High-dose melphalan continues to be the gold standard regimen for multiple myeloma patients prior to autologous stem cell therapy, according to a recent review of research investigating alternative preparative treatments before stem cell transplantation. 

The authors of the review pointed out, however, that current research on variations of this regimen may provide improved transplantation response rates for myeloma patients in the future. 

High-dose chemotherapy prior to stem cell transplantation, often called a preparative or conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow. High-dose chemotherapy followed by autologous stem cell transplantation is considered the standard of care for frontline treatment of newly diagnosed multiple myeloma patients under the age of 65.

High-dose melphalan ^[1] (Alkeran), administered as a single dose of 200 mg/m², is currently the most widely accepted conditioning regimen for multiple myeloma.

Recently, a number of studies have explored the possibility of altering the conditioning regimen to improve transplantation response rates. 

In their article, three French myeloma specialists reviewed studies that investigated changes in melphalan dosage as well as the addition of other agents to the regimen. 

Changes In Melphalan Dosing

The possibility of increasing the melphalan dose has been studied in three clinical trials.  According to the authors of the review, increasing the melphalan dose to 220 mg/m² led to encouraging results regarding the efficacy of the treatment.  However, severe mouth ulcers were associated with the higher-dose treatment. The authors also pointed out that the higher 220 mg/m² dose and the standard 200 mg/m² dose need to be compared directly in a trial to fully understand the value of the higher dose.  For more information, please see the studies in Bone Marrow Transplantation, 2003 ^[2] and 1999 ^[3] (abstracts), and the British Journal of Haematology ^[4] (abstract). 

The results of a Phase 3 trial comparing two doses of melphalan, 100 mg/m²  and 200 mg/m²,were also summarized in the review.  In this study, researchers found that decreasing the melphalan dosage to 100 mg/m² in a tandem transplant setting had no effect on overall survival, although the progression-free survival was longer in patients treated with 200 mg/m² (see related Beacon ^[5] news). The authors of the review noted that strategies to reduce the side effects of treatment need to be explored further, since the decrease of the melphalan dose by 50 percent yielded no improvement in the side effects. For more information, please see the study in the journal Blood ^[6] (abstract).

Addition of Alternative Chemotherapeutic Agents

The review also summarized a recent Spanish study, in which researchers found that a conditioning regimen with oral busulfan ^[7] and 200 mg/m² melphalan increased progression-free survival following transplantation compared to melphalan alone (see related Beacon ^[8] news). However, there was no difference in overall survival between the two treatments. 

Furthermore, oral busulfan treatment was associated with an increased risk of death due to veno-occlusive disease, a complication of high-dose chemotherapy in which some of the small veins of the liver are blocked.

The intravenous formulation of busulfan, which other studies have demonstrated to reduce or eliminate the risk of veno-occlusive disease, may reduce the toxicity of the regimen and, according to the authors of the review, warrants further investigation. For more information, please see the full article in Haematologica ^[9].

Addition Of Radiotherapy

The use of radiotherapy as part of a conditioning regimen is also an area of active research, according to the review.  Radiotherapy can be used to kill cancer cells before a stem cell transplant by using radioactive material that preferentially targets to the bone. This results in reduced side effects, especially to the liver and kidneys, compared to traditional total body irradiation. 

The Phase 1/2 study of radiotherapy with an agent called holmium 166 in combination with 200 mg/m² melphalan achieved encouraging complete response rates.  However, long-term follow-up revealed the delayed onset of severe blood- and kidney-related side effects, which would exclude holmium 166 from routine clinical use. For more information, please see the study in Blood ^[10] (abstract)

The results from a Phase 1 study of a radiotherapy called ¹⁵³Sm-EDTMP in combination with 200 mg/m² melphalan were much more promising, however.  No delayed side effects were observed and the overall response rate was 94 percent. For more information, please see the study in Leukemia ^[11] (abstract).

In the subsequent Phase 2 study, in which ¹⁵³Sm-EDTMP was administered prior to 200 mg/m² melphalan, 33 percent of patients achieved a complete response while another 26 percent achieved a very good partial response.  There was, however, no difference in the overall survival or progression-free survival of patients taking ¹⁵³Sm-EDTMP compared with melphalan alone.  Researchers of the study concluded that further studies in the Phase 3 setting were needed.  For more information, please see the American Journal of Hematology ^[12] (abstract) and Leukemia (abstract).

Addition Of Novel Agents

Results from preclinical studies have suggested that treatment with melphalan in combination with Velcade ^[13] (bortezomib) results in increased myeloma cell death.

Several studies have been conducted to determine what effects the addition of Velcade to a conditioning regimen has on the treatment of multiple myeloma. 

Two studies were conducted in France to evaluate the response rates and tolerability of Velcade and 200 mg/m² melphalan compared to melphalan alone as conditioning therapy in newly diagnosed patients.  The complete response rate was found to be higher in the group receiving Velcade and melphalan than those receiving melphalan alone (35 percent compared to 11 percent, respectively).  The addition of Velcade did not lead to an increase in blood-related side effects. For more information, please see the studies in Blood ^[14] (abstract) and the Journal of Clinical Oncology ^[15] (abstract).

These findings were confirmed in a similar small Phase 1/2 clinical trial conducted in the United States (see related Beacon ^[16] news).  The overall response rate was 87 percent, with 51 percent of patients achieving a very good partial response or better. No severe side effects were observed. For more information, please see the study in Clinical Cancer Research ^[17] (abstract).

For more information, please see the review in Bone Marrow Transplantation ^[18] (abstract).