-dose oral melphalan (29 percent), Revlimid before or after high-dose melphalan (24 percent), Revlimid plus dexamethasone (16 percent), Revlimid plus cyclophosphamide (13 percent), high-dose melphalan (7 percent), oral melphalan plus thalidomide (7 percent), or oral melphalan (5 percent).

Study Results

The investigators found that 3 percent of the patients who received Revlimid and 3 percent of the patients who did not receive Revlimid developed secondary cancers.

However, further analysis showed that after three years and five years, secondary cancer rates – particularly rates of secondary blood cancers – were higher for those who were treated with Revlimid.

After three years, 3.9 percent of patients treated with Revlimid and 3.3 percent of patients who did not receive Revlimid developed secondary cancers.  In particular, 1.4 percent of patients treated with Revlimid de­vel­oped a secondary blood cancer compared to 0.4 percent of patients who did not receive Revlimid.

Likewise, after five years, 6.9 percent of patients treated with Revlimid and 4.8 percent of patients who did not receive Revlimid as part of their therapy developed secondary cancers.  In particular, 3.1 percent of pa­tients treated with Revlimid developed a secondary blood cancer compared to 1.4 percent of patients who did not receive Revlimid.

The investigators also found that patients who received Revlimid for more than 24 months were more likely to develop secondary blood cancers and more likely to develop secondary solid cancers than those who received it for less than 24 months.

Impact Of Other Treatments

The investigators attribute the difference in secondary blood cancer rates mainly to an increased risk in patients exposed simultaneously to both Revlimid and oral melphalan – as opposed to Revlimid given simultaneously with cyclophosphamide or dexamethasone, or Revlimid before or after plus high-dose melphalan.

They found that patients treated with Revlimid plus oral melphalan were nearly five times as likely to develop a second blood cancer compared to those treated with melphalan alone.

There was a trend toward higher risk of developing a second blood cancer among patients treated with Revlimid before or after high-dose melphalan compared to those treated with melphalan alone.  However, the increased risk was not statistically significant.

Moreover, patients treated with Revlimid plus oral melphalan were more than three times as likely to develop a second blood cancer compared to those treated with Revlimid before or after high-dose melphalan.

Impact Of Secondary Cancers On Survival

The researchers then investigated the impact secondary cancers had on overall survival.

After a median follow-up of 26 months, 21 percent of the patients had died.

Overall, the death rate was lower among patients treated with Revlimid.

Among the patients treated with Revlimid, 21 percent died; 1 percent died due to secondary cancers, 6 percent due to side effects, and 14 percent due to progression of their myeloma.

Among those who were not treated with Revlimid, 24 percent died; 1 percent due to secondary cancers, 7 percent due to side effects, and 17 percent due to disease progression.

There was a trend toward a higher rate of death due to secondary cancers in the Revlimid-treated group.  However, in both groups, the most common cause of death was progression of their myeloma followed by side effects.

For more information, please refer to the study in the journal The Lancet Oncology (abstract).

Photo by rodrigo senna on Flickr – some rights reserved.
Tags: , , , , , ,


Related Articles:

8 Comments »

  • Mulitbilly said:

    Nice write up Beacon staff!

    In case you missed this article on the debate of using alkylating agents (including melphalan) as an upfront mm treatment.

    http://journals.lww.com/oncology-times/blog/onlinefirst/pages/post.aspx?PostID=875

  • Eric said:

    Is this going to change the way Melphalan is used by the MM medical teams? Sounds like there is cautionary evidence that should cause one to separate Melphalan from Revlimid as a combo treatment.

  • Mulitbilly said:

    Not to sound USA-centric, but is melphalan even prescribed that much any more in the USA for mm (outside of its use as an HD-chemo agent prior to an ASCT)?

  • Mark said:

    It is always important to remember that patients with MGUS have a higher incidence of MDS (myelodysplastic syndromes) even if they have never been treated.

    "Our findings confirm the Swedish study16 and support the hypothesis that there is an inherent increased risk of MDS in patients with plasma cell disorders that is independent of therapy for myeloma. Our study also suggests that the risk is smaller than previously reported with a risk ratio of 2.0 for AML and MDS. Whether MGUS is a biomarker of patients who have an inherent increased risk of developing hematologic disorders, including myeloma and MDS, or the clonal plasma cell has a causal role in the development of acute leukemia is yet to be elucidated."
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676476/

    Long term Revlimid use seems to impair the bodies ability to produce CD4+ helper t cells.

    "Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 − effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 − /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance."

    Read More: http://informahealthcare.com/doi/abs/10.3109/10428194.2013.865182

    That could lead to more secondary cancers long term. Only time will tell if it does. I know we will have you keeping us up to date on the latest statistics!

  • stann said:

    I stopped maintenance Revlimid after 2 years because after tandem transplants, I had been exposed to high does melphalan twice. The original plan was to keep me on Revlimid a lot longer when I started. So the "decision tree" might have swayed towards staying on Rev longer, assuming I'm understanding this study.
    But having been exposed twice to melphalan, I think I'll be content staying off Revlimid.

  • stann said:

    MulitBilly -- I think it is prescribed as one of the treatments for those who can't have an SCT.

  • Myeloma Beacon Staff said:

    Thanks for all the great comments and perspectives, everyone.

    Yes, oral melphalan therapy is relatively uncommon in the U.S. It seems to be more common in Europe and elsewhere in the world, in part due to cost considerations (it's been generic for a very long time). Also, as Stann suggested, it seems to be favored more for patient who are considered ineligible for a stem cell transplant.

    Only a very limited number of the Beacon's readers who completed a poll on the subject said that their initial treatment regimen after diagnosed included melphalan:

    http://www.myelomabeacon.com/forum/weekly-poll-initial-myeloma-therapy-2013-t2137.html

  • Randy Strode said:

    My question then is since I am a prime candidate for an upcoming autologous stem cell transplant in the near future. I believe that HD melphalan is used to kill the myeloma cells in the bone marrow pre-transplant. Is it safe to use this in the stem cell transplant or are their other agents they are using preferred now? Or since it is a single HD and not long term oral use would the risk then be a lot lower?