“For patients with an incurable disease such as multiple myeloma (MM), it remains unclear when treatment for relapse should be re-initiated,” explains Shaji K. Kumar, MD. “Patients with MM tend to exhibit similar symptoms at relapse as they present with at diagnosis, but the development of the symptoms may be preceded by a phase where there is slow increase in the monoclonal protein. This clinical scenario resembles the precursor phase of smoldering myeloma where treatment is often delayed until disease-defining characteristics reappear.”

In the case for smoldering myeloma, there is a proportion of patients who may not progress to active myeloma, Dr. Kumar says. “During relapse, however, the progression to new myelomarelated symptoms is definite, although the rate of progression may vary among patients. It is debatable whether a patient with slow progression in only the M protein who exhibits no clinical features should be observed for some time and start treatment only when they begin showing early evidence of end-organ damage.”

Earlier Initiation of Treatment Linked With Better Outcome

To examine progression patterns and their effect on survival outcomes, Dr. Kumar and colleagues published a study in Blood Advances, retrospectively evaluating 1,347 patients with relapsing MM. “Using a large existing patient database from Mayo Clinic, we identified individuals who had treatment initiated for biochemical or clinical progression and explored the differences in outcomes between them,” Dr. Kumar says.

As they had hypothesized, the study team observed that earlier initiation of therapy is associated with better outcomes. “Our hypothesis suggested that this would be the case, as it may prevent the tumor clone from becoming bigger and undergoing more clonal evolution,” Dr. Kumar says.

Bone Disease Most Prevalent Symptom at Relapse

Among all study participants, 60.4% had biochemical progression, and 39.6% experienced clinical progression, including 6.9% with an aggressive form of relapse (Table). “For patients with clinical progression, different CRAB (hyperCalcemia, Renal insufficiency, Anemia, and Bone lesion) symptoms occurred at relapse, with the most prevalent being bone disease (80.9%), followed by anemia (38.0%) and renal failure (12.7%),” Dr. Kumar points out. “Hypercalcemia was observed in 6.6% of patients with clinical progression at relapse and 13.5% presented with more than one CRAB symptom at relapse.”

About half of patients with clinical progression developed CRAB symptoms while receiving active treatment, indicating that even patients monitored closely may develop these symptoms at relapse. “Predictors of clinical progression include male sex, a plasma cell labeling index of greater than or equal to 2%, and extramedullary disease at diagnosis,” Dr. Kumar says. “However, patients with better response to first-line treatment are less likely to develop clinical progression.”

Clinicians Should Not Wait to Initiate Treatment for Relapsing MM

These data suggest that it may be better not to wait for clinical features to appear before starting therapy in patients with relapsing MM, but begin treatment earlier. “However, we do need to account for other disease characteristics that may also impact outcomes based on starting treatment, such as high-risk disease features at baseline,” Dr. Kumar notes.

The researchers acknowledge limitations of this study, namely that it was retrospective. “Therefore, our findings need confirmation through a prospective trial that adjusts for the biases of a retrospective study,” he says. “This study lacked protocol standardization, including follow-up frequency and tests for progression and CRAB symptoms.”

For future research, Dr. Kumar and colleagues would like to see a prospective trial that randomly assigns patients to early or late start of therapy, like what is being done for patients with smoldering myeloma. “We are in the process of initialing a trial that will randomize patients to either starting the therapy at relapse from complete response or at International Myeloma Working Group progression. This trial will further examine the concept of early versus delayed progression.”