ANNUAL REVIEWS
Annu.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
Rev. Med.1991. 42:167-78 Copyright © 1991 by Annual Reviews
Further
Quick links to online content Inc. All
rights reserved
PLASMA CELL MYELOMA: BIOLOGY AND TREATMENT Daniel E. Bergsagel, C.M., M.D., D.Phil.
Department of Medicine, University of Toronto, and The Ontario Cancer Institute,Toronto, Ontario, Canada M4X lK9 KEY WORDS:
oncogenes, clonal origin, tumor progression, interferon alpha
ABSTRACT
Plasma cell myeloma results from malignant transformation in an early hemopoietic precursor cell. The disease progresses from an asymptomatic stable phase through a symptomatic phase to a terminal acute phase marked by aggressive cell growth and marrow failure. The activation of a series of oncogenes may govern the initiation and stepwise progression of these neoplasms. Chemotherapy causes the tumor to regress in about 50% of patients and improves survival, but it does not alter the course of the disease. Interferon maintenance therapy prolongs remission durations and appears to alter the course of the disease. INTRODUCTION
homogeneous protein peak is frequently found in serum electrophoresis patterns. A Swedish screening study of blood donors revealed an M protein (M for monoclonal or myeloma) in 0.9% of those over the age of 25 (1). Most of these subjects were asymptomatic and remained so for many years (2). This abnormality is commonly referred to as a Monoclonal Gammopathy of Undetermined Significance, or MGUS. These proteins are called monoclonal because they are composed of a single type of heavy and light chain. The variable region contains idiotypic arrangements of amino acids that mark the immunoglobulins as being produced by a clone of cells derived from a single transformed cell. The clone must multiply to A
167 0066-4219/91/0401--0167$02.00
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
168
BERGSAGEL
reach a population of about 5 x 109 before enough M-protein is produced to be detected in a serum electrophoresis pattern. This monoclone has the distinctive property of proliferating extensively to reach a certain size, and then it stops expanding and forms a stable monoclone that maintains the M-protein at the same serum concentration for years. However, the M protein is not stable in all patients with MGUS: 2% per year progress to develop symptomatic myeloma (3). The transformed cell that gives rise to the monoclone in MGUS may not have the uncontrolled growth po tential that characterizes symptomatic myeloma, but it is one step along the way. Subsequent events lead to the development of symptomatic myeloma, a progressive increase in the growth rate during relapses in the chronic phase of the disease, and the terminal progression to marrow failure during the acute phase, or transformation to acute leukemia. The mechanisms governing the initial malignant transformation of the precursor of the myeloma cell, and the subsequent progression, are unknown, but they hold the key to understanding and controlling the disease. TUMOR BIOLOGY Origin of the Transformed Cell in Plasma Cell Neoplasms
Myeloma was once thought to be a malignancy of bone marrow plasma cells, but new evidence suggests that the oncogenic event that gives rise to this heterogeneous, but monoclonal, popUlation probably occurs in a much earlier precursor cell. Many myeloma patients have a circulating monoclonal population of lymphocytes bearing a membrane immu noglobulin that reacts with an antibody specific for the idiotype of the M protein (4), which suggests that these cells belong to the same clone as the myeloma cells. This finding is strongly supported by two observations: (a) the immunoglobulin gene rearrangement of blood lymphocytes is identical with the rearrangement of their marrow plasma cells in seven of nine myeloma patients (5), and (b) the monoclonal lymphocytes differentiate into plasma cells in cell culture and produce the same M-protein as the patient's myeloma cells, either spontaneously (6) or with stimulation by phorbol ester (7). The earliest identifiable cell in the B-Iymphocyte lineage is the pre B cell, which is distinguished by the presence of cytoplasmic IgM. The cytoplasmic IgM of the pre-B cells of two IgA myeloma patients was found to react with antisera specific for the idiotype of the M-protein (8); thus the immunoglobulin gene rearrangement of the malignant clone, and prob ably the malignant transformation event, occurred either at the pre-B stage of differentiation or in an even earlier precursor cell.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
MYELOMA BIOLOGY AND TREATMENT
169
Two pieces of information suggest that the transformation event may occur in a precursor cell that is common to both the B and the T lymphocyte lineage. First, both the B and T lymphocytes reportedly bore identical idiotypic determinants in two IgGjk myeloma patients (9, 10). In a later study, five of seven patients had small subsets of T cells (1.8 to 8% of a purified T cell population) that wcrc idiotypically cross-reactive with the M-protein (11). Second, two myeloma patients were reported to have unusual crystalline structures in the myeloma cells and in B and T lym phocytes, which suggests that all of these cells are derived from the same clone (12). New findings suggest that the transformation event initiating myeloma may occur at an even earlier stage in the development of the hemopoietic stem cell. Studies of both fresh and cultured myeloma marrow cells have demonstrated that many myeloma cells express both plasma cell and myeloid antigens (13). In an extension of this line of investigation, Epstein and his coworkers (14) identified aneuploid plasma cells from myeloma patients that expressed plasma cell and the pre-B-cell antigen CALLA (common acute lymphoblastic leukemia antigen) in specimens from 58% of patients, and of megakaryocytic (88% ), myelomonocytic (65%), and erythroid (39% ) surface markers. These findings indicate that multiple cell lineages are involved in myeloma and suggest that the transformation event in myeloma occurs in an early hemopoietic precursor cell that gives rise to all of these lineages. Chronic myelogenous leukemia (CML) probably arises in the pluri potent hemopoietic stem cell, since the erythroid, myeloid, mega karyocytic, and monocytic cells, the B lymphocytes, and probably the T lymphocytes, belong to the same clone (reviewed in 15). It is of interest that about 10% of CML patients die with an acute lymphoblastic leukemia of a B lymphocyte phenotype, and furthermore, at least 12 patients with CML have developed a monoclonal gammopathy (16). An aberration in the differentiation of a transformed hemopoietic stem cell may be respon sible for the development of both CML and plasma cell neoplasms, as well as other hematologic malignancies (17). Chromosome Abnormalities and Oncogenes
Nonrandom chromosome translocations are found in 90% of pristane induced plasmacytomas in BALBjc mice (18). The breakpoints are always the same, carrying c-myc from the distal portion of chromosome 15 to fuse with the heavy chain locus on chromosome 12, or with the kappa chain region on chromosome 6. The translocation of c-myc to a func tionally active immunoglobulin gene region is thought to activate c-myc and play a role in generating these plasmacytomas. Chromosome abnor-
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
170
BERGSAGEL
malities have been reported in from 18 to 36% of newly diagnosed patients, and 37 to 50% of treated myeloma patients (19, 20), but neither a non random pattern of abnormalities nor an increased frequency of trans locations to the loci controlling immunoglobulin production has been recognized in human myeloma. Chromosome studies have been difficult because the growth fraction is so small in most myeloma cell populations. Abnormalities probably occur more frequently than can be recognized by morphological studies since aneuploidy has been detected in 80% of myeloma marrow samples by flow cytometry (21). Although c-myc appears to play a role in the genesis of mouse plas macytomas, it is of interest that both c-myc and v-Ha-ras oncogenes are required for the rapid induction of plasmacytomas in pristane-primed mice (22). Further, Seremetis and her colleagues (23) showed that the expression of the c-myc oncogene induces malignant transformation of Epstein-Barr virus-immortalized human lymphoblastoid cells, but these cells do not differentiate. The introduction of an activated H-ras allele into these transformed lymphoblasts potentiates the transformed phenotype and leads to plasmacytoid differentiation and the production of IgM. This model fits human myeloma rather well for both are characterized by a small tumor stem cell population capable of self renewal, and differentiation into a much larger number of functioning plasma cells. Alterations of proto-oncogene loci, including chromosomal trans locations, amplifications, mutations, or deletions, are found in several cancers. Neri et al (24) determined the frequency of activating mutations of ras (H-, K-, and N-ras) and c-myc oncogenes in marrow or tumor biopsies from 56 multiple myeloma patients. Mutations, involving the N or K-ras genes were detected in 12 of 43 patients (27% ) at diagnosis, and 6 of 13 (46%) after treatment. No structural alterations of the c-myc gene were detected in this study. In a few cases, rearranged (25-27) or mutated (28) c-myc oncogenes or elevated levels of c-myc RNA (27) have been reported in myeloma marrow or cell lines. In addition, the presence of activated c-myc and N-ras oncogenes has been reported in a myeloma cell line derived from a patient in the terminal, aggressive, acute phase of the disease (29). A study of the expression of the H-ras oncogene product, p2l , in myeloma patients revealed that 74% of 23 patients with active myeloma had higher p 2l fluorescence in aneuploid myeloma cells than was observed in the marrow of normal patients or those in myeloma remission (30). The expression of high p 2l levels in myeloma cells was associated with short survival. Similarly, Neri et al (24) noted that none of the myeloma patients with ras oncogene mutations responded to chemotherapy, which implies a poor prognosis. The increased expression of p 21 and the correlation of
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
MYELOMA BIOLOGY AND TREATMENT
171
increased p2l expression in myeloma cells and ras mutations with a poor prognosis both argue for a role of ras oncogenes in the genesis of multiple myeloma. The initiation of neoplasia is believed to be a multistep process, and the progression of plasma cell neoplasms from the stable MGUS stage through the symptomatic myeloma stage (during which there is a progressive increase in the growth rate) to the terminal acute phase must also require a series of changes leading to more aggressive growth of the myeloma cells. It is tempting to speculate that tumor induction and progression results from the activation of a series of oncogenes. While the observations men tioned above prompt this speculation, much remains to be discovered before the series of changes are understood.
TREATMENT
Treatment of plasma cell myeloma is usually delayed until symptomatic disease progression is clearly documented. Starting treatment earlier, dur ing the asymptomatic stable phase, does not delay progression nor improve survival, and usually fails to lower the M-protein level. Treating symptomatic myeloma patients with effective agents results in objective tumor regression in from 32 to 72%, with response rates of 4555% in most series (Table 1). Response rates are significantly lower for patients with earlier stages of disease (Stages I and II) and higher for those in Stage III (37, 44). Patients who respond experience an improvement in both pain, weight gain, a rise in hemoglobin, and a fall in the M-protein. The serum M protein disappears from the serum electrophoresis pattern in about 10% of patients, or it reaches a stable plateau below 50% of the pretreatment value in another 40% of patients. Treatment is usually stopped after a stable response lasting for at least four months is achieved. This stable remission lasts from a few months to more than five years, with a median of 21 months from the start of therapy (45). Maintenance therapy with melphalan/prednisone (MP) prolongs the remission duration, without improving overall survival (45). About 50% of patients who relapse on no maintenance therapy respond again to the same chemotherapy (45). Subsequent remissions become shorter and shorter because the regrowth rate of the relapsing myeloma cell mass increases progressively (46). Eventually, it becomes impossible to control the disease with chemotherapy. Marrow failure develops as the patient enters the acute phase, marked by pancytopenia and uncontrolled growth of the myeloma cells.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
Table 1
Melphalan/prednisone vs drug combinations in the treatment of plasma cell myeloma Median Survival (Mo) MP/Comb.
-
Sil!!!illcance of difference !R! Response Survival
Numbers MP/Comb.
%Response"· MP/Comb.
125/174
40/39 (A)
28/31
NS
NS
-....] IV
Group·lYear
(Ref)
Drug·· Combination
NO.c/1979
(31)
BCMP
ECOG/1982
(32)
BCP
92/96
43/50 (B)
19/25
NS
NS
� Cl
GATLA/1988
(33)
MeCCP
67/83
40/40 (B)
38/30
NS
NS
:> Cl
Denmark/1985
(34)
VBCMP (M2)
31/33
45/48 (B)
21/21
NS
NS
Norway /1988
(35)
VBCMP (M2)
48/44
48/54 (B)
29/33.5
NS
NS
ECOG/1987
(36)
VBCMP (M2)
217/214
51/72 (B)
30/31
MP
NS
GATLA/1988
145/115
33/44 (B)
42/44
NS
NS
77/160
32/53 (A)
23/43
0.002 Comb.>MP
0.004 Comb.> MP
37/26
NS
NS
0.02 Comb.>MP
NS
(33)
VMeCCMP
SWOG/1983
(37)
VMCP,VCAP +VBAP
A lexanian/l984
(38)
same
30/75
53/57 (A)
132/128
50/65 (B)
29/25
69/56 (B)
46/33
NS
NS
VMCP/VBAP-Stage m
55/53
58/57
26/24
NS
NS
44/42
61/52 (B)
28/24
NS
NS
NS
NS
NS
Comb.
as above
PETIiEMA/1989
(39)
VMCP/VBAP
MGWS/1990
(40)
VMCP
-
Stage n
MGCS/1989
(41)
VMCP/VBAP
IMMSG/1989
(42,43)
VMCP/VBAP
152/152
47/51 (B)
GMTG/1988
(44)
VMCP
170/150
39/39 (A)
>54/42
·ECOG - Eastern Cooperative Oncology Group; GATLA - Grupo Argentino de Tratarniento de Ia Leukemia Aguda; NO-e National Cancer Institute of Canada; PETHEMA - Spanis tive Group for Hemato cal Malignancies Treatment; SWOG - Southwest Oncology Gro ; GMTG - German - Italian Multiple Myeloma tudy Group; MGCS - Myeloma Group of Central Sweden; MGW - Myeloma Group Myeloma Treatment Group; of Western Sweden. "A - adriamycin (doxorubicin), B - BCNU (Carmustine), C - cyclosphosphamide, V - vincristine, M - melphalan, MeC - methyl CCNU (Semustine), Pprednisone -Response criteria: A - SWOG >75% reduction in M-protein synthetic index; B - Myeloma Task Force>50% fall in M-protein concentration.
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Annu.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
Rev. Med.1991. 42:167-78 Copyright © 1991 by Annual Reviews
Further
Quick links to online content Inc. All
rights reserved
PLASMA CELL MYELOMA: BIOLOGY AND TREATMENT Daniel E. Bergsagel, C.M., M.D., D.Phil.
Department of Medicine, University of Toronto, and The Ontario Cancer Institute,Toronto, Ontario, Canada M4X lK9 KEY WORDS:
oncogenes, clonal origin, tumor progression, interferon alpha
ABSTRACT
Plasma cell myeloma results from malignant transformation in an early hemopoietic precursor cell. The disease progresses from an asymptomatic stable phase through a symptomatic phase to a terminal acute phase marked by aggressive cell growth and marrow failure. The activation of a series of oncogenes may govern the initiation and stepwise progression of these neoplasms. Chemotherapy causes the tumor to regress in about 50% of patients and improves survival, but it does not alter the course of the disease. Interferon maintenance therapy prolongs remission durations and appears to alter the course of the disease. INTRODUCTION
homogeneous protein peak is frequently found in serum electrophoresis patterns. A Swedish screening study of blood donors revealed an M protein (M for monoclonal or myeloma) in 0.9% of those over the age of 25 (1). Most of these subjects were asymptomatic and remained so for many years (2). This abnormality is commonly referred to as a Monoclonal Gammopathy of Undetermined Significance, or MGUS. These proteins are called monoclonal because they are composed of a single type of heavy and light chain. The variable region contains idiotypic arrangements of amino acids that mark the immunoglobulins as being produced by a clone of cells derived from a single transformed cell. The clone must multiply to A
167 0066-4219/91/0401--0167$02.00
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
168
BERGSAGEL
reach a population of about 5 x 109 before enough M-protein is produced to be detected in a serum electrophoresis pattern. This monoclone has the distinctive property of proliferating extensively to reach a certain size, and then it stops expanding and forms a stable monoclone that maintains the M-protein at the same serum concentration for years. However, the M protein is not stable in all patients with MGUS: 2% per year progress to develop symptomatic myeloma (3). The transformed cell that gives rise to the monoclone in MGUS may not have the uncontrolled growth po tential that characterizes symptomatic myeloma, but it is one step along the way. Subsequent events lead to the development of symptomatic myeloma, a progressive increase in the growth rate during relapses in the chronic phase of the disease, and the terminal progression to marrow failure during the acute phase, or transformation to acute leukemia. The mechanisms governing the initial malignant transformation of the precursor of the myeloma cell, and the subsequent progression, are unknown, but they hold the key to understanding and controlling the disease. TUMOR BIOLOGY Origin of the Transformed Cell in Plasma Cell Neoplasms
Myeloma was once thought to be a malignancy of bone marrow plasma cells, but new evidence suggests that the oncogenic event that gives rise to this heterogeneous, but monoclonal, popUlation probably occurs in a much earlier precursor cell. Many myeloma patients have a circulating monoclonal population of lymphocytes bearing a membrane immu noglobulin that reacts with an antibody specific for the idiotype of the M protein (4), which suggests that these cells belong to the same clone as the myeloma cells. This finding is strongly supported by two observations: (a) the immunoglobulin gene rearrangement of blood lymphocytes is identical with the rearrangement of their marrow plasma cells in seven of nine myeloma patients (5), and (b) the monoclonal lymphocytes differentiate into plasma cells in cell culture and produce the same M-protein as the patient's myeloma cells, either spontaneously (6) or with stimulation by phorbol ester (7). The earliest identifiable cell in the B-Iymphocyte lineage is the pre B cell, which is distinguished by the presence of cytoplasmic IgM. The cytoplasmic IgM of the pre-B cells of two IgA myeloma patients was found to react with antisera specific for the idiotype of the M-protein (8); thus the immunoglobulin gene rearrangement of the malignant clone, and prob ably the malignant transformation event, occurred either at the pre-B stage of differentiation or in an even earlier precursor cell.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
MYELOMA BIOLOGY AND TREATMENT
169
Two pieces of information suggest that the transformation event may occur in a precursor cell that is common to both the B and the T lymphocyte lineage. First, both the B and T lymphocytes reportedly bore identical idiotypic determinants in two IgGjk myeloma patients (9, 10). In a later study, five of seven patients had small subsets of T cells (1.8 to 8% of a purified T cell population) that wcrc idiotypically cross-reactive with the M-protein (11). Second, two myeloma patients were reported to have unusual crystalline structures in the myeloma cells and in B and T lym phocytes, which suggests that all of these cells are derived from the same clone (12). New findings suggest that the transformation event initiating myeloma may occur at an even earlier stage in the development of the hemopoietic stem cell. Studies of both fresh and cultured myeloma marrow cells have demonstrated that many myeloma cells express both plasma cell and myeloid antigens (13). In an extension of this line of investigation, Epstein and his coworkers (14) identified aneuploid plasma cells from myeloma patients that expressed plasma cell and the pre-B-cell antigen CALLA (common acute lymphoblastic leukemia antigen) in specimens from 58% of patients, and of megakaryocytic (88% ), myelomonocytic (65%), and erythroid (39% ) surface markers. These findings indicate that multiple cell lineages are involved in myeloma and suggest that the transformation event in myeloma occurs in an early hemopoietic precursor cell that gives rise to all of these lineages. Chronic myelogenous leukemia (CML) probably arises in the pluri potent hemopoietic stem cell, since the erythroid, myeloid, mega karyocytic, and monocytic cells, the B lymphocytes, and probably the T lymphocytes, belong to the same clone (reviewed in 15). It is of interest that about 10% of CML patients die with an acute lymphoblastic leukemia of a B lymphocyte phenotype, and furthermore, at least 12 patients with CML have developed a monoclonal gammopathy (16). An aberration in the differentiation of a transformed hemopoietic stem cell may be respon sible for the development of both CML and plasma cell neoplasms, as well as other hematologic malignancies (17). Chromosome Abnormalities and Oncogenes
Nonrandom chromosome translocations are found in 90% of pristane induced plasmacytomas in BALBjc mice (18). The breakpoints are always the same, carrying c-myc from the distal portion of chromosome 15 to fuse with the heavy chain locus on chromosome 12, or with the kappa chain region on chromosome 6. The translocation of c-myc to a func tionally active immunoglobulin gene region is thought to activate c-myc and play a role in generating these plasmacytomas. Chromosome abnor-
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
170
BERGSAGEL
malities have been reported in from 18 to 36% of newly diagnosed patients, and 37 to 50% of treated myeloma patients (19, 20), but neither a non random pattern of abnormalities nor an increased frequency of trans locations to the loci controlling immunoglobulin production has been recognized in human myeloma. Chromosome studies have been difficult because the growth fraction is so small in most myeloma cell populations. Abnormalities probably occur more frequently than can be recognized by morphological studies since aneuploidy has been detected in 80% of myeloma marrow samples by flow cytometry (21). Although c-myc appears to play a role in the genesis of mouse plas macytomas, it is of interest that both c-myc and v-Ha-ras oncogenes are required for the rapid induction of plasmacytomas in pristane-primed mice (22). Further, Seremetis and her colleagues (23) showed that the expression of the c-myc oncogene induces malignant transformation of Epstein-Barr virus-immortalized human lymphoblastoid cells, but these cells do not differentiate. The introduction of an activated H-ras allele into these transformed lymphoblasts potentiates the transformed phenotype and leads to plasmacytoid differentiation and the production of IgM. This model fits human myeloma rather well for both are characterized by a small tumor stem cell population capable of self renewal, and differentiation into a much larger number of functioning plasma cells. Alterations of proto-oncogene loci, including chromosomal trans locations, amplifications, mutations, or deletions, are found in several cancers. Neri et al (24) determined the frequency of activating mutations of ras (H-, K-, and N-ras) and c-myc oncogenes in marrow or tumor biopsies from 56 multiple myeloma patients. Mutations, involving the N or K-ras genes were detected in 12 of 43 patients (27% ) at diagnosis, and 6 of 13 (46%) after treatment. No structural alterations of the c-myc gene were detected in this study. In a few cases, rearranged (25-27) or mutated (28) c-myc oncogenes or elevated levels of c-myc RNA (27) have been reported in myeloma marrow or cell lines. In addition, the presence of activated c-myc and N-ras oncogenes has been reported in a myeloma cell line derived from a patient in the terminal, aggressive, acute phase of the disease (29). A study of the expression of the H-ras oncogene product, p2l , in myeloma patients revealed that 74% of 23 patients with active myeloma had higher p 2l fluorescence in aneuploid myeloma cells than was observed in the marrow of normal patients or those in myeloma remission (30). The expression of high p 2l levels in myeloma cells was associated with short survival. Similarly, Neri et al (24) noted that none of the myeloma patients with ras oncogene mutations responded to chemotherapy, which implies a poor prognosis. The increased expression of p 21 and the correlation of
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
MYELOMA BIOLOGY AND TREATMENT
171
increased p2l expression in myeloma cells and ras mutations with a poor prognosis both argue for a role of ras oncogenes in the genesis of multiple myeloma. The initiation of neoplasia is believed to be a multistep process, and the progression of plasma cell neoplasms from the stable MGUS stage through the symptomatic myeloma stage (during which there is a progressive increase in the growth rate) to the terminal acute phase must also require a series of changes leading to more aggressive growth of the myeloma cells. It is tempting to speculate that tumor induction and progression results from the activation of a series of oncogenes. While the observations men tioned above prompt this speculation, much remains to be discovered before the series of changes are understood.
TREATMENT
Treatment of plasma cell myeloma is usually delayed until symptomatic disease progression is clearly documented. Starting treatment earlier, dur ing the asymptomatic stable phase, does not delay progression nor improve survival, and usually fails to lower the M-protein level. Treating symptomatic myeloma patients with effective agents results in objective tumor regression in from 32 to 72%, with response rates of 4555% in most series (Table 1). Response rates are significantly lower for patients with earlier stages of disease (Stages I and II) and higher for those in Stage III (37, 44). Patients who respond experience an improvement in both pain, weight gain, a rise in hemoglobin, and a fall in the M-protein. The serum M protein disappears from the serum electrophoresis pattern in about 10% of patients, or it reaches a stable plateau below 50% of the pretreatment value in another 40% of patients. Treatment is usually stopped after a stable response lasting for at least four months is achieved. This stable remission lasts from a few months to more than five years, with a median of 21 months from the start of therapy (45). Maintenance therapy with melphalan/prednisone (MP) prolongs the remission duration, without improving overall survival (45). About 50% of patients who relapse on no maintenance therapy respond again to the same chemotherapy (45). Subsequent remissions become shorter and shorter because the regrowth rate of the relapsing myeloma cell mass increases progressively (46). Eventually, it becomes impossible to control the disease with chemotherapy. Marrow failure develops as the patient enters the acute phase, marked by pancytopenia and uncontrolled growth of the myeloma cells.
Annu. Rev. Med. 1991.42:167-178. Downloaded from www.annualreviews.org by University of California - San Francisco UCSF on 01/26/15. For personal use only.
Table 1
Melphalan/prednisone vs drug combinations in the treatment of plasma cell myeloma Median Survival (Mo) MP/Comb.
-
Sil!!!illcance of difference !R! Response Survival
Numbers MP/Comb.
%Response"· MP/Comb.
125/174
40/39 (A)
28/31
NS
NS
-....] IV
Group·lYear
(Ref)
Drug·· Combination
NO.c/1979
(31)
BCMP
ECOG/1982
(32)
BCP
92/96
43/50 (B)
19/25
NS
NS
� Cl
GATLA/1988
(33)
MeCCP
67/83
40/40 (B)
38/30
NS
NS
:> Cl
Denmark/1985
(34)
VBCMP (M2)
31/33
45/48 (B)
21/21
NS
NS
Norway /1988
(35)
VBCMP (M2)
48/44
48/54 (B)
29/33.5
NS
NS
ECOG/1987
(36)
VBCMP (M2)
217/214
51/72 (B)
30/31
MP
NS
GATLA/1988
145/115
33/44 (B)
42/44
NS
NS
77/160
32/53 (A)
23/43
0.002 Comb.>MP
0.004 Comb.> MP
37/26
NS
NS
0.02 Comb.>MP
NS
(33)
VMeCCMP
SWOG/1983
(37)
VMCP,VCAP +VBAP
A lexanian/l984
(38)
same
30/75
53/57 (A)
132/128
50/65 (B)
29/25
69/56 (B)
46/33
NS
NS
VMCP/VBAP-Stage m
55/53
58/57
26/24
NS
NS
44/42
61/52 (B)
28/24
NS
NS
NS
NS
NS
Comb.
as above
PETIiEMA/1989
(39)
VMCP/VBAP
MGWS/1990
(40)
VMCP
-
Stage n
MGCS/1989
(41)
VMCP/VBAP
IMMSG/1989
(42,43)
VMCP/VBAP
152/152
47/51 (B)
GMTG/1988
(44)
VMCP
170/150
39/39 (A)
>54/42
·ECOG - Eastern Cooperative Oncology Group; GATLA - Grupo Argentino de Tratarniento de Ia Leukemia Aguda; NO-e National Cancer Institute of Canada; PETHEMA - Spanis tive Group for Hemato cal Malignancies Treatment; SWOG - Southwest Oncology Gro ; GMTG - German - Italian Multiple Myeloma tudy Group; MGCS - Myeloma Group of Central Sweden; MGW - Myeloma Group Myeloma Treatment Group; of Western Sweden. "A - adriamycin (doxorubicin), B - BCNU (Carmustine), C - cyclosphosphamide, V - vincristine, M - melphalan, MeC - methyl CCNU (Semustine), Pprednisone -Response criteria: A - SWOG >75% reduction in M-protein synthetic index; B - Myeloma Task Force>50% fall in M-protein concentration.
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