A team of European researchers recently found that advanced age, kidney failure, infections, heart and gastrointestinal complications, and drug discontinuation are associated with poor survival among elderly myeloma patients.

The results are from a combined analysis of data from four major Euro­pean clinical trials.  All the trials involved elderly multiple myeloma patients treated with either conventional anti-myeloma agents or combi­na­tions of conventional and novel agents.

The study also found that intensive anti-myeloma treatment regimens – that is, regimens combining conventional agents with more than one novel agent – may be counterproductive in elderly myeloma patients due to their toxicity.

Indeed, across all the patients in the study, almost one quarter died as a result of treatment-related toxicity.

Based on their findings, the researchers recommend detailed geriatric assessments, organ evaluations, and more personalized therapy for elderly myeloma patients.

Background

Multiple myeloma most commonly affects the elderly. More than half of myeloma patients are at least 65 years of age, and more than a third are over 75 years.

Aggressive therapies such as stem cell transplantation are not commonly used to treat elderly patients, since they often are not able to withstand such regimens due to poor overall health or concurrent diseases.

Before the era of novel agents, a combination of melphalan (Alkeran) and prednisone was a standard treatment regimen for patients over 65 years.  In recent years, the addition of agents such as thalido­mide (Thalomid) and Velcade (bortezomib) to the melphalan-prednisone regimen has led to an improve­ment in survival outcomes (see related Beacon news). However, these improvements have occurred primarily in patients under the age of 75 years.

The fact that newer therapies have not necessarily improved treatment outcomes for the oldest myeloma patients has raised the question of whether less intensive treatment might more be appropriate for them.

While prior studies have evaluated the influence of age and kidney failure on long-term survival outcomes, the European researchers point out that the current study is the first to assess the impact of treatment-related side effects and drug discontinuation on these outcomes.

Study Design

For the current analysis, the European investigators retrospectively analyzed data from 1,435 newly diag­nosed myeloma patients who were not eligible for stem cell transplantation due to age (65 years or older) or concurrent illnesses. These patients were participants in one of four European Phase 3 clinical trials that involved combination therapies involving melphalan, prednisone, Velcade, and thalidomide.

Of the evaluated patients, 36 percent were aged 75 years or older.

Overall, 23 percent of the patients received melphalan-prednisone (MP), 23 percent received melphalan-prednisone-thalidomide (MPT), 27 percent received Velcade-melphalan-prednisone (VMP), and 27 percent received either Velcade-thalidomide-predisone (VTP) or Velcade-melphalan-prednisone-thalidomide followed by Velcade-thalidomide maintenance therapy (VMPT-VT).

Information that was available for each patient across all four studies included age, gender, disease stage at diagnosis, date of death, and the severity and type of treatment-related side effects.

Patient Characteristics And Survival Outcomes

After a median follow-up time of 33 months, the median overall survival across all patients in the study was 50 months, and the three-year overall survival rate was 64 percent.

Both age and kidney failure affected survival outcomes in patients across all the treatment regimens.

Patients under the age of 75 years had an estimated three-year overall survival rate of 68 percent, compared to 57 percent for patients 75 years and older.

More aggressive combination regimens, including either Velcade or thalidomide and Velcade together, were found to increase the risk of death in patients 75 years and older.

Specifically, this risk was increased by 1.6-fold in patients 75 and older who were treated with VMP, and 3-fold in patients 75 and older who were treated with either VTP or VMPT-VT.

Additionally, the estimated three-year overall survival rate for patients without kidney failure was 66 percent, compared to 38 percent for those with kidney failure. However, kidney failure did not significantly increase the risk of death in patients who were treated with VMP.

Side Effects And Survival Outcomes

Among the patients included in the analysis, 39 percent experienced severe to life-threatening blood-related side effects. The most common were low white blood cell counts (27 percent), followed by low platelet counts (10 percent), and anemia (3 percent).

Patients who received MPT experienced lower rates of blood-related side effects (33 percent) than patients treated with VMP (44 percent) or VMPT-VT (43 percent).

Furthermore, 29 percent of patients experienced other types of severe to life-threatening side effects, includ­ing infections (10 percent), peripheral neuropathy (pain, tingling, or loss of sensation in the extremities) (8 percent), heart complications (6 percent), and gastrointestinal complications (5 percent).

Interestingly, patients who received MPT experienced higher rates of non-blood-related side effects (43 percent) than patients treated with VMP (24 percent) or VTP/VMPT-VT (32 percent).

The researchers noted that the rate of all side effects increased across all treatment groups during the first six months of treatment and plateaued thereafter.

The researchers also found that certain side effects negatively affected survival.

In particular, severe to life-threatening infections, as well as heart and gastrointestinal complications, were the most significant predictors of shorter overall survival, increasing the risk of death within the first six months of treatment.

Severe to life-threatening blood-related side effects, however, did not increase the risk of death within the first six months or thereafter.

Drug discontinuation was also associated with an increased risk of death within the first six months of treatment, especially among patients who received either VMP or VTP/VMPT-VT.

Among patients treated with just MP, only 1 percent discontinued treatment due to side effects. For patients whose regimens included novel agents, on the other hand, 27 percent discontinued treatment due to intolerable side effects.

Across all patients in the studies, the investigators found that 76 percent died due to disease progression, while the remaining 24 percent died due to treatment-related side effects.

The four most common treatment-related side effects leading to death included infections (8 percent), heart complications (8 percent), secondary cancers (2 percent), and blood clots in the veins (2 percent).

For more information, please see the study in Haematologica (pdf, full text).