Chapter 2 – Diagnosis and staging

Contributors: Carlos Fernández de Larrea and Joan Bladé

5 – Response criteria

Measurability of the disease is a critical issue in MM that also has an impact on the follow-up of patients in daily clinical practice. Most of the patients, particularly at diagnosis, will have measurable disease in their serum and/or urine, defined by at least 10 g/L and/or light chain urine protein excretion higher than 200 mg in a 24-hour urine specimen. Therefore, paraprotein monitoring is mandatory in patients with a secretory monoclonal gammopathy. Oligosecretory MM are under these thresholds but with positive immunofixation; truly non-secretory myelomas are rare (≈1%).

The first modern and still used classification for the assessment of response to treatment in MM is the one developed by the European Society for Blood and Marrow Transplantation (EBMT) group (Table 2.10) [26]. Complete remission (CR) was defined as the disappearance of the M-protein by serum and urine immunofixation, along with the disappearance of plasmacytomas and normal numbers of bone marrow plasma cells. These three elements (serum and urine component, medullary disease, and extramedullary involvement) constitute the basis of MM response evaluation.

A uniform classification by the IMWG has been more recently developed (Table 2.11) [27]. This classification is currently used as standard response criteria worldwide. Complete remission and partial remission categories were defined as per the (EBMT) criteria. One of the major amendments was the incorporation of the definition of ‘stringent complete remission’ (sCR).

Table 2.10 EBMT, IBMTR, ABMTR criteria for definition of response, relapse, and progression in patients with multiple myeloma treated by high-dose therapy and stem cell transplantation.

*All response categories must be maintained at least 6 weeks. **Excluding oligoclonal bands. ABMTR, Autologous Blood and Marrow Transplant Registry; EBMT, European Society for Blood and Marrow Transplantation; IBMTR, International Bone Marrow Transplant Registry. Adapted from © Blackwell Science Ltd, 1998. All rights reserved. Bladé et al [26].

Another novel concept was the definition of ‘very good partial response’ (VGPR), requiring a 90% reduction of serum M-spike reduction, which was more stringent with urine criteria. Other minor changes included the elimination of the mandatory 6-week wait time to confirm achievement of response required by the EBMT and incorporation of response criteria for the serum FLC assay to enable assessment of response in patients with oligo- and non-secretory disease.

For PCL, no previous specific criteria had been described. Traditionally, EBMT and/or IMWG criteria have been used without distinctive considerations, such as the leukemic nature of the disease, and the relative higher percentage of light-chain only (Bence Jones) and oligosecretory forms. Evaluation of response in primary PCL is based on a combination of acute leukemia and MM response criteria (Table 2.12) [14]. High frequency of extramedullary involvement requires additional evaluation by imaging techniques such as MRI and, particularly, PET/CT.

In the EBMT criteria, progression and relapse were defined according to the previous response achieved in the patients (less than complete remission [partial response, very good partial response] or complete

Table 2.11 IMWG criteria for evaluating response in patients with multiple myeloma.

*All response categories require two consecutive measurements made at any time. **Bone marrow plasma cells analyzed by immunohistochemistry and/or multiparametric flow cytometry. IMWG, International Myeloma Working Group. Adapted from © Nature Publishing Group, 2006. All rights reserved. Durie et al [27].

remission, respectively) (Table 2.13) [26]. For partial response, it is important to consider the lower M-protein value as nadir or point of comparison to analyze the absolute and relative increase. When evaluating complete remission, the appearance of a serum M-protein that is different from that observed at diagnosis should be taken into account. This oligoclonal phenomenon is almost exclusively restricted to patients in complete remission compared with other degrees of response, and is associated with a significantly longer progression-free and overall survival [28]. At the time of relapse, the original M-protein reappears. The IMWG criteria for progression are similar to the EBMT criteria (Table 2.14) [27]. Specific modifications for patients relapsing from complete remission have been proposed as the following: an increase ≥25% plus the absolute number of more than 5 g/L of the serum M-protein and/or >200 mg/24 h in the urine M-protein. Minimal response should be reported separately in clinical trials. When minimal response is reported, the specific rate of minimal response should be distinguished from partial response or better.

Table 2.12 Response criteria for plasma cell leukemia.

FLC, free light chain. Adapted from © Nature Publishing Group, 2013. All rights reserved. Fernández de Larrea et al [14].

Table 2.13 EBMT criteria for relapsing/progressing multiple myeloma.

*Confirmed on at least one repeated sample. EBMT, European Society for Blood and Marrow Transplantation. Adapted from © Blackwell Science Ltd, 1998. All rights reserved. Bladé et al [20].

Table 2.14 IMWG criteria for relapsing/progressing multiple myeloma.

*Requires two consecutive assessments made at any time before classification as relapse or disease progression and/or the institution of any new therapy. FLC, free light chain; IMWG, International Myeloma Working Group. Adapted from © Nature Publishing Group, 2006. All rights reserved. Durie et al [27].