A group of Spanish researchers published a summary last year of the patterns of re­lapse and progression they observed in multiple myeloma patients who underwent stem cell trans­plan­ta­tion as part of their upfront therapy.

The researchers observed re­lapse in over half of the patients included in the study.  Among these patients, the majority had only achieved a partial re­sponse after trans­plan­ta­tion.

They also found that how a patient re­lapsed had an impact on their prog­nosis after re­lapse.  Patients who re­lapsed based solely on changes in disease markers, such as their M-spike level, typically survived longer than patients whose re­lapse was marked by one of the typical symp­toms of myeloma, such as increased calcium levels in the blood, kidney failure, anemia, or bone in­volve­ment.

Interestingly, the researchers found that the symp­toms patients experienced at re­lapse were often very sim­i­lar to those that they had at the time of diagnosis.

The investigators recommend that patients who have myeloma symp­toms at the time of re­lapse be treated immediately.

However, for patients who re­lapse without any of the typical myeloma-related symp­toms, the timing of re-treatment is less clear. The researchers recommend using increasing monoclonal (M) protein level as a indicator for early treatment.

The researchers also note that early detection of progression remains a challenge. They explain that at­tempts have been made to use biomarkers to detect early re­lapse. However, according to the Spanish re­searchers, it is not clear yet if these tools provide a clinical benefit.

Background

Autologous stem cell trans­plan­ta­tion is commonly used in the treatment of multiple myeloma.

In this procedure, a patient’s stem cells are harvested prior to high-dose chemo­therapy. The stem cells are then re-infused into the patient after chemotherapy to replace the healthy bone marrow cells that were de­stroyed during the chemotherapy.

Previous studies have shown that patients who achieve a complete re­sponse after trans­plan­ta­tion tend to have longer progression-free survival and overall survival compared to those who achieve only a partial re­sponse.

However, the authors of the current study note that all patients, even those who achieve a complete re­sponse, are at high risk of re­lapse over time.

The Spanish researchers point out that there is currently little data available on the patterns of re­lapse.  What research there is indicates that such patterns are very heterogeneous.

The researchers therefore sought to investigate the characteristics of multiple myeloma patients at re­lapse following an autologous stem cell transplant that was given as part of the patient's initial treatment.

Specifically, the investigators assessed the presence and type of myeloma symp­toms at the time of re­lapse. They defined asymp­tomatic re­lapse as re­lapse based on changes in biochemical markers of myeloma, such as high M-protein levels or an abnormal free-light chain ratio, in the absence of the typical myeloma symp­toms.

Study Design

Investigators from the university hospital in Barcelona, Spain, retrospectively assessed data from 170 multiple myeloma patients who had received an autologous stem cell transplant as part of their initial treatment at their institution between March 1994 and December 2011.

The median patient age was 56 years.

Two-thirds of the patients (67 percent) received conventional chemotherapy as their induction therapy; the remaining patients received regimens that included novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide).

Following trans­plan­ta­tion, 73 patients received maintenance therapy with either interferon alpha-2b (77 percent), thalidomide alone (12 percent), or thalidomide plus Velcade (11 percent).

The median follow-up time was 3.9 years.

Results

The researchers found that 48 percent of the patients achieved a complete re­sponse after trans­plan­ta­tion.

Overall, 55 percent of the patients had re­lapsed or progressed as of December 2011. The majority of the patients (60 percent) who re­lapsed or progressed had only achieved a partial re­sponse after trans­plan­ta­tion, while the remaining 40 percent re­lapsed or progressed from a complete re­sponse.

Half of the patients had symp­toms of myeloma at the time of re­lapse, while the other half had no symp­toms.

The investigators note that asymp­tomatic re­lapse was less common before 2000 than in the most recent decade (26 percent versus 55 percent, respectively). They explain that the difference may be due to the development of more effective drugs and therapies in recent years.

More patients with symp­tomatic re­lapse had an above-median bone marrow plasma cell percentage rate (67 percent versus 38 percent), anemia (49 percent versus 26 percent), and advanced myeloma (34 percent versus 7 percent) at diagnosis, compared to patients with asymp­tomatic re­lapse.

The median bone marrow plasma cell percentage at diagnosis was 43 percent, and advanced myeloma was defined in the study as Stage 3 myeloma according to the International Staging System.

Additionally, according to the Spanish researchers, the symp­toms at re­lapse were similar to those at the time of diagnosis. For example, of the patients who had kidney failure at re­lapse, 55 percent had kidney impairment at diagnosis. Similarly, 59 percent of patients with extramedullary disease at re­lapse had extramedullary disease at diagnosis.

Extramedullary disease occurs when myeloma cells form tumors outside of the bone marrow, in the soft tissues or organs of the body. Previous research has shown that myeloma patients with extra­med­ul­lary disease have a poorer prognosis than those without (see related Beacon news).

Reasons For Treatment At Relapse & Treatment Outcomes

The main reasons patients started treatment after re­lapse or progression were anemia (43 percent), new bone lesions (36 percent), extramedullary disease (24 percent), bone pain (14 percent), kidney failure (12 percent), and high calcium levels (9 percent).

The most common salvage (post-re­lapse) therapies were regimens based on Velcade (41 percent), fol­lowed by thalidomide (10 percent) and Revlimid (10 percent).

The overall re­sponse rate to salvage therapy was 45 percent, with 3 percent of patients achieving a complete re­sponse, 16 percent a very good partial re­sponse, and 26 percent a partial re­sponse.

More patients with asymp­tomatic re­lapse achieved at least a minimal re­sponse to salvage therapy than patients with symp­tomatic re­lapse (69 percent versus 44 percent).

Following stem cell trans­plan­ta­tion, the median progression-free survival was 3.3 years and the median overall survival was 6.8 years.

Patients with asymp­tomatic re­lapse had a significantly longer overall survival (7.1 years) than those with symp­tomatic re­lapse (3.6 years).

The median overall survival after salvage therapy was 2.5 years.

When the researchers controlled for a number of different factors that could affect a patient's survival after re­lapse, they found that the only factors with a statistically significant impact on survival were: time to re­lapse, type of re­lapse (asymp­tomatic versus symp­tomatic), and the use of a second transplant as part of salvage therapy.

Patients who underwent a second transplant as part of their salvage therapy typically survived longer than those who did not.  The authors of the study note, however, that this may be the result of other factors that they were not able to control for statistically.  For example, patients who underwent a second transplant may have been in better overall health than those who did not.

For more information, please refer to in the journal Bone Marrow Transplantation (abstract).