International staging system (ISS) — An International Staging System (ISS), was developed based on 10,750 previously untreated patients with myeloma from over 17 institutions worldwide. It incorporates data on the levels of serum beta-2 microglobulin (B2M) and serum albumin alone to divide disease burden into three stages with prognostic significance

• Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL
• Stage II — neither stage I nor stage III
• Stage III — B2M ≥5.5 mg/L

Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months, respectively.

The prognostic value of the various chromosomal translocations and deletions detected by FISH analysis discussed above has been studied in 351 patients treated with conventional chemotherapy in an ECOG clinical trial Based on this study, patients with myeloma can be stratified into three groups with differing prognosis, as follows:

• Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13. Of note, while t(4;14) is associated with chemotherapy-sensitive disease, it is associated with a high rate of relapse, even in those undergoing high-dose chemotherapy followed by autologous hematopoietic cell transplantation
• Intermediate prognosis (median survival 42 months): -13q14
• Good prognosis (median survival 50 months): all others

Laboratory testing — Besides the bone marrow immunophenotyping and cytogenetics discussed earlier, several other tests may be helpful once the diagnosis of multiple myeloma is established. Serum concentrations of beta-2 microglobulin, C-reactive protein, and lactate dehydrogenase should be measured, since elevated values are associated with a worse prognosis (see below)

Overexpression of cyclin D1 (bcl-1) was noted in 30 percent of patients with MM in one study, and, in a multivariate model, correlated significantly with reduced survival (relative risk 7.3) This observation needs to be confirmed, since it contradicts most other studies

Monoclonal protein — The clinical course may be determined in part by the type of monoclonal protein produced:

• Patients with light chain or IgD myeloma have a higher incidence of renal failure and associated amyloidosis, a smaller serum M component, and a higher rate of light chain excretion than those with IgG or IgA myeloma
• Patients with a cryoglobulin (type I cryoglobulinemia) may develop renal disease, or may have problems with hyperviscosity or other symptoms related to the presence of a cold-insoluble protein.
• It is not clear whether the survival of patients with light chain myeloma is adversely affected. In three large reviews, light chain myeloma was reported to be not associated with a difference in prognosis, associated with a significant reduction in survival or with a significant reduction in survival only if accompanied by renal impairment at presentation

Circulating plasma cells — Monoclonal plasma cells can be detected using a slide-based immunofluorescence assay in the peripheral blood of 100 percent of patients with plasma cell leukemia, 80 percent of those with active multiple myeloma, and in more than 90 percent of those with relapsed or refractory myeloma.

Using a two-color immunoassay technique (ELISPOT), monoclonal plasma cells were detected at a concentration of 0.36, 0.85, and 9.3 percent of peripheral blood mononuclear cells in patients with stage I/II MM, stage III MM, and plasma cell leukemia, respectively. The number of these cells was also significantly correlated with the serum level of beta-2 microglobulin, suggesting the use of this technique for estimating tumor burden

Circulating myeloma cells can also be detected via flow cytometry by gating on CD38+/CD45- cells. When present at the time of hematopoietic cell transplantation, they serve as a surrogate for high-risk disease, especially when found in combination with abnormal cytogenetics.

In comparison to overt myeloma or plasma cell leukemia, most patients with MGUS or SMM have few or no circulating monoclonal plasma cells that can be detected using the assays described above. The presence of circulating plasma cells in a patient with apparent MGUS or SMM may suggest early disease progression and the need for careful follow up.

The presence of circulating plasma cells in patients with SMM is a risk factor for progression. In one series of 57 patients with smoldering myeloma, for example, 16 showed signs of progression within 12 months. Almost two-thirds of these patients had increased plasma cells of the same isotype in the peripheral blood compared with only 10 percent of those who remained stable.

The prognostic value of determining the number of circulating plasma cells (PCs) by flow cytometry of CD38+/CD45- cells was evaluated in 302 patients with previously untreated multiple myeloma. Patients with ≤10 versus those with >10 circulating PCs per 50,000 mononuclear cells had significantly longer median survivals (59 versus 37 months, respectively). On multivariate analysis, the prognostic value of circulating PCs was independent of the two components of the ISS (ie, serum levels of beta-2 microglobulin and albumin;

A risk stratification model with a prognostic value exceeding that of the ISS alone incorporated the following three adverse risk factors:

• Beta-2 microglobulin >3.5 mg/L
• Albumin <3.5 g/dL
• Circulating PCs >10 per 50,000 mononuclear cells

Patients with no (low risk), one (low-intermediate risk), two (high-intermediate risk), or three (high risk) of these adverse factors had median survivals of >79, 48, 32, and 13 months, respectively. This assay, which will require development and validation in other centers, may be especially valuable for identifying a subset of patients with a particularly poor prognosis prior to chemotherapy or hematopoietic cell transplantation

The presence of circulating myeloma cells and abnormal cytogenetics also has been shown to stratify patients at increased risk of progression following autologous HCT. In a Mayo Clinic study of 246 subjects undergoing autologous HCT, those with neither, one, or both of these adverse prognostic factors had median times to progression of 22, 15, and 6 months, respectively.