Plasma Cells Neoplasms

5 PROGNOSIS

5.1 Natural history

5.1.1 Multiple myeloma
Myeloma is a low-growth fraction tumor with only a small percentage of tumor cells in cycle during almost all of the disease duration. The doubling-time of serum M-component is usually long and the growth of myeloma is assumed to follow gompertzian kinetics with 3 consecutive periods (5.XI):

a subclinical phase before clinical diagnosis (several years).
a chronic phase which may last from 1 to 10 or more years and which is comparable to the chronic phase of chronic myeloid leukemia.
an aggressive (or terminal) phase which is comparable to the blast crisis of chronic myeloid leukemia. During this phase, the growth kinetics is more rapid and the doubling time is shorter. Patients present with high tumor burden myeloma and have a propensity for extramedullary involvement (soft tissue, CNS, effusions). These patients have a very poor prognosis.

The overall median survival from diagnosis is 30-36 months. Median survival is approximately in excess of 60 months for stage I patients, and approximately 40 and 20 months for stage II and III patients, respectively.

5.1.2 Indolent or smoldering multiple myeloma
Asymptomatic patients whose myeloma is diagnosed by chance after a routine laboratory analysis are usually not treated until disease progression. The median time to progression is approximately 2 years.
However this group is heterogeneous. Patients with an initial low tumor burden and with no lytic bone lesion may remain stable for more than 5 years while patients with a lytic bone lesion or a serum peak greater than 3 g/dL and Bence-Jones proteinuria have a median time to progression of only 10 months.

5.1.3 Solitary plasmacytoma of bone and extramedullary plasmacytoma
Patients with only one bone lesion and without evidence of bone marrow plasmacytosis are usually treated with local radiotherapy. The disappearance of serum monoclonal immunoglobulin with radiotherapy predicts long term disease-free survival (up to 10 years) and possible cure. However, approximately 2/3 of the patients experience generalized multiple myeloma within 3 years, suggesting that occult disease had not been detected originally. Overall, median survival of patients with solitary plasmacytoma of bone is over 10 years.
The prognosis of extramedullary plasmacytoma is more favorable, with 80% progression-free survival at 10 years.

5.1.4 Waldenström's Macroglobulinemia
Some patients have very indolent macroglobulinemia (analogous to indolent myeloma) with survivals of more than 2 decades. When treatment is required, the median survival of patients responding to systemic chemotherapy is 4-5 years whereas nonresponsive patients have survivals about half that long. Transformation to large-cell lymphoma may occur, as also observed in chronic lymphocytic leukemia (Richter's syndrome) (5.XVII).

5.1.5 MGUS
Approximately 20 to 30of these patients will develop in their life span malignant disease such as multiple myeloma, macroglobulinemia, amyloidosis or lymphoproliferative diseases after a median time of 8-10 years (range 2 to 30 years). No clear risk factors for progression to malignant disease have been identified so far, and periodic clinical and laboratory follow-up is recommended.

5.2 Prognostic factors in multiple myeloma

5.2.1 Clinical staging system
In multiple myeloma, survival is related to tumor burden (Durie-Salmon classification), where patients can be simply divided into 3 tumor burden groups. Median survival is approximately in excess of 60 months for stage I patients, and approximately 40 and 20 months for stage II and III patients, respectively. As renal function independently affects prognosis, serum creatinine value has been also included in the staging system.

5.2.2 Biological prognostic factors
Monoclonal immunoglobulin type significantly influences survival in multiple myeloma: Bence-Jones (or light chain) multiple myeloma and IgD myeloma are associated with a higher incidence of renal failure and amyloidosis and with a shorter survival. ß2-microglobulin (ß2-m), the light chain of the HLA antigen, has been identified as an important independent prognostic factor in multiple myeloma. As ß2-m levels are a function of both myeloma and renal function, measurement of ß2-m is a useful alternative to clinical staging to predict survival, with median survival ranging from >70 months for patients with ß2-m <4 mg/L to 20 months for patients with ß2-m>6 mg/L. With a cut-off value of 6 mg/L the relationship of ß2-m to survival is highly significant (median survival 60 vs 25 months).
Other useful serologic parameters are the serum albumin level, the C-reactive protein (CRP) level. Another important prognostic factor is the proliferative rate of myeloma as evaluated by the plasma cell labelling index (PCLI). Patients with higher PCLI have a higher percentage of plasma cells synthesizing DNA and a poorer outcome. The pre-B common acute lymphoblastic leukemia antigen can be expressed by tumor cells and has been associated with a poorer prognosis by some investigators but not by others. The ki 67 proliferative index could also be a strong indicator of myeloma survival, patients with a high index being at risk for early death.

5.2.3 Other prognostic factors
In multiple myeloma, presence of circulating plasma cells and plasmablastic bone marrow infiltration are associated with a poor clinical outcome.

Interleukin-6 is currently considered as the major factor of myeloma growth stimulation. This prognostic impact has not been fully understood until recently when interleukin-6 has been implicated in the pathogenesis of multiple myeloma. Serum albumin level is inversely correlated to IL-6 activity, while, on the opposite, CRP level is a reflection of the IL-6 activity.

5.3 Predictive factors in multiple myeloma

The response rate after conventional chemotherapy is partly dependent on tumor cell proliferation kinetics and it has been shown that early response might be a poor prognostic factor when it is associated with a high plasma cell proliferative activity. Studies of nucleic acids have provided useful prognostic information: patients with DNA hypodiploidy respond poorly to chemotherapy while patients with increased cellular RNA content have higher response rates.

5.4 Prognostic factors in Waldenström's Macroglobulinemia

In multivariate analysis, the most significant parameters have been age, male sex, general symptoms, hemoglobin, neutrophils, cryoglobulinemia.
Recently, a simple system based on 4 negative prognostic variables (age >70 yrs, hemoglobin <9 g/dL, weight loss and cryoglobulinemia) has been proposed, with median survival of>96 months and of 48 months for patients with only 1 or more than one of these factors, respectively. The response to systemic chemotherapy is an important prognostic factor.

References

5.I
Alexanian R, Barlogie D, Dixon D. Prognosis of asymptomatic multiple myeloma. Arch Intern Med 1988;148:1963-5.

5.II
Bataille R, Sany J. Solitary myeloma: clinical and prognostic features of a review of 114 cases. Cancer 1981;48:845-51.

5.III
Bataille R, Durie BGM, Grenier J. Serum b2-microglobulin and survival duration in multiple myeloma: a simple reliable marker for staging. Br J Haematol 1983;55:439-47.

5.IV
Bataille R, Durie BGM, Grenier J, Sany J. Prognostic factors and staging in multiple myeloma: a reappraisal. J Clin Oncol 1986;4:80-7.

5.V
Bataille R, Boccadoro M, Klein B, Durie B, Pileri A. C-reactive protein and b2-microglobulin produce a simple and powerful myeloma staging system. Blood 1992;80:733-7.

5.VI
Boccadoro M, Marmont F, Tribalto M et al. Early responder myeloma: kinetic studies identify a patients subgroup characterized by very poor prognosis. J Clin Oncol 1989;7:119-25.

5.VII
Dimopoulos MA, Barlogie B, Smith TL et al. High serum lactic dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991;115:931-5.

5.VIII
Dimopoulos MA, Glodstein J, Fuller L, Delasalle K, Alexanian R. Curability of solitary bone plasmacytoma. J Clin Oncol 1992;10:587-90.

5.IX
Dimopoulos MA, Moulopoulos A, Smith T, Delasalle K, Alexanian R. Risk of disease progression in asymptomatic multiple myeloma. Am J Med 1993;94:57-61.

5.X
Dimopoulos M, Alexanian R. Waldenstr&oumlm's macroglobulinemia. Blood 1994;83:1452-9.

5.XI
Drewinko B, Alexanian R, Boyer H et al. The growth fraction of human myeloma cells. Blood 1981;57:333-38.

5.XII
Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 1975;36:842-54.

5.XIII
Facon T, Brouillard M, Duhamel A. Prognostic factors in Waldenstr&oumlm's macroglobulinemia. J Clin Oncol 1993;11:1153-8.

5.XIV
Gobbi PG, Bettini R, Montecucco C et al. Study of prognosis in Waldenstr&oumlm's macroglobulinemia: a proposal for a simple binary classification with clinical and investigational utility. Blood 1994;83:2939-45.

5.XV
Greipp PR, Katzmann JA, O'Fallon WN, Kyle RA. Value of b2-microglobulin level and plasma cell labelling indices as prognostic factors in patients with newly diagnosed myeloma. Blood 1988;72:219-23.

5.XVI
Greipp PR, Lust JA, O'Fallon WM, Katzmann JA, Witzig TE, Kyle RA. Plasma cell labelling index and b2-microglobulin predict survival independent of thymidine kinase and C reactive protein in multiple myeloma. Blood 1993;81:3382-7.

5.XVII
Harousseau JL, Flandrin G, Tricot G, Brouet JC, Seligman M, Bernard J. Malignant lymphoma supervening in chronic lymphocytic leukemia and related disorders. Cancer 1981;48:1302-8.

5.XVIII
Harousseau JL, Attal M, Divine M et al. Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French registry on autologous transplantation in multiple myeloma. Blood 1995;85:3077-85.

5.XIX
Kawano M, Hirano T, Matsuda T et al. Autocrine generation and essential requirement of BSF-2/IL-6 for human multiple myeloma. Nature 1988;332:83-5.

5.XX
Klein B, Zhang XG, Jourdan M et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 1989;73:517-26.

5.XXI
Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood 1995;85:863-72.

5.XXII
Knowling MA, Harwood AR, Bergsagel DE. Comparison of extramedullary plasmacytoma with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1983;1:255-62.

5.XXIII
Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347-9.

5.XXIV
Norfolk D, Child JA, Cooper EH et al. Serum b2-microglobulin in myelomatosis: potential value in stratification and monitoring. Br J Cancer 1980;42:510-5.

5.XXV
Wiltshaw E. The natural history of extramedullary plasmacytoma and its relation to solitary myeloma of bone and myelomatosis. Medicine 1976;55:217-38.

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