Early intervention prolonged time to progression in smoldering myeloma

Mateos MV. N Engl J Med. 2013;369:438-447.

  • August 14, 2013

Induction therapy with lenalidomide and dexamethasone increased time to progression and improved survival in patients with smoldering multiple myeloma, according to results of a randomized phase 3 trial.

Observation, which is the standard of care for patients with smoldering multiple myeloma, may not be effective for identifying high-risk patients who are candidates for early intervention, according to researchers.

The current open-label trial included 119 individuals with high-risk smoldering disease.

Patients in the treatment arm were assigned nine cycles of an induction regimen of lenalidomide (Revlimid, Celgene) at 25 mg per day on days 1 to 21, plus dexamethasone at 20 mg/day on days 1 to 4 and days 12 to 15 at 4-week intervals. This regimen was followed by maintenance lenalidomide therapy at 10 mg/day on days 1 to 21 of each 28-day cycle for 2 years.

Patients in the other arm underwent observation.

Progression to symptomatic disease served as the primary endpoint. Secondary outcome measures included response rate, OS and safety.

Median follow-up was 40 months.

Researchers reported a significantly longer median time to progression in the treatment arm compared with the observation arm (not reached vs. 21 months; HR for progression=0.18; 95% CI, 0.09-0.32).

The 3-year survival rate was 94% in the treatment group and 80% in the observation group (HR for death=0.31; 95% CI, 0.10-0.91), which the researchers noted was also a significant difference.

Seventy-nine percent of patients in the treatment group achieved a partial response or better after induction, and 90% achieved this response during maintenance.

Safety profile results indicated that most toxicities were grade 2 or lower.

Perspective

Frederic Reu

  • The study by Mateos and colleagues found survival benefit after a 40-month median follow-up from early treatment of high-risk asymptomatic myeloma (HR AMM) defined by diagnosis within 5 years, myeloma burden parameters, suppression of normal immunoglobulins and dominance of phenotypically aberrant plasma cells in the bone marrow. It was not designed to change standard of care. The primary endpoint was time to progression, the observation group did not have access to the same treatment when progression occurred, there was no intention to investigate the effect early therapy could have on resistance to subsequent therapy, and the study size of 119 patients enrolled at 22 sites is low to prevent distortion by subtle differences in baseline patient characteristics and/or site expertise.

    Furthermore, according to current consensus criteria (Dimopoulos M. Blood. 2011;117:4701-4705; Munshi N. Consensus guidelines for diagnostic criteria and indication for treatment and retreatment in plasma cell disorders. 2011. Available at: http://myeloma.org/pdfs/XIV-06_Panel2.pdf. Accessed on Aug. 19, 2013), a substantial proportion of study subjects might now be classified as symptomatic MM, either through imaging with MRI and CT that detects up to 80% more bone lesions than utilized plain films (Regelink JC. Br J Haematol. 2013;162:50-61) or because kidney dysfunction and hypercalcemia thresholds have been lowered.

    If felt related to MM, estimated glomerular filtration rate (eGFR) of <50 ml/min, decrease of eGFR by >30% in 12 months and/or corrected serum calcium of >11 mg/dL now classify symptomatic MM compared with serum creatinine of >2 mg/dL and/or uncorrected serum calcium of >11.5 mg in this study.

    Bone criteria for initiating therapy for symptomatic MM are now: >1 cm lytic lesion on CT; or one large hyperintense lesion on MRI; or more than three small lytic lesions on CT; or more than three small hyperintense lesions on MRI; or, as in the current study, lytic lesions seen on skeletal survey.

    In contrast to common practice in the United States, observed HR AMM patients had no follow-up bone imaging, which might have improved outcome by earlier detection, as most patients who died had bone disease. In my opinion, HR AMM patients should undergo thorough assessments to rule out MM-related organ dysfunction, but more research is needed before routinely recommending therapy.

    • Frederic Reu, MD
    • Associate staff physician
      Department of hematologic oncology and blood disorders
      Cleveland Clinic Taussig Cancer Institute
  • Disclosures: Reu reports research support from Celgene and a speakers’ bureau role with Onyx.
Perspective
Joseph Mikhael, MD

Joseph Mikhael

  • This was a very well done study that selected the highest-of-risk patients with smoldering myeloma to be treated, but it is not easily reproducible, as the means by which researchers define high risk with flow cytometry are not easily accessible to most treating clinicians.

    The study does, however, teach us that there is a small percentage of patients with smoldering myeloma who should likely be considered true myeloma and be treated. Indeed, this has been long believed by the myeloma community, as the precise definitions of monoclonal gammopathy of unknown significance (MGUS), smoldering myeloma and active myeloma are not concrete, and must constantly be redefined to ensure the right patients are treated while those who do not need treatment are spared therapy. More studies are needed to further define when treatment is necessary in myeloma. 

    Although lenalidomide is an excellent option of therapy, other active agents in myeloma should be considered if one is simply redefining active myeloma (needs treatment) vs. smoldering myeloma (does not need treatment). Clinicians should be aware of the improvements in defining MGUS, smoldering myeloma and active myeloma so that, in turn, patients can be treated appropriately. This study helps move the field forward but will not result in many patients now being treated who otherwise would not have previously.

    • Joseph Mikhael, MD
    • Consultant hematologist
      Mayo Clinic
      Scottsdale/Phoenix, Ariz.
      Vice chair, ASH Committee on Communications
  • Disclosures: Mikhael reports research funding from Celgene, Onyx and Sanofi.