In patients with smoldering multiple myeloma, antitumor treatment alone (primarily with an immunomodulating agent) or in combination with bisphosphonates improves survival compared with observation alone, according to a meta-analysis of pharmacotherapy trials.
“We found that there are significant subgroups of patients that we call ‘smoldering,’ who actually benefit from starting therapy rather than being followed with observation alone,” coinvestigator Parameswaran N. Hari, MD, MS, of the Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, told Value-Based Care in Myeloma.
Asymptomatic, or smoldering, myeloma is seen in 10% to 15% of all patients with myeloma. Currently, national guidelines do not recommend the early treatment of smoldering myeloma, although the investigators noted that the majority of patients eventually progress to active disease over time.
Multiple trials have evaluated the implications of early therapy for smoldering disease, and some have shown benefit, most notably the randomized phase 3 study by Mateos and colleagues (Mateos MV, et al. N Engl J Med. 2013;369:438-447). After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs 21 months; hazard ratio [HR] for progression, 0.18; P <.001). The 3-year survival rate was also significantly higher in the treatment group than in the observation-only group (94% vs 80%, respectively; P = .03).
However, there has been a lack of consensus as to whether early treatment before symptomatic disease progression is superior to observation alone. These investigators, therefore, performed a meta-analysis of such studies.
Improved Survival and Remission with Treatment
The researchers identified 12 phase 2 and 3 clinical trials that allocated patients with smoldering myeloma to treatment or to observation, but excluded 4 trials because of a lack of survival curves for overall survival, progression-free survival, and time to progression. The remaining 8 trials involved 666 patients who received chemotherapy, a bone-protective agent (ie, bisphosphonate [pamidronate, zoledronic acid]), or both. Chemotherapy was primarily thalidomide; 2 studies evaluated lenalidomide plus dexamethasone and melphalan plus prednisone.
“Participants treated for early smoldering myeloma had reduced mortality and better progression-free survival compared to the observation group,” said Jayanthi Vijayakumar, MBBS, Fellow, Medical College of Wisconsin, who presented the study results at the 2014 annual meeting of the American Society of Hematology.
The HRs were 0.64 for overall survival (95% confidence interval [CI], 0.4-1.0) and 0.83 for progression-free survival (95% CI, 0.64-1.07) compared with the observation group.
In a subgroup analysis, patients who received chemotherapy or the combination of chemotherapy and a bisphosphonate had better overall survival and progression-free survival than patients undergoing observation, whereas treatment with bisphosphonate only did not impact these outcomes (Table).
Table Subgroup Analysis of Treatment versus Observation
|Observation only||1.0 (Reference)||1.0 (Reference)|
|Chemotherapy only||0.75 (95% CI, 0.54-1.03)||0.58 (95% CI, 0.36-0.93)|
|Bisphosphonate||0.97 (95% CI, 0.73-1.30)||0.86 (95% CI, 0.51-1.43)|
|Chemotherapy plus bisphosphonate||0.72 (95% CI, 0.51-1.00)||0.38 (95% CI, 0.18-0.81)|
|CI indicates confidence interval.|
The investigators acknowledge that their conclusion “merits caution,” given that the studies used variable definitions of smoldering myeloma in patient selection and therapy was not uniform. They maintain that the findings warrant further exploration of early therapy for smoldering myeloma, “especially since the risk–benefit ratio of therapy” has improved compared with treatment with thalidomide since the time of these studies.
“We cannot speculate whether the outcomes would have been better if [newer agents] were used. My guess is yes: better agents mean that the survival and progression-free survival difference would be better,” Dr Hari suggested.