Results of a recent study conducted in the United Kingdom show that elderly and transplant-ineligible multiple myeloma patients who are treated with a reduced-dose combination of cyclophosphamide, thalidomide, and dexamethasone as initial therapy achieve a greater overall response rate than patients who are treated with melphalan plus prednisone.

However, patients who received the three-drug combination had comparable overall survival and progression-free survival rates as patients who received melphalan plus prednisone.  Additionally, side effects were more common among patients treated with the three-drug combination.

High-dose chemotherapy followed by autologous stem cell transplantation is the standard of care for transplant-eligible myeloma patients.

Patients who are elderly or who have concurrent illnesses, however, are often ineligible for transplantation and require safer forms of treatment.

One option for these patients is melphalan ^[1] (Alkeran) plus prednisone ^[2], known as MP, a standard initial treatment for myeloma inEurope.

Although not as widely used, the combination of cyclophosphamide ^[3], thalidomide ^[4] (Thalomid), and dexamethasone ^[5] (Decadron), known as CTD, produces fewer blood-related side effects compared to MP.

A previous study conducted in Polandshowed that CTD is safe and effective both for newly diagnosed myeloma patients prior to stem cell transplantation as well as relapsed and treatment-resistant patients (see related Beacon ^[6] news).

In the current study, the authors compared the efficacy and safety of a reduced-dose regimen of cyclophosphamide, thalidomide, and dexamethasone, called CTDa, to that of the MP regimen in myeloma patients ineligible for stem cell transplantation.

The study was part of the larger Phase 3 MRC Myeloma IX trial, which compared the efficacy of the bisphosphonates Zometa ^[7] (zoledronic acid) and Bonefos ^[8] (clodronic acid) in myeloma patients (see related Beacon ^[9] news) who were also treated with different myeloma therapies depending on whether they were transplant eligible. Upon completion of the MRC Myeloma IX trial in 2010, the study authors conducted a follow-up analysis comparing CTDa and MP in the subset of patients treated with either of these two regimens.

The analysis included 856 newly diagnosed transplant-ineligible myeloma patients, all of whom were randomized at the start of the trial to receive either Zometa or Bonefos until disease progression. These patients were also randomized to receive either CTDa (419 patients) or MP (418 patients).

The median age of patients in both the CTDa and MP treatment groups was 73 years. In addition, 76 percent of patients in both treatment groups had advanced myeloma. Both treatment groups received a median of six cycles of therapy.

Furthermore, 225 patients in the CTDa group and 215 patients in the MP group were screened for chromosomal abnormalities.

High-risk patients were those who had at least one of the following chromosomal abnormalities: +1q, t(4;14), t(4;14), t(14;2), t(14;16), or del(17p). Standard-risk patients were those who did not have any of these chromosomal abnormalities.

Among those screened for chromosomal abnormalities, the percentage of high-risk patients was similar between the CTDa group and the MP group (43 percent and 42 percent, respectively).

Patients in the CTDa group received 500 mg of cyclophosphamide weekly, escalating doses of thalidomide from 50 mg per day to 200 mg per day, and 20 mg of dexamethasone daily on days 1 to 4 and days 15 to 18 of successive 28-day cycles until maximum response.

Patients in the MP group received 7 mg/m² of melphalan per day plus 40 mg of prednisone per day on days 1 to 4 of successive 28-day cycles until maximum response.

The researchers found that patients in the CTDa group had a significantly higher overall response rate (64 percent) than patients in the MP group (33 percent), with 13 percent of the CTDa group achieving a complete response compared to 2 percent of the MP group. Similarly, 17 percent of patients treated with CTDa achieved a very good partial response rate compared to 2 percent of patients treated with MP.

However, after a median follow-up of 44 months, median progression-free survival (12 months for CTDa versus 13 months for MP) and overall survival (31 months for CTDa and 33 months for MP) were similar for the two treatment groups.

The researchers also found that among patients in the CTDa group, standard-risk patients had a significantly better overall survival than high-risk patients. Based on these findings, they suggested that standard-risk patients were most likely to benefit from the CTDa regimen.

Compared to patients in the MP group, patients in the CTDa group had higher rates of infection (32 percent versus 26 percent), constipation (41 percent versus 18 percent), blood clots (16 percent versus 5 percent), rash (15 percent versus 7 percent), and sensory neuropathy characterized by pain and tingling in the extremities (24 percent versus 6 percent).

Fifty-seven percent of patients in the CTDa group and 62 percent of patients in the MP group died. The most common causes of death were disease progression, infection, treatment, and kidney failure.

For more information, please see the article in the journal Blood ^[10] (abstract).