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 2 in a series, summarizes the European physician’s treatment recommendations for newly diagnosed patients. Part 1 compares availability of myeloma treatments in Europe and the U.S., and subsequent articles will summarize treatment recommendations for relapsed patients and management of side effects.

First-Line Treatment Practices

Due to more restrictive approved uses in Europe, there are also significant differences in treatment practices between Europe and the U.S. 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.

For Transplant-Eligible Patients

In Europe, high-dose chemotherapy with autologous stem cell transplantation remains the standard first-line treatment for transplant-eligible patients.

Although the VAD combination regimen of vincristine, doxorubicin (Adriamycin), and dexamethasone was considered to be the standard chemotherapy option in the 1990s, only a small number of patients achieved a complete response. Furthermore, the patient’s response to VAD had no impact on the outcome after the transplant, which is typically the only time period when complete responses are achieved.

Based on the improved response rates from the addition of novel therapeutic agents in relapsed and refractory myeloma, a number of studies are now investigating possible induction regimens that include thalidomide, Velcade, and Revlimid.

Thalidomide, in combination with dexamethasone (TD), which is currently approved in the U.S. as a first-line therapy, was found to be superior to VAD in terms of overall response rates, but the complete response rates still remained low. Researchers have also examined three-drug regimens, including TAD (thalidomide, doxorubicin, and dexamethasone) and CTD [cyclophosphamide (Cytoxan), thalidomide, and dexamethasone]. Both of these combinations resulted in improved overall response rates and complete response rates.

Velcade in combination with dexamethasone (VD) was found to be significantly superior to the standard VAD regimen, and the addition of thalidomide (VTD) may further improve response rates.

Revlimid in combination with dexamethasone, which is approved in patients who have received at least one prior therapy, is currently being investigated as an induction therapy for newly diagnosed patients. The addition of Velcade to the combination is also being studied.

Revlimid can negatively impact collection of stem cells. Therefore, it is recommended that stem cells should be collected after no more than six months of Revlimid treatment.

In Europe, there are currently no guidelines on therapy following stem cell transplantation. Many studies have indicated that continued treatment may have a benefit in terms of slowing progression of myeloma. However, there is no significant evidence to indicate that the treatment extends overall survival.

For Transplant-Ineligible Patients

In Europe, the current treatment options for patients who are ineligible for transplantation remain limited to melphalan plus prednisone (MP) or cyclophosphamide plus prednisone. Although approximately 50 percent of patients respond to these treatments, patients rarely achieve a complete response, and the median overall survival time is three years.

A number of studies have recently investigated the addition of novel agents to the standard MP regimen.

Five studies have recently reported results that assess the addition of thalidomide to MP (MPT). In all studies, the MPT treatment induced superior overall response rates, progression-free survival, and event-free survival, in comparison to MP alone. However, effects on overall survival were inconsistent.

Thalidomide has also been investigated in combination with dexamethasone and cyclophosphamide and in combination with dexamethasone alone. However, it is not clear that these regimens are superior to MP.

Results from a Phase 1/2 trial indicated that the addition of Revlimid to MP (MPR) induced an 81 percent overall response rate and a 24 percent complete response rate. However, further randomized studies are needed to confirm the results.

A Phase 3 trial, which examined the addition of Velcade to MP (VMP), found that VMP was significantly superior to MP in complete response rates (71 percent versus 35 percent), overall response rates (30 percent versus 4 percent), and overall survival time (24 months versus 17 months).

An Italian study investigated the addition of thalidomide to VMP (VMPT), which resulted in improved overall response rates (84 versus 78 percent) and complete response rates (35 versus 21 percent).

The VMPT study, as well as another study, compared the standard twice weekly administration of Velcade with a reduced once weekly dosing. Both studies found that efficacy was similar between the two administration schedules, but the rates of severe side effects were significantly reduced with less frequent dosing.

For Patients With Kidney Failure

Kidney failure, which is a frequent but serious complication of myeloma, requires fast-acting myeloma treatments with low-toxicity.

Velcade, which has a rapid onset of action, does not require dose adjustments in patients with kidney failure and is therefore a very useful therapeutic agent for these patients. Furthermore, an improvement in kidney function has been observed for some patients during treatment with Velcade.

A study that investigated the effect of Velcade, doxorubicin, and dexamethasone treatment on kidney response resulted in improvement of kidney function in 62 percent of patients and a complete kidney response in 31 percent of patients.

Thalidomide, which is another possible treatment option for kidney failure, has resulted in recovery of kidney function in the majority of patients whose myeloma responded to thalidomide treatment.

Revlimid, which is excreted by the kidneys, requires dose adjustments if it is used as a treatment in patients with kidney failure. Prospective studies investigating the effect of Revlimid on kidney function have been initiated.

For Patients With High-Risk Myeloma

Various chromosomal abnormalities are associated with a poor prognosis, known as high-risk myeloma. Novel agents may improve outcomes for high-risk patients.

A number of studies have indicated that Velcade is effective in patients with chromosomal abnormalities. In relapsed as well as newly diagnosed elderly patients, response to Velcade was unaffected by chromosomal abnormalities.

The addition of thalidomide to the Total Therapy 2 protocol significantly improved survival of high-risk myeloma patients. However, TD was not as effective in high-risk patients with multiple chromosomal abnormalities compared to patients with a single abnormality.

Revlimid has also been studied in several groups of high-risk patients. However, response varies depending on the type of chromosomal abnormality.

Larger prospective studies are needed to establish a better approach to treating patients based on their chromosomal abnormalities.

Recommendations For First-Line Treatment

Based on available data from novel agents, the authors of the study concluded that the following treatments may be recommended as a first-line therapy over VAD for transplant-eligible patients: VD, VTD, CTD, prednisone-doxorubicin-dexamethasone (PAD), and thalidomide-doxorubicin-dexamethasone (TAD). Both TD and VAD were similar, in terms of efficiency, and TD is therefore not an optimal substitute.

In elderly patients and transplant-ineligible patients, the standard MP treatment should be supplemented with novel therapeutic agents. MPT and VMP have been shown to significantly improve response rates, compared to MP alone. Revlimid plus dexamethasone as well as MPR may both be viable treatment options for elderly patients.

In case of kidney failure, Velcade may be the ideal treatment, although thalidomide also improves kidney function and Revlimid studies are not yet completed.

In high-risk patients, use of Velcade is supported by the most evidence, but more studies are still needed.

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