September-October 2011, Volume 8, Issue 5
Reaching a Consensus on the Definition of Complete Response in Myeloma
Published on: September 01, 2011
Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol. 2011;29:1627-1633.
Complete response (CR) remains the optimal objective in front-line treatment of myeloma to improve survival. The definition of CR has evolved in recent years from normalization of serum protein electrophoresis and bone marrow morphology with negative immunofixation, to normal serum free light-chain ratio test (stringent CR), and more recently to normal immunophenotype (IR). The latter is achieved when the malignant plasma cell signature is undetectable using multiparameter flow cytometry (MFC) at a sensitivity level of ≤10-4 - 10-5.
Paiva and colleagues from Salamanca, Spain, have investigated the impact of IR versus CR and stringent CR in 260 newly diagnosed elderly (> 65 years) patients with multiple myeloma treated with novel agents in the PETHEMA/GEM 05 trial (Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma). Forty-three percent of patients achieved
CR, 30 percent achieved stringent CR, and 30 percent achieved IR. The patients in IR showed significantly increased three-year rates of progression-free survival (PFS) and time to progression (TTP) as compared with those in stringent CR or CR – 90 percent versus 69 percent and 60 percent, and 96 percent versus 71 percent and 68 percent (p < .001), respectively. On a multivariate Cox regression analysis for PFS, only IR status was an independent prognostic factor (relative risk, 4.1; 95% CI, 1.4 to 12.0; p < .01). Some discrepancies between the three techniques were seen,however; the patients displaying IR also had stringent CR and CR. Interestingly, patients in stringent CR plus IR compared with those in stringent CR but with persistent malignant plasma cells by MFC showed a significantly longer PFS (median not reached; 95% at three years vs. 35 months, respectively; p < .02) and TTP (p.003). Identical results were observed with MFC-positive patients who were immunofixation negative (CR) who showed a tendency toward early reappearance of the M-component (median, 3 months).
The authors accurately concluded that these techniques provide complementary information, and thus an effort should be made to refine response criteria in myeloma. The plot thickens, though. Ladetto et al. recently evaluated the impact of minimal residual disease (MRD) during the consolidation in 32 patients with myeloma following autologous transplantation.1 They monitored MRD every six months after consolidation. Tumor shrinkage was evaluated by real time quantitative (RQ)-PCR using specific DNA probes for immunoglobulin heavy-chain rearrangements. Molecular CR was defined as a negative PCR with a sensitivity threshold of 10-6. The CR rate increased from 15 percent to 49 percent after the consolidation courses, while 15 percent of the patients achieved molecular CR. Interestingly, none of the patients who reached molecular CR relapsed, with a median follow-up of 27 months. Conversely, patients with detectable MRD had significantly poorer outcome and higher risk of relapse. Although further investigations are needed to consider MRD evaluation as a decisionmaking tool in myeloma, these results provide another argument for the relevance of reaching a consensus on the definition of complete response. On the road to technical progress, today’s complete response might well be tomorrow’s partial response. One might agree on the use of the term “minimal residual disease” in place of complete response.
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- Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28:2077-2084.