The United States Food and Drug Administration (FDA) approved Thalomid® (thalidomide) in combination with the steroid dexamethasone for the treatment of newly diagnosed multiple myeloma in 2006.

Multiple myeloma is a cancer of the blood that affects the plasma cells. Plasma cells are an important part of the immune system; they produce antibodies to help fight infection and disease. Multiple Myeloma is characterized by an excess production of abnormal plasma cells. Symptoms include increased risk of bacterial infections and impaired immune responses.

Myeloma may also damage the kidneys and cause osteoporosis, anemia, and an elevated blood calcium level.

Multiple myeloma is the second most common cancer of the blood in the United States. It affects approximately 50,000 individuals in the U.S., with about 14,600 cases diagnosed annually.

About Thalomid

Thalomid is an immunomodulatory agent that helps the immune system fight cancer. In addition, Thalomid stops or prevents blood vessels from growing and providing cancer cells with nutrients and oxygen for their spread and growth.

Cancer cells require food, oxygen, and growth proteins in order to grow and spread. These essential nutrients are transported to the cancer cells by blood vessels. Angiogenesis is the process of creating new blood vessels necessary to transport “food” to the cancer cells. Several new drugs appear to prevent angiogenesis and may help prevent cancers from growing. There is evidence that patients with multiple myeloma have increased angiogenesis that may facilitate growth of the cancer.

Thalidomide was developed and originally used as a sleeping pill until it was found to cause birth defects. Because multiple myeloma occurs in individuals who are mostly beyond the child-bearing age, the concern regarding birth defects is less relevant. Doctors became interested in thalidomide as an anti-cancer therapy because it appears to have anti-angiogenesis activity that is not toxic to the bone marrow and does not affect blood counts.

These doctors treated 84 patients with refractory myeloma, including 76 who had failed high-dose chemotherapy with stem cell support. Overall, 32% of patients had partial or complete disappearance of their cancer following treatment with thalidomide. At the time of this report, 58% of patients survived beyond 1 year of treatment. The therapy was well tolerated with side effects consisting mainly of constipation, weakness, and excessive sleep.1

The clinical trial prompting the new indication for Thalomid was a direct comparison of Thalomid plus dexamethasone to dexamethasone alone in the treatment of newly diagnosed multiple myeloma. Patients treated with Thalomid/dexamethasone had improved anticancer responses compared to those treated with dexamethasone alone.4

Initial Treatment with Thalidomide Superior to VAD for Multiple Myeloma

Researchers from Italy conducted a clinical trial to compare thalidomide to the chemotherapy regimen VAD (vincristine, doxorubicin, dexamethasone) in patients with newly diagnosed multiple myeloma. This trial included 200 patients who received either thalidomide or VAD prior to an autologous stem cell transplant. An autologous stem cell transplant involves the collection of a patient’s stem cells (immature blood cells) prior to therapy, and re-infusion of the stem cells following therapy so that normal blood cell levels can be maintained. Approximately 75% of patients treated with thalidomide achieved an anti-cancer response, compared with approximately 50% of patients treated with VAD. In both groups of patients, mortality rates were 6% during treatment.

The researchers concluded that thalidomide appears superior to VAD as treatment prior to autologous stem cell infusion in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma may wish to speak with their physician regarding their individual risks and benefits of utilizing thalidomide as part of their treatment regimen.5

Velcade, Alkeran, Prednisone, & Thalomid Effective for Relapsed Multiple Myeloma

The optimal treatment of patients with multiple myeloma is rapidly evolving with the availability of novel treatment strategies; these include high-dose Alkeran® (melphalan) and autologous stem cell transplantation and new agents such as Thalomid® (thalidomide), Revlimid® (lenalidomide), and Velcade® (bortezomib). Relapsed multiple myeloma refers to cancer that has returned after initial treatment and stopped responding to prior therapies. Researchers continue to evaluate novel therapeutic agents and combinations of agents in the treatment of relapsed multiple myeloma.

Researchers affiliated with the Italian Multiple Myeloma Network, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEA) recently conducted a clinical trial to evaluate VMPT (Velcade, Alkeran, Thalomid, and prednisone) in the treatment of 30 patients with relapsed multiple myeloma.

  • Partial regression of cancer (partial response) occurred in 67% of patients.
  • At one year progression-free survival was 61%.
  • At one year overall survival was 84%.
  • Side effects that resulted in dose reductions or delays included low levels of immune cells (neutropenia) and low levels of platelets (thrombocytopenia).

The researchers concluded that the novel treatment combination referred to as VMPT provides significant anticancer activity for patients with relapsed multiple myeloma. Future clinical trials may evaluate VMPT as initial therapy for newly diagnosed multiple myeloma.8

Addition of Thalidomide to Melphalan Appears Promising for Elderly Patients with Newly Diagnosed Multiple Myeloma

Researchers from France reported that the addition of thalidomide to standard melphalan chemotherapy improves progression-free and overall survival compared to either melphalan alone or high-dose melphalan and autologous stem cell support in the treatment of newly diagnosed, elderly patients with multiple myeloma.

Melphalan/prednisone is the standard treatment for patients with newly diagnosed multiple myeloma. Autologous stem cell transplantation is also a standard treatment option for eligible patients with multiple myeloma, and with the advent of newer agents such as thalomide and Velcade® (bortezomib) emerging as effective agents in the treatment of multiple myeloma, researchers continue to directly compare treatment strategies in order to provide optimal and individualized therapeutic approaches for every patient.

The phase III trial, referred to as the IFM 99-06 trial, was initiated in May 2000 and included newly diagnosed patients between the ages of 65 and 75 years. Patients were randomly assigned to receive one of three treatments:

  • Standard melphalan with prednisone
  • Standard melphalan/prednisone plus thalidomide
  • High-dose melphalan with autologous stem cell support

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Recruitment was stopped while this trial was still in progress as the melphalan plus thalidomide treatment demonstrated clear improvements over the other two treatments.

At approximately three years after treatment, patients who were treated with melaphalan plus thalidomide experienced significantly longer progression-free and overall survival compared to patients who received the other two treatments.

  • Progression free survival was 27 months for patients receiving melaphalan plus thalidomide, compared to 17 months for melaphalan and 19 months for high-dose melphalan with autologous stem cell support.
  • Overall survival was 54 months for patients receiving melaphalan plus thalidomide, compared to 32 months for melaphalan and 39 months for high-dose melphalan with autologous stem cell support

Patients who received thalidomide had higher rates of low white blood cell counts (neutropenia) compared to those who received only melphalan. Other side effects of thalidomide included peripheral neuropathy (6%) and constipation (10%).6

Combination of Melphalan, Prednisone, and Thalidomide 

Researchers found the combination of melphalan, prednisone, and thalidomide (MPT) effective in newly diagnosed multiple myeloma patients.and researchers from France conducted a clinical study in 447 patients with multiple myeloma who had not received prior therapy between 2000 and 2005.11   eThe median overall survival times was 51.6 months for patients treated with MPT compared to 33.2 months for patients with Alkeran/prednisone.

VAD-Doxil +/- Thalomid

The addition of Thalomid to VAD-Doxil improves progression-free survival and might improve overall survival compared to VAD-Doxil when used as initial therapy in multiple myeloma. 

The rate of overall side effects was greater in the group treated with Thalomid; however, the rate of severe side effects was similar between the two groups. Side effects uniquely associated with Thalomid included constipation, peripheral neuropathy (loss of sensation of the palms of hands or soles of feet), skin rash, and edema (swelling).12

Other Thalomid Combinations

ThaDD - Thalomid, Doxil (pegylated doxorubicin), and dexamethasone.9

DVd-T - Doxil®, Oncovin® (vincristine), dexamethasone and Thalomid10

Post ASCT Thalomid Maintenance

One year of treatment with Thalomid and prednisone after a single autologous stem cell transplant prolonged survival in patients with newly diagnosed multiple myeloma.13

Researchers conducted a study in 269 patients with newly diagnosed multiple myeloma. After undergoing a single ASCT, 129 patients were randomly assigned to receive indefinite prednisone and 114 were assigned to receive one year of Thalomid in addition to indefinite prednisone. After a median follow-up of three years, the overall survival for the Thalomid group was 86% compared with 75% for the control group and the progression-free survival was 42% for the Thalomid group and 23% for the control group.

Researchers from the University of Arkansas however found that Thalomid alone (without prednisone) did not prolong survival. Their  trial included 668 patients who were treated between 1998 and 2004. All patients were treated with melphalan-based intensive chemotherapy followed by autologous stem cell transplantation; approximately half of the patients also received thalidomide during treatment (thalidomide was continued until cancer progression or intolerable side effects).

Thalidomide did not improve overall survival at 5 years:

  • Complete disappearances of cancer occurred in 62% of patients who received thalidomide, compared with 43% of patients who did not receive thalidomide.
  • At 5 years, 56% of patients who received thalidomide survived without recurrence (event-free survival), compared to 44% for patients who did not receive thalidomide.
  • At 5 years, overall survival was approximately 65% for both groups of patients.
  • If a patient experienced a cancer recurrence following therapy, the median survival time following the recurrence was 1.1 years for those treated with thalidomide, and 2.7 years for those not treated with thalidomide.
  • Side effects including blood clots (34% for those treated with thalidomide vs. 18% for those not treated with thalidomide), severe peripheral neuropathy (burning, tingling, loss of sensation in extremities), obstruction of the bowel, fainting, and low levels of immune cells were significantly more common among patients treated with thalidomide compared to those who did not receive thalidomide.

The researchers concluded that, although the addition of thalidomide improved anticancer responses and reduced recurrences at 5 years after treatment, overall survival was not improved with thalidomide in patients with newly diagnosed multiple myeloma undergoing treatment with autologous stem cell transplantation.14

Thalomid may increased risk of developing deep vein thrombosis.

Researchers from the University of Arkansas  conducted a clinical trial further evaluating thalidomide in the treatment of multiple myeloma. In this study, 100 patients with multiple myeloma received combination chemotherapy and dexamethasone (steroid). Fifty of these patients were also treated with thalidomide. Following treatment, nearly 30% of patients who received thalidomide developed deep vein thrombosis (DVT), compared with only 4% not given the agent. DVT is the accumulation of cellular elements, platelets, fibrin and clotting proteins which develop into a thrombus (clot) on the inside of a deep blood vein. DVT can be life threatening as it can develop in major veins or dislodge and travel to the lungs, blocking necessary blood flow and oxygen exchange. Patients who developed DVT in this trial were treated with anticoagulants, which resolved the problem in 75% of patients and allowed them to continue treatment with thalidomide.

These findings suggest that the addition of thalidomide to combination chemotherapy and dexamethasone in patients with multiple myeloma increases the risk of the development of DVT. However, treatment with anticoagulants appear to resolve this complication in the majority of patients and allow continued treatment.3

Reference: 

  1. New England Journal of Medicine, Vol 341, No 21, pp 1565-1571, 1999.
  2. Proceedings from the VII International Myeloma Workshop, Banff Springs Hotel, Banff, Alberta, Canada, May 4-8, 2001
  3. Blood, Vol 98, No. 5, pp. 1614-1615, 2001.
  4. Celgene Corporation. ECOG Phase III Study on Thalomid (Thalidomide) Plus Dexamethasone Reports Final Results for Newly Diagnosed Multiple Myeloma. Available at: . Accessed December 2004.
  5. Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005;first edition paper, prepublished online March 10, 2005;DOI 10.1182/blood-2005-02-0522.
  6. Facon T, Mary J, Harousseau F, et al. Superiority of Melphalan-Prednisone (MP) + Thalidomide (THAL) over MP and Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Elderly Patents with Multiple myeloma. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology (ASCO). Plenary Session Presented June 4, 2006. Abstract #1.
  7. Palumbo A, Bertola A, Musto P et al. Oral Melphalan, Prednisone, and Thalidomide for Newly Diagnosed Patients with Myeloma. Cancer. 2005;104:1428-33.
  8. Palumbo A, Ambrosini MT, Benevolo C, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007;109:2672-2673.
  9. Offidani M, Corvata L, Piersantelli M-N, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108:2159-2164.
  10. Agrawal NR, Hussein MA, Elson P, et al. Pegalated Doxorubicin (D), Vincristine (V), Reduced Frequency Dexamethasone (D) and Thalidomide (T) (DVd-T) in Newly diagnosed (Nmm) and Relapse/Refractory (Rmm) Multiple Myeloma Patients. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:237a, Abstract #831.
  11. Facon T, Mary J, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. The Lancet. 2007;370:1209-1218.
  12. Zervas K, Mihou D, Katodritou E, et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of the Greek Myeloma Study Group. Annals of Oncology. 2007; 18:1369-1375.
  13. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. Journal of Clinical Oncology. 2009; 27: 1788-1793.
  14. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and Hematopoietic-Cell Transplantation for Multiple Myeloma. New England Journal of Medicine. 2006; 354:1021-1030.

Celgene. Thalomid(R) sNDA Granted FDA Approval for Treatment of Newly Diagnosed Multiple Myeloma. Available at: . Accessed May 2006.