Commenting on the evidence for treating precursor myeloma in the study by Mateos et al,¹ Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute in Boston, said, “This study is paradigm-changing but not practice-changing. It opens up the opportunity for clinical evaluation of novel agents, vaccines, monoclonal antibodies, and others to delay progression of smoldering to active myeloma. Importantly, this study highlights the need to redefine active myeloma and the category of patients who can benefit from therapy in myeloma.”

Three Important Questions

Asked how she would interpret the data from the Mateos et al trial, Martha Q. Lacy, MD, Professor of Medicine at the Mayo Clinic in Rochester, Minnesota, said that the study needed to be confirmed before concluding that lenalidomide (Revlimid) plus dexamethasone should be the standard for all patients with high-risk smoldering myeloma. She added that the study raises three important questions:

What should be the standard for considering smoldering myeloma to be high risk?

“The study used aberrant plasma cell phenotype and suppressors of uninvolved immunoglobulins to define a high-risk group rather than molecular markers that are commonly accepted as high-risk markers in overt myeloma. Recent reports have shown that smoldering myeloma patients with serum immunoglobulin free light chain ratio > 100 or bone marrow plasma cells > 60% are at high risk of progression,” said Dr. Lacy.

Why did the high-risk observation patients do so poorly?

“The 3-year survival rate of high-risk smoldering myeloma patients in this study was 94% in the treatment arm vs 80% in the observation arm. The 3-year 80% survival for the observation group is surprising. This group did not start treatment until CRAB criteria [hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells] were met; yet their survival is no better than that seen in many trials of overt myeloma,” she noted.

How were the observation patients treated at the time of progression?

“The supplementary appendix [to the Mateos et al study publication] includes a table that gives details regarding the 13 patients in the observation arm who died. None received lenalidomide as their first therapy, and it is not stated whether they ever received lenalidomide. If many observation patients died without ever getting lenalidomide, then this is an important flaw in the study,” Dr. Lacy commented. ■

Disclosure: Dr. Lacey reported no potential conflicts of interest.

Reference

1. Mateos MV, Hernandez M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.