Test

From Wikilite

NOT IN PRINT

Chapter 10	SECTION 2A - Multiple Myeloma
	Intact immunoglobulin multiple myeloma (IIMM) - theoretical considerations of sFLC and Ig measurements

Contents 1 2 10.1. Introduction 3 10.2. Half-life of serum free light chains 4 References

Summary:

sFLC concentrations are low because of fast renal clearance. sFLC κ/λ ratios inherently compensate for changing clearance rates. Serum IgG half-life is both prolonged and variable because of FcRn recycling. Changes in haematocrit and blood volume alter immunoglobulin concentrations. The 2-6 hour half-life of sFLCs allows tumour cell killing rates, early responses, residual disease and early tumour relapse to be quickly observed during treatment.

10.1. Introduction

Serum concentrations of FLCs and intact monoclonal immunoglobulins result from the balance between production and clearance rates. Production rates vary, not only between different patients but also in individual patients as their tumours progress or respond to treatment. Salmon and Smith in 1970 ^[1], showed that for IgG myeloma, average synthetic rates per myeloma cell, per minute for IgG varied from 12,500 to 85,000 molecules between different patients. However, this was constant over time which means that changes in total synthetic rates reflect changes in tumour mass for an individual patient. This is presumably also true for monoclonal FLC synthesis.

Clearance rates are more complicated. For sFLCs, there is normally rapid clearance by renal glomeruli but in renal failure, clearance is by general pinocytosis with a half-life of 2-3 days. Between these two half-lives there is a continuous range depending upon the degree of renal impairment. For IgA and IgM the half-lives appear constant at 5-6 days, with clearance by pinocytosis, while for IgG, clearance is prolonged to 21 days by saturable recycling receptors (Brambell receptors; more recently called neonatal receptors [FcRn]). These various influences on the serum concentrations of FLCs and immunoglobulins mean that both isolated and serial measurements may not reliably relate to tumour size or changing tumour size.

These variable clearance rates apply equally to monoclonal immunoglobulins and their normal counterparts. Hence the value of sFLC κ/λ ratios, that inherently compensate for varying clearance rates as renal function changes. The same argument applies to IgG monoclonal immunoglobulins; ratios of the monoclonal Igs to normal immunoglobulins (eg. IgGκ/IgGλ) numerically compensates for varying removal rates. This is discussed in detail later (see Hevylite, Chapter 32).

In addition, other factors need consideration. Large molecules such as IgM and to a lesser extent IgA and IgG are affected by changes in blood volume. In contrast, the smaller FLC molecules are 70-80% extravascular and are least affected. Furthermore, sFLC κ/λ ratios automatically compensate for volume changes.

The purpose of this chapter is to analyse the theoretical basis for the utility of sFLC measurements in patients with multiple myeloma who produce both intact monoclonal immunoglobulins and FLCs.

10.2. Half-life of serum free light chains

As indicated in Chapter 3, the dominating clearance mechanism for sFLCs is filtration through the renal glomerular fenestrations. At 25kDa, monomeric FLC molecules (usually κ) have a half-life of 2 hours while dimeric molecules (usually λ) have a halflife of 4-6 hours (Figure 10.1). Serum FLCs that are more highly polymerised have longer half-lives. The 200 to 300-fold shorter serum half-life of FLCs compared with IgG (21 days) allows a much more sensitive evaluation of changing monoclonal protein production and hence tumour size, during treatment ^[2].

Test Questions
What is the ideal serum half-life of a tumour marker? What is the mechanism of slow clearance of IgG? Why do IgG and FLC half-lives vary with concentration? Do blood volume changes affect sFLC concentration ratios?

Answers
The shorter the half-life the better, provided sufficient amounts remain for accurate detection (Section 10.2). Recycling receptors bind IgG and protect it from acid degradation in pinocytotic vescicles (Section 10.3). IgG receptors saturate at high IgG concentrations so the half-life shortens (page 75). FLCs damage the kidney so filtration slows (Section 10.3). No (Section 10.5).

TEST HIDDEN

Chapter 9

Back to Contents Page

Chapter 11

References