Leading myeloma specialists from across Europe recently published an article in the journal The Oncologist that summarized the current treatment options and availability of therapeutic agents for multiple myeloma patients in Europe. This article, Part 3 in a series, summarizes the European physicians’ treatment recommendations for patients with relapsed myeloma. Part 1 compares availability of myeloma treatments in Europe and the U.S., and part 2 summarizes physician’s treatment recommendations for newly diagnosed patients. Part 4 will cover the management of side effects.

Although recent clinical trials have demonstrated that novel agents, particularly thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide), significantly improve response rates in refractory (treatment-resistant) and relapsed myeloma patients, the approved uses of these novel agents differ, sometimes significantly, between Europe and the United States.

In general, novel agents are less accessible in Europe because many European countries have centralized health care systems. Under this system, each government can limit the availability of a drug in their country, even if the European Medicines Agency has approved it as safe and effective.

Treatment Practices For Relapse

Prior to the introduction of novel agents, the outcome for patients diagnosed with relapsed and/or refractory myeloma was usually unfavorable. However, the increased availability of the novel agents has resulted in a more promising outlook for these patients.

Based on the latest research results, European treatment approaches are summarized below, although not all of the regimens are approved or available throughout all of Europe.

Thalidomide

Although thalidomide is widely used as a treatment for relapsed/refractory myeloma, it is not yet approved in Europe for patients with this type of myeloma. It is currently approved, in combination with melphalan (Alkeran) and prednisone, as a first-line treatment for myeloma patients who have never been treated, are at least 65 years old, or are ineligible for high-dose chemotherapy.

The efficacy of thalidomide as a single agent is limited. It is therefore frequently used in combination with dexamethasone (Decadron) or chemotherapy.

The most common side effects observed with thalidomide include peripheral neuropathy (pain and numbness in the hands and feet), deep vein blood clots, sedation, and gastrointestinal problems. These side effects are also seen in patients who receive thalidomide as a first-line treatment.

Velcade

In Europe, Velcade, in combination with melphalan and prednisone, is approved for previously untreated myeloma patients who are ineligible for high-dose chemotherapy with a stem cell transplant. It is also approved as a single therapeutic agent in patients with progressive myeloma who have received at least one prior therapy and have received or are ineligible for transplantation.

A large number of studies have investigated Velcade as both a single agent and in combination with steroids, conventional chemotherapy, or other novel agents.

The Phase 3 APEX trial noted that Velcade as a single agent induced superior response rates, time to progression (TTP), and overall survival rates (OS) than high-dose dexamethasone. Another clinical trial found that the addition of Doxil (pegylated liposomal doxorubicin) to Velcade resulted in a significantly longer TTP and OS time. The studies that examined Velcade as part of a combination regimen observed that the addition of Velcade increased the efficacy of the treatment.

The Phase 2 RETRIEVE trial investigated the retreatment of Velcade in patients whose disease had responded to previous Velcade treatment and relapsed after at least six months. Approximately two-thirds of the patients treated again with Velcade responded to treatment.

The most common side effects observed with Velcade include low platelet count, low white blood cell count, peripheral neuropathy, and gastrointestinal problems.

Revlimid

Revlimid, in combination with dexamethasone, is approved in Europe and the U.S. for myeloma patients who have received at least one prior therapy.

Two Phase 3 trials demonstrated that the Revlimid-dexamethasone regimen induced significantly greater response rates, TTP, and OS time, compared to dexamethasone alone.

Revlimid is currently being investigated in combination with a number of other agents, including doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), Velcade, and thalidomide. Although longer follow-up is still needed to assess the overall survival time, in general the response rates with the combination regimens are superior to those seen with Revlimid-dexamethasone.

The most common side effects observed with Revlimid include low platelet count, low white blood cell count, deep vein blood clots, and infection. 

Stem Cell Transplantation

A number of studies are currently examining the use of autologous or allogeneic stem cell transplantation as treatment for relapsed/refractory patients.

In autologous stem cell transplantations, the patients’ own stem cells are collected before high-dose chemotherapy, then transplanted back into the patients. According to the study authors, the success of the procedure depends on the efficacy and number of previous treatments as well as the time between the first and second step of the procedure. However, most myeloma patients retain a small number of cancerous cells in their blood and bone marrow after autologous stem cell transplantation, which may lead to relapse.

In allogeneic stem cell transplantations, the patients receive stem cells from a donor. Allogeneic stem cell transplantations may be particularly useful for patients with high-risk myeloma. However, the authors pointed out that the procedure is still under investigation in Europe.

Recommendations For Treatment At Relapse

Based on available data, the authors of the study concluded that the use of novel agents for treatment at relapse is associated with better outcomes for the patient. Determining which treatment to use depends on the patient’s duration of remission since the initial therapy and the presence or risk of side effects.

If the patient was in remission for at least one year, then it may be possible to repeat the initial first-line treatment. However, if the patient experienced a remission of six months or less, then the authors advised doctors to switch to a different treatment.

Additionally, the presence or risk of side effects may require a change from the first-line treatment. The authors advised that patients who experience peripheral neuropathy from the first-line treatment should switch to an agent that is not associated with peripheral neuropathy, such as Revlimid. Patients with a history or high risk for blood clot-related side effects may need to switch from thalidomide and Revlimid to a Velcade-based regimen and the use of heparin.

The authors noted that the standard treatment options for relapsed myeloma will continue to be challenged and modified based on the increased use of novel agents as first-line treatments.

For more information, please read the original article in the journal The Oncologist (abstract).