Revlimid® Treatment and Multiple Myeloma

Revlimid is effective treatment for all stages of Multiple Myeloma. Understand the risk of developing a secondary cancer

Revlimid® Approved for Multiple Myeloma

The United States Food and Drug Administration (FDA) initially approved Revlimid® (lenalidomide), in combination with dexamethasone, for the treatment of multiple myeloma in patients who have received at least one prior therapy in 2006.(1) Since then Revlimid as been incorporated into treatment regimens in the following settings because clinical trials have demonstrated that it prolongs myeloma patient survival in these settings.

  • Initial treatment for newly diagnosed patients.
  • Maintenance therapy
  • Treatment of recurrent or refractory myeloma

About Revlimid

Revlimid is an orally administered immunomodulatory agent that is a derivative of thalidomide, which is a very active agent for the treatment of multiple myeloma. Revlimid however has less toxicity than thalidomide. Revlimid fights cancer through several biological mechanisms, many of which are still being evaluated. One action Revlimid uses against cancer is to prevent or reduce blood vessel growth to the cancer. This ultimately “starves” the cancer cells of nutrients and oxygen.

Revlimid Increases Risk of Some New Cancers

Patients with newly diagnosed multiple myeloma who receive Revlimid® (lenalidomide) may be at an increased risk of developing new cancers, according to a safety announcement released by the U.S. Food and Drug Administration (FDA).

Clinical trials have been ongoing since Revlimid was approved in 2006 and new data indicates that newly diagnosed patients treated with Revlimid have an increased risk of developing acute myelogenous leukemia (AML), myelodysplastic syndromes, and Hodgkin’s lymphoma as a result of Revlimid treatment.

The FDA reports that there was nearly a three-fold increase in new cancers in the Revlimid group compared to the placebo group, with 65 second primary cancers among 824 Revlimid patients and 19 second primary cancers among 665 placebo patients. The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years.

RVD

For example chemotherapy induction Revlimid (lenalidomide), Velcade (bortezomib), and dexamethasone (RVD) followed by ASCT, two RVD consolidation cycles and 1 year of Revlimid maintenance therapy attained a very good partial response in 58% of patients by the completion of 3 cycles of RVD induction therapy. This improved to 70% following ASCT, and 87% after Revlimid consolidation therapy. Maintenance Revlimid resulted in and upgrade of the best response in 27% of patients and 3-year overall survival was 100%.

The RVD and ASCT treatment program is one example of how physicians combine induction, ASCT, and maintenance therapy.

Revlimid and Dexamethasone for Induction

The most commonly studied Revlimid regimen for the initial treatment of patients with myeloma involves the addition of dexamethasone. Researchers involved in a multicenter trial reported that time to tumor progression and progression-free survival in patients receiving Revlimid and dexamethasone were worse in patients with adverse cytogenetics (higher risk features) compared with patients with standard risk features.[1] Median progression-free survival was 18.5 months for 16 patients with adverse cytogenetics compared with 36.5 months for 84 patients with standard risk features. However, because of the success of salvage therapy, there were no differences in overall survival between the good and bad risk groups.

Revlimid, Cytoxan, and Dexamethasone for Induction

Researchers from the Mayo Clinic reported an overall response rate of 83% for 53 patients with newly diagnosed multiple myeloma with the combination of Revlimid, Cytoxan® (cyclophosphamide), and dexamethasone.[2] The complete and very good partial remission rate was 40%. This regimen appeared to be well tolerated.

Relvimid, Velcade®, and Dexamethasone for Induction

Researchers affiliated with a multicenter U.S. clinical trial reported the results of a Phase I/II evaluation of induction with the combination of Revlimid, Velcade® (bortezomib), and dexamethasone in previously untreated patients with myeloma with high-risk features.[3] There were 63 patients in this study, and 39 had abnormal cytogenetics. All patients in this study had a partial or greater response, and 66% had a very good partial response or complete response. Among patients with adverse cytogenetics, 79% had a very good partial response or better. Fifteen patients proceeded to transplantation following successful completion of stem cell collection. This regimen appears to be very active in producing remissions in patients prior to autologous stem cell transplantation.

Revlimid, Velcade, Cytoxan, and Dexamethasone for Induction

Researchers involved in a U.S. multicenter trial reported that the combination of Velcade, dexamethasone, Cytoxan, and Revlimid for initial treatment of patients with myeloma was well-tolerated and produced a high response rate.[4] Preliminary data showed that 100% of patients achieved a partial response or better, with approximately 50% achieving a complete response. These authors suggest that this regimen is tolerable and highly active in newly diagnosed patients with myeloma.

Revlimid for Consolidation/Maintenance

Italian researchers presented the results of a study where Revlimid was administered as consolidation/maintenance therapy after reduced-intensity autologous stem cell transplants in elderly patients with newly diagnosed myeloma.[5] This study included over 100 patients aged 65-75 years with newly diagnosed myeloma. All patients received induction therapy with Velcade, dexamethasone, and Adriamycin® (doxorubicin) followed by tandem autologous stem cell transplants with 100 mg/m2 of Alkeran® (melphalan). Peripheral blood stem cells were harvested after Cytoxan and Neupogen® (figrastim). Revlimid was given after recovery from tandem autologous transplants. After consolidation/maintenance with Revlimid, 88% of patients achieved at least a very good partial remission and 53% a complete remission. One-year survival was 92%.

Revlimid therapy is associated with an increased risk of developing a new cancer, especially in older adults

Results from a pivotal clinical trial have supported the use of Revlimid (lenalidomide) as maintenance therapy for patients with multiple myeloma. A new analysis from the trial just published in the Journal, Blood raises concerns about the safety of Revlimid maintenance reporting an increased risk of developing secondary cancer.

Doctors from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust in London examined the relationship between Revlimid therapy and the development of a new cancer in patients receiving Revlimid maintenance and found they had a significantly higher occurrence.

The study involved 2,732 patients with multiple myeloma; some of who received Revlimid induction and or maintenance therapy, and some who did not. With median follow-up of 34.3 months for patients receiving Revlimid and 24.2 months for those undergoing observation the authors observed a total of 104 new cancers occurring in 96 patients that occurred on average 22.3 months from beginning therapy.

Overall thirteen (.48%) of the new cancers were more serious hematologic malignancies, 55 were solid tumors and 36 were non-melanoma skin cancers. The overall incidence of developing a new cancer was 3.8 percent at three years from treatment and they occurred more frequently in transplant patients (5.2% vs. 2.7%).

Advanced age was the risk factor associated with the highest secondary cancer incidence. Among patients exposed to Revlimid at any time, the researchers observed 73 secondary cancers. Patients receiving Revlimid maintenance had a significantly higher three-year incidence of developing a secondary cancer when compared with patients not treated with Revlimid: 8.9% versus 4%.

The authors concluded that the overall benefit observed in patients receiving maintenance Revlimid for the management of multiple myeloma outweighs the secondary cancer risk with overall trial mortality, as a consequence being only 1 percent. Patients should be informed of the higher incidence of secondary malignancy at three years associated with Revlimid maintenance, but be reassured that more than one-third of all confirmed second malignancies are non-invasive, low-risk skin cancers.

Reference: Jones JR, Cairns DA, Gregory WM, et al. Second malignancies in the context of Revlimid treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016 December 9.

Relatively Low Incidence of Secondary Cancers After Use of Revlimid for Treatment of Multiple Myeloma

Three separate studies have suggested that the benefit of Revlimid® (lenalidomide) for the initial treatment of patients with multiple myeloma outweighs the possible increased risk of developing secondary malignancies. These three studies were presented at the 2011 annual meeting of the American Society of Clinical Oncology.

Multiple myeloma is a cancer of plasma cells, which are a special type of white blood cell that are part of the body’s immune system. Patients with multiple myeloma have increased numbers of abnormal plasma cells that may produce increased quantities of dysfunctional antibodies detectable in the blood and/or urine.

Revlimid is an oral medication that can stop or slow the growth of cancerous myeloma cells within the bone marrow. It has been approved by the US Food and Drug in combination with dexamethasone for multiple myeloma patients who have received at least one prior therapy. Revlimid has also been evaluated in combination with other agents for the initial treatment of patients with newly diagnosed myeloma.

All cancer chemotherapy drugs have the potential for causing secondary cancers. Recently, there has been concern that the addition of Revlimid to other chemotherapy could be associated with an unacceptable increased incidence of secondary malignancies. The three studies sought to determine the risk of adding Revlimid to other chemotherapy agents for the treatment of patients with multiple myeloma.

A multi-center international study compared the incidence of second malignancies in patients who were treated with a regimen of Revlimid, melphalan and prednisone with (n=150) or without Revlimid maintenance (n=152) or with melphalan and prednisone without Revlimid (n=153).[1] The incidence of solid tumors appeared to be similar in the three groups but there were two cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in each of the two Revlimid groups (0.07%) versus none in the melphalan and prednisone group. These authors reported that the addition of Revlimid reduced disease progression by 60% with a median progression-free survival of 31 months for the Revlimid group compared with 13 months for the no-Revlimid group. These authors concluded that “The rate of secondary cancers is low, and the benefit-risk ratio is strongly in favor of continuous Revlimid maintenance.”

A multi-center US study also reported on the long-term outcomes of 72 patients treated with Biaxin® (clarithromycin), Revlimid and dexamethasone.[2] Patients on this study received therapy until progression of disease. The researchers reported that 16% of patients in this study developed secondary malignancies, 6 of which were skin cancers and none of which were blood cancers. This seems like a high incidence but these authors reported that the 2.85% per year frequency seen in this study was similar to the 2.1% per year frequency that would be expected in patients without myeloma. In addition, the most common type of secondary cancer was cancer of the skin which is often highly curable. Furthermore, the Revlimid regimen used in this study was extremely effective with a 38.9% complete remission rate.

The third study presented at ASCO was a US multi-center trial evaluating the risk of secondary cancers in patients receiving Revlimid and dexamethasone (n=353) versus placebo and dexamethasone (n=350) for relapsed multiple myeloma.[3] Treatment in both arms was given until disease progression. There were eight cases of secondary cancer in the Revlimid arm and two cases in the control group. There were two cases of MDS in the Revlimid arm and none in the control arm. The median survival of patients receiving Revlimid was 31 months compared with 24 months for the control group. These authors concluded that “the observed secondary cancer rates in both treatment arms were comparable to rates expected for the general population.”

These three studies will undoubtedly be followed by other studies in attempts to determine the impact of Revlimid on secondary cancers. However, at the present time the anti-myeloma effects of Revlimid appear to outweigh any adverse effects due to secondary cancers.

References:

[1] Palumbo AP, Delforge M, Catalano J, et al. Incidence of secondary primary malignancy (SPM) in melphalan-prednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) age 65 or older. Journal of Clinical Oncology 29:2011 (supplement, abstract 8007).

[2] Rossi AC, Mark TM, Jayabalan D, et al. Incidence of second primary malignancies (SPM) after 6 years of follow-up of continuous lenalidomide in first-line treatment of multiple myeloma (MM). Journal of Clinical Oncology 29:2011 (supplement, abstract 8008).

[3] Dimopoulos MA, Orlowski RZ, Niesvizky R, et al. Lenalidomide and dexamethasone (LEN plus DEX) treatment in relapsed/refractory multiple myeloma (RRMM) patients (pts) and risk of secondary primary malignancies (SPM): Analysis of MM-00/010). Journal of Clinical Oncology 29:2011 (supplement, abstract 8009).

References:

  1. Celgene Corporation. Revlimid. Available at: www.revlimid.com. Accessed June 2006.
  2. FDA Drug Safety Communication: Safety review update of cancer drug Revlimid (lenalidomide) and risk of developing new types of malignancies [FDA Safety Announcement]. U.S. Food and Drug Administration website.
  3. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome. Journal of Clinical Oncology. Published online before print July 14, 2014, doi: 10.1200/JCO.2013.54.8164

Newly dxn

Celgene Corporation. ECOG Phase III newly diagnosed multiple myeloma trial (E4A03) reports lenalidomide plus low-dose dexamethasone suggests survival advantage for patients with multiple myeloma. Available at: =. Accessed April 2007.

Rajkumar S, Hayman S, Lacy M, et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood. 2005. E-Pub ahead of print. DOI: 10.1182/blood-2005-07-2817

Recurrent

Dimopoulous M, Weber D, et al. Phase III randomized, double blind placebo controlled trials of lenalidomide-dexamethasone vs. dexamethasone for refractory and relapsed multiple myeloma. Proceedings from the 41st annual meeting of the American Society of Clinical Oncology. Orlando FL. 2005.

[1] Kapoor P, Kumar S, Fonseca R, et al. Survival in patients with newly diagnosed myeloma undergoing therapy with lenalidomide and dexamethasone: Impact of high-risk cytogenetic risk status on outcome. Blood. 2008;112:42, abstract number 95.

[2] Kumar S, Hayman S, Buadi F, et al. Phase II trial of lenalidomide (Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. Blood. 2008;112:40, abstract number 91.

[3] Richardson P, Lonial S, Jakubowiak A, et al. Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: Encouraging efficacy in high risk groups with updated results of a phase I/II study. Blood. 2008;112:41, abstract number 92.

[4] Kumar S, Finn IW, Noga SJ, et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: Initial results from the Phase I/II Multi-Center EVOLUTION Study. Blood. 2008;112:41, abstract number 93.

[5] Palumbo A, Falco P, Gay F, et al. Bortezomib-doxorubicin-dexamethasone as induction prior to reduced intensity autologous transplantation followed by lenalidomide as consolidation/maintenance in elderly patients. Blood. 2008;112:66, abstract number 159.

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