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Partial response

■ >50% reduction of serum M protein and

■ Reduction in 24-h urinary M protein by >90% or to <200 mg/24 h

■ If present at baseline, a >50% reduction in size of soft-tissue plasmacytomas

■ If serum and urine M protein unmeasurable, a >50% decrease in the difference between involved and uninvolved free light-chain (FLC) levels is required in place of the M-protein criteriab

Not a response requirement except in nonsecretory myeloma where a >50% reduction in plasma cells is required in place of M protein

°The criteria for response require M-protein reductions to be confirmed by consecutive determinations and that there be no known increase in the size or number of lytic bone lesions on skeletal imaging.

^Should not be used to assess response if serum and/or urine M protein are measurable. Baseline involved FLC level must be 10 mg/dL (100 mg/L) or higher and serum FLC ratio must be abnormal for FLC criteria to be used to assess response.

°The criteria for response require M-protein reductions to be confirmed by consecutive determinations and that there be no known increase in the size or number of lytic bone lesions on skeletal imaging.

^Should not be used to assess response if serum and/or urine M protein are measurable. Baseline involved FLC level must be 10 mg/dL (100 mg/L) or higher and serum FLC ratio must be abnormal for FLC criteria to be used to assess response.

higher. At Mayo Clinic, these bone marrow criteria are also used for patients in whom neither the serum nor the urine M-protein levels are "measurable" at baseline, i.e., patients with oligosecretory myeloma.

Stable disease Failure to meet response criteria for CR, VGPR, PR, or progressive disease is considered as stable disease.

Relapse from CR Patients in CR are considered to have "relapse from CR" if there is reappearance of serum or urine M protein by immunofixation or electrophoresis, development of >5% plasma cells in the bone marrow, or appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, or hypercalcemia). Relapse from CR is used only to calculate disease free survival (DFS).

Progressive disease Progressive disease for patients not in CR is defined by the presence of one or more of the following features, and is used to calculate time to progression (TTP) and progression free survival (PFS):

■ increase in serum M protein to >25% above the lowest response level, which must also be an absolute increase of at least 0.5 g/dL;

■ increase in 24-h urine M protein to >25% above the lowest remission value, which must also be an absolute increase of at least 200 mg/24 h of urine M protein;

■ increase in bone marrow plasmacytosis by >25% above the lowest remission value, which must also be an absolute increase of at least 10% bone marrow plasma cells;

■ development of new soft-tissue plasmacytomas or bone lesions. Compression fracture does not exclude continued response and may not indicate progression;

■ definite increase in size of existing plasmacytomas or bone lesions. At Mayo Clinic, a definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross diameters of the measurable lesion; and

■ development of hypercalcemia as defined by serum calcium >11.5 mg/dL (not attributable to any other cause);

■ progression based on FLC criteria (see below).

The Blade criteria require that M-protein levels for relapse from CR and progression listed above be confirmed by at least one repeat investigation.

Definitions for response using the free light-chain assay

The serum free light-chain (FLC) assay is of particular use in monitoring response to therapy in patients who have oligosecretory or nonsecretory myeloma, in whom serial bone marrow biopsies are often impractical and cumbersome.

The test is highly sensitive and consists of two separate assays: one to detect free kappa (normal range 0.33-1.94 mg/dL) and the other to detect free lambda (normal range 0.57-2.63 mg/dL) light chains.12 In addition to measuring the levels of free-light chain, the test also allows assessment of clonality based on the ratio of kappa/lambda light-chain levels (normal reference range 0.26-1.65).13 Patients with a kappa/lambda FLC ratio <0.26 are typically defined as having monoclonal lambda FLC, and those with ratios >1.65 are defined as having a monoclonal kappa FLC. The monoclonal light-chain isotype is referred to as the "involved" FLC isotype, and the opposite light-chain type is the "uninvolved" FLC type. Thus, a patient with a ratio of >1.65 on the FLC ratio has a monoclonal kappa FLC isotype, where the kappa is the "involved" FLC and the lambda is the "uninvolved" FLC.

When using the FLC assay, the FLC levels vary considerably with changes in renal function and do not solely represent monoclonal elevations. Thus, both the level of the involved and the uninvolved FLC isotype (i.e., the involved/uninvolved ratio or involved/uninvolved difference) should be considered in assessing response. The criteria listed below take this factor into account.

Until further validation, the serum FLC assay criteria should be used in assessing response and progression only if the baseline serum and/or urine M proteins are not "measurable" by the traditional criteria discussed earlier. In addition, the baseline level of the involved FLC should be at least >10 mg/dL and the FLC assay should have an abnormal ratio (clonal).

Complete response To be considered a CR, normalization of the FLC ratio and negative serum and urine immunofixation are required. In addition, patients should meet other nonparaprotein requirements for CR.

Partial response To be considered a PR, a 50% decrease in the difference between involved and uninvolved FLC levels, is required in place of the M-protein criteria. Other requirements of PR must also be met.

Progressive disease The following change qualifies as progression:

■ a 50% increase in the difference between involved and uninvolved FLC levels from the lowest response level, which must also be an absolute increase of at least 10 mg/dL.

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