Results from a recently completed Phase 3 trial suggest that thalidomide may delay disease progression in patients with smoldering myeloma.

Specifically, patients in the trial who received thalidomide in combination with Zometa had a noticeably longer time to disease progression than patients who received Zometa alone.

Over a third of the patients who received thalidomide and Zometa also showed a tumor response, whereas none of the patients treated with Zometa alone had such a response.

However, more patients who received the thalidomide- Zometa combination experienced peripheral neuropathy (pain, tingling, or loss of sensation in the extremities), a side effect that is commonly observed in patients receiving thalidomide (Thalomid) treatment.

Based on their findings, the investigators conclude that Revlimid (lenalidomide) -- which is in the same class of drugs as thalidomide -- may be the better treatment option for patients with smoldering myeloma because Revlimid is not typically associated with peripheral neuropathy. They point out that their trial was designed before Revlimid was available.

Smoldering multiple myeloma, also called inactive or asymptomatic myeloma, is an early stage of myeloma in which the patient does not yet show any of the common myeloma-related symptoms, such as elevated calcium levels in the blood, anemia, bone disease, or kidney damage.

Diagnosis of smoldering myeloma is usually based on the presence of at least 30 g/L of monoclonal protein in the blood or at least 10 percent plasma cells in the bone marrow.

The current standard of care for smoldering myeloma is a ‘watch and wait’ approach, which involves monitoring the patient regularly and beginning treatment only once the disease progresses to symptomatic myeloma.  This approach is based on previous evidence that treatment at this stage does not have an impact on overall survival but exposes patients to chemotherapy, and therefore side effects, for a longer period of time.

However, with the development of novel agents such as thalidomide, Velcade (bortezomib), and Revlimid, which are better tolerated than older chemotherapeutic drugs, recent studies are investigating whether treatment can delay progression of smoldering myeloma to symptomatic disease.

For instance, one recent study showed that a combination of Revlimid and dexamethasone (Decadron) may delay disease progression in smoldering myeloma patients who are at high risk for progression (see related Beacon news).

Zometa (zoledronic acid) belongs to a class of drugs called bisphosphonates that reduce bone loss and fractures by preventing the activity of cells that break down bones. Previous studies have suggested that Zometa may increase progression-free and overall survival rates among multiple myeloma patients (see related Beacon news).

In the current Phase 3 study, researchers from the Mayo Clinic compared the effect of thalidomide in combination with Zometa to Zometa alone on disease progression in patients with smoldering myeloma.

The study was conducted from 2003 to 2011 and included 68 newly diagnosed smoldering myeloma patients with a median age of 63 years. Patients had no bone lesions, and tests showed that their plasma cells were not multiplying rapidly.

Almost two thirds of the patients had two out of the two factors frequently linked to a high risk of progressing from smoldering myeloma to active myeloma: high serum or urine M-protein levels, and a high percentage of plasma cells in the bone marrow.

Most of the remaining patients had at least one of the two risk factors.

All patients received 4 mg of intravenous Zometa per month; 51 percent of patients also received 200 mg of oral thalidomide per day.

After the start of the study, the Zometa dosage was reduced to 4 mg every three months for the first year, and once a year thereafter, because other studies showed that bisphosphonate treatment sometimes leads to osteonecrosis of the jaw, a loss of blood supply to the jaw bone resulting in its deterioration (see related Beacon news).

Median follow-up time was 5.9 years.

Results showed that 37 percent of patients in the thalidomide- Zometa group showed a tumor response, compared to none in the Zometa-only group.  The median duration of response was 3.3 years.

In addition, 86 percent of patients treated with thalidomide-Zometa remained progression-free after a year of treatment, compared to 55 percent of patients treated with Zometa alone.

Median progression-free survival was significantly longer in the thalidomide-Zometa arm (2.4 years) than the Zometa-only arm (1.2 years). However, overall survival was not statistically different between the two arms.

The researchers also calculated the time to disease progression based on the development of typical myeloma-related symptoms (anemia, kidney or bone problems, or an increase in blood calcium levels). Patients receiving thalidomide-Zometa showed a median time to progression of 4.3 years, compared to 3.3 years with Zometa alone. However, this difference was not considered statistically significant.

Eighty percent of patients in the thalidomide-Zometa arm developed mild to moderate neuropathy, compared to 18 percent of patients in the Zometa-only arm. The frequency of more serious side effects, however, was not significantly different between the two arms.

For more information, please see the study in Leukemia (abstract).