Treatment of plasma cell myeloma.

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Ann. Rev. Med. 1979. 30:431-43 Copyright @ 1979 by Annual Reviews Inc. All rights reserved

TREATMENT OF PLASMA

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Annu. Rev. Med. 1979.30:431-443. Downloaded from www.annualreviews.org Access provided by McMaster University on 02/13/15. For personal use only.

CELL MYELOMA Daniel E. Bergsagel, M.D., D. Phil 1 Department of Medicine, University of Toronto, and Ontario Cancer Institute, Toronto, Canada M4X 1K9

INTRODUCTION The investigation of plasma cell neoplasms during the past two decades has revealed much about the biology of the tumors, the structure and functions of the immunoglobulins (M-proteins) they produce, the prognostic factors, the clinical staging, and the response to treatment. Attempts to improve the effectiveness of treatment have been disappointing. In this review I consider the prognostic factors and assess the effective ness of various drug combinations in the treatment of myeloma patients. The failure of intensive chemotherapy to increase the duration of remissions or survival, and the absence of a correlation between cell-kill and survival suggests that the beneficial effects of treatment may not be directed against the neoplastic plasma cells. Evidence presented in the final section suggests that a growth control mechanism may be operative in some patients with plasma cell neoplasms. '

PROGNOSTIC FACTORS Many of the clinical trials designed to evaluate the effectiveness of treatment have now been analyzed to identify the important clinical features that influence prognosis

(1-4).

General features of the disease, the immuno

globulin class of M-protein, clinical manifestations related to the total body myeloma cell number, and renal function have all been found to influence, prognosis. ISupported by Grant

143, Ontario Cancer

Treatment and Research Foundation.

431

0066-4219/79/0401-0431$01.00

BERGSAGEL

432

General Features The performance status of a patient summarizes the effects of pain, an orexia, weight loss, anemia, renal failure, and other manifestations of the disease. It is not surprising to find that myeloma patients who present with a good performance status have the best survival prognosis

(1).

A history of weight loss has not been examined critically as a prognostic factor in myeloma, though weight loss is frequently reported by myeloma


patients. It is probably just as important a prognostic factor in myeloma as it is in the malignant lymphomas. An unexplained fever frequently develops during the acute terminal

(5). Survival following 17 patients included

phase of myeloma

short, for all of the months ( median

the appearance of this fever is in this report died within

1-9

months) after the fever was recognized.

3

Immunoglobulin Class of M-Protein Neoplasms arising from cells that produce different immunoglobulins might be expected to express different biologic properties, such as preferences for the growth of neoplastic cells in certain tissues, and differences in growth rate. Indeed, plasma cell tumors producing different classes of immuno globulins do have different clinical manifestations. IgM-producing plasma cell neoplasms frequently cause lymphadenopathy and splenomegaly, but lytic bone lesions are uncommon. In contrast, myelomas producing other types of immunoglobulins usually cause lytic bone lesions, while splenomeg aly and lymphadenopathy are unusual. The type of M-protein produced by the plasma cell neoplasm also influ ences survival

(6).

Those producing IgM are reported

(7)

to have the best

survival ( median SO months). The median survival ofIgG myeloma patients is about

(8,9),and 30 months (9, 10). The shortest median survivals reported are 9 months for IgD myeloma (11),and 10 months for those producing only lambda light chains (9,10). A retrospective analysis of the clinical manifestations and response to therapy of 52 myeloma pa tients producing kappa, and 45 producing lambda, light chains failed to 29

months

(8,9),for

IgA about

21

months

for those producing only kappa light chains

identify a reason for the shorter survival of patients with lambda light-chain disease

(10). No differences in the degree of anemia, uremia, hypercalcemia,

hypoalbuminemia, Bence Jones proteinuria, the severity of lytic skeletal disease, the frequency of amyloidosis, or the therapeutic response to alkylat ing agents were found in patients with kappa and lambda light-chain dis ease. Similarly, it was not possible to explain the shorter survival of patients with lambda light-chain disease on the basis of the stage of disease when treatment was started. Thus, the explanation for the shorter survival of patients with lambda light-chain disease remains to be found.


PLASMA CELL MYELOMA

433

A review of the factors affecting the survival of patients treated by the Cancer and Acute Leukemia Group B revealed that patients who excrete light chains in the urine have a worse prognosis than those who do not. The survival prognosis for those excreting type kappa was significantly better than for those excreting type lambda, if the blood urea nitrogen (BUN) was less than 30 mg/dl. The type of light chain excreted did not affect the prognosis of patients with a BUN greater than 30 mg/dl (8). The poor prognosis for IgD myeloma patients is probably related to the amount and type of light chain excreted, for 90% of these patients excrete large amounts of lambda light chains, and 67% present with a BUN of greater than 30 mgldl (11). Clinical Manifestations Related to Total Myeloma Cell Number

The total myeloma cell number can be estimated by dividing the total body M-protein synthesis rate by the synthesis rate of single myeloma cells in vitro (12). Durie & Salmon (3) estimated the myeloma cell mass of 71 myeloma patients and made a search for laboratory and clinical parameters that would predict the total myeloma cell number. They found that the myeloma cell mass could be accurately predicted from: (a) extent of bone lesions, (b) hemoglobin level, (c) serum calcium level, and (d) the M protein levels in serum and urine. A clinical staging system (3) that uses these four parameters divides patients into those with low (Stage I), inter mediate (Stage II), and high (Stage III) myeloma cell numbers. This staging system is useful for stratifying patients for randomization in clinical trials. Blood Urea Nitrogen

Many investigators have recognized that an elevated BUN is an adverse prognostic factor in myeloma patients (1-4, 8). In the first Medical Re search Council (MRC) myelomatosis trial, the initial blood urea concentra tion proved such a strong determinant of prognosis that its influence had to be taken into account in assessing whether other prognostic factors acted independently (2). The median survival of 37 months for patients with a BUN less than 20 mgldl, decreased to 20 months for those with a BUN of 20-39 mgldl and to 2 months if the BUN was greater than 40 mgldl (2). The adverse effect of light-chain proteinuria is closely linked with the occurrence of uremia; the latter occurs more frequently in patients who excrete large amounts of light-chain protein. This association is in keeping with the view that light-chain proteinuria is harmful to renal function. The MRC group (2) found that the correlation of proteinuria with prognosis disappeared after adjustment for blood urea concentration. Others found that for patients with an initial BUN of less than 30 mg/dl, the excretion of lambda light chains shortened the survival of myeloma patients produc-

434

BERGSAGEL

ing an IgG M-protein (8),or light chains only (10), whereas the excretion of kappa light chains did not adversely affect survival. Renal function is the major factor affecting prognosis that appears to act independently of the total body myeloma cell number (3). Thus,the progno sis for a patient who presents with a BUN of greater than 40 mgldl is equally bad for patients with Stages I, II, and III disease.


THE EFFECTIVENESS OF TREATMENT Good objective responses to systemic chemotherapy were rarely observed in myeloma patients prior to the use of alkylating agents. The demonstra tion that melphalan relieved bone pain, caused weight gain, decreased the serum M-protein (which occasionally disappeared from the serum electro phoresis pattern),decreased proteinuria to normal, shrank plasmacytomas, and occasionally healed lytic skeletal lesions was greeted with great en thusiasm (13-15). The fact that a few patients appeared to achieve complete remissions stirred the hope that it might be possible to eliminate all neoplas tic plasma cells by chemotherapy. A more careful evaluation of the cell-kill achieved by treatment with an alkylating agent and prednisone revealed that good remissions were achieved with a reduction in the myeloma cell mass of one half to one order of magnitude and that a reduction by more than two orders of magnitude was unusual (16, 17). Many chemotherapeutic agents have been tested against both murine (18) and human plasma cell tumors. Most of the alkylating agents tested appear to be about as active as melphalan. Unfortunately,few nonalkylating agents are active against plasma cell neoplasms. A few, such as procarbazine (19, 20),vincristine (21),adriamycin (22,23),and cis-platinum (24),reportedly show some activity against mouse or human myeloma. All attempts to improve the response and survival of myeloma patients by using combinations of chemotherapeutic agents have yielded disappoint ing results. The comparison of the effectiveness of drug combinations in Table 1 has been restricted to an analysis of the results of cooperative groups that use the Southwest Oncology Group (SWOG) criteria for the evaluation of response (25). The addition of prednisone (P) to intermittent courses of melphalan (M) doubled the response rate but had little influence on survival. The improved response rate could result from effects of P that are not directed at myeloma cells. For example, a P-stimulated increase in the catabolic rate of the M-protein (29), or a decrease in bone resorption as a result of P blocking the effects of osteoclast-activating factor (30), could increase the response rate without changing the myeloma cell mass. Even though P may not have a strong antineoplastic action against myeloma cells, its nonspecific effects

PLASMA CELL MYELOMA

435

Table 1 Effectiveness of combination chemotherapy for plasma cell myeloma No. responsiveb Drugsa

Group

M

SWOG

MP

SWOG NCI-C

MP

+

Proc.


MAP

SWOG SWOG

CAP

SWOG

MCP

SWOG

MCBP

SWOG

Response

Survivalc

No. evaluable

rate (%)

median (mo.)

13/54 67/139 40/100 120/205 31/67 23/59 35/74 34/70

24 48 40 59 46 39 47 49

18 21 28 23 21-26d 21-26d 21-26d -34

28/91 39/83 64/127 48/77 42/74

31 47 50 62 57

27 30 34 -34 -34

NCI-C alternating concurrent VMP

+

Proc.

SWOG

VMCP

SWOG

VCAP

SWOG

Reference

25 25 26e 25 27 27 27 27 26e 26e 27,28 27 27

a Abbreviations used are: M melphalan, P prednisone, Proc. procarbazine, A mycin, C cyclophosphamide, B carmustine, V vincristine. bResponsive as defined by SWOG (25), i.e. ;;. 75% regression. c Survival from the onset of treatment. dThe survival of these groups of patients is reported to be within this range. eUpdated. =

=

=

=

=

=

adria-

=

are so useful that it is now included in most therapeutic drug trials for plasma cell myeloma. Combining procarbazine with melphalan and prednisone (MP) appeared to increase the response rate but, again, had little effect on survival. Further experience suggests that procarbazine contributes little in the management of myeloma, and it has been dropped from subsequent SWOG myeloma trials. The addition of adriamycin (A) to MP or cyclophosphamide (C) and P, did not improve the response rate or survival. The discovery that mouse (31) and human (32) plasma cell tumors, which were resistant to one alkylating agent, still responded to another dnig of this class, indicated that different alkylating agents are not necessarily cross resistant. Furthermore, combinations of alkylating agents were shown to be synergistic in the treatment of two murine tumors (33, 34). These observa tions stimulated clinical trials of combinations of alkylating agents in the treatment of plasma cell myeloma. The SWOG found that combinations containing MC, or MC and carmustine (B), did not significantly change the response rate or survival. Similarly, the National Cancer Institute of Can ada (NCI-C) Clinical Trials group found no advantage for the MCBP


436

BERGSAGEL

combination, administered either alternately or concurrently, over MP alone. In contrast, the Cancer and Acute Leukemia Group B (CALGB) found that MCBP significantly improved the response rate in several parameters over that obtained with MP alone, but did not improve the survival of the patients (35). The CALGB study of MCBP differs from those of the SWOG and NCI-C in that all of the alkylating agents in the combina tion were administered intravenously; the results were compared with the oral administration of M to the MP group. Since the absorption of M may be erratic (36, 37), the improved response rate could be the result of the intravenous administration of M to the MCBP group. Studies of the labeling index of myeloma marrow plasma cells before and after treatment demonstrated a marked rise in the index after treatment with alkylating agents (21, 38). This obserVation led to the suggestion that an increase in the growth fraction after treatment maintained the myeloma cell mass constant after an initial reduction of one to two orders of magni tude. Thus, a trial of cycle-specific agents in these patients was initiated. In a preliminary trial, vincristine (V) caused a modest further decrease in myeloma cell number (21 ), and was selected for further study in drug combinations. The SWOG was encouraged by the modest improvement in response rate and survival of patients treated with combinations containing V (27, 29). However, as noted in Table 1, combinations that do not contain V reportedly produce similar high response rates (e.g. MP + Procarbazine) and survival (e.g. MCBP). The M-2 protocol for myeloma patients, em ployed at Memorial Hospital in New York, combines VMCBP; this combi nation reportedly produces a higher response rate and longer survival than MP (39). However, the trial of the M-2 protocol was not a controlled study; patients treated with VMCBP were compared with a historical control group treated with MP. The fact that only one of 46 patients died during the first 10 months on VMCBP suggests that poor-risk patients may not have been entered in this trial, for most myeloma survival curves show a loss of 20-25% within 10 months (26, 27).

CELL-KILL ACHIEVED AND REMISSION DURATION AND SURVIVAL If the improved survival of myeloma patients who respond to treatment results from the effect of that treatment on myeloma cells, one would expect to find a correlation between the estimated cell-kill and survival. The esti mated myeloma cell-kill following 12 courses of treatment varied from 10-0.3 to 10-6.4, with survivals ranging from three months to more than 10 years: No correlation was demonstrated between cell-kill and survival (17).


PLASMA CELL MYELOMA

437

The results of treating a patient with total body irradiation are also consistent with this view (17). The radiation sensitivity of myeloma cells (40) suggested that a dose of 225 rads would reduce the myeloma cell number by a factor of ten and result in a remission of about three years. The administration of this dose of irradiation to one patient caused the serum M-protein to disappear, and lytic skeletal lesions to heal; this excel lent remission has now persisted for more than eight years. It is not possible to explain the duration of this remission on the basis of the myeloma cell-kill expected from the dose of irradiation that was used. The failure of maintenance therapy to prolong the duration of remissions or survival (28, 41) provides additional evidence that these myeloma� response parameters are not determined by the tumor cell-kill achieved by treatment.

INCREASED GROWTH RATE OF MYELOMA CELLS The myeloma growth rate, as reflected by the M-protein doubling time, has been measured repeatedly on myeloma patients in unmaintained remissions (17). A progressive shortening in the M-protein doubling time was ob served. Most of the patients who progressed to an M-protein doubling time of less than 30 days also developed marrow failure (5). This marrow failure apparently did not result from treatment, because the marrow remained cellular and the pancytopenia persisted after all therapy was stopped. About one third of myeloma patients progressed to develop marrow failure and died during the "acute terminal phase" of the disease (5). The M-protein doubling time during relapse correlates strongly with subsequent survival (17); short M-protein doubling times predict brief survival. The survival of myeloma patients appears to be determined largely by the time required for a progressive loss of myeloma growth control and marrow failure to occur. A high incidence of acute leukemia has been reported in myeloma pa tients (17, 42 '!'!). The NCI-C Clinical Trials group recorded six deaths from acute leukemia during three years of following 364 myeloma patients being treated with MP or MCBP. The expected number of acute leukemias in this group of patients, based on the 1974 incidence figures compiled by Statistics Canada, is 0.0489. The ratio of observed to expected acute leu kemias is 122 (26). Two hypotheses have been proposed to explain the unusually high incidence of acute leukemia in myeloma patients: (a) Acute leukemia is induced by leukemogens, such as irradiation or alkylating agents, used in treatment; (b) Acute leukemia occurs as part of the natural history of myeloma. Conclusive evidence is not available to establish either of these hypotheses. I believe, however, that the available evidence favors the second.


438

BERGSAGEL

To establish the first hyPothesis it is necessary to demonstrate that the incidence of acute leukemia is significantly higher in myeloma patients treated with irradiation and alkylating agents than in a comparable group of untreated patients. Of course it would be unethical to do this study, because treatment with alkylating agents does prolong survival. And be cause of the prolonged survival of treated patients, it is not possible to do a retrospective analysis of the incidence of acute leukemia now as compared to what it was prior to the introduction of alkylating agents in the treatment of myeloma. Favoring the second hypothesis is the occurrence of acute leukemia in untreated myeloma patients, and certain features occurring during the course of myeloma that resemble the progression of chronic granulocytic leukemia to the blast phase. Acute leukemia has been reported to develop prior to the onset of therapy in at least 15 myeloma and 3 macroglobulinemia patients (43, 44). This suggests that the incidence of acute leukemia is increased in patients with plasma cell neoplasms, even in the absence of treatment. The progressive increase in the myeloma growth rate observed during the course of the disease, which leads to marrow failure and acute leukemia, resembles the course of chronic granulocytic leukemia as it evolves to the acute blast phase. The acute leukemia that occurs in myeloma patients may possibly be part of the natural history of the disease, as it is in chronic granulocytic leukemia, polycythemia rubra vera, and myelofibrosis.

ACTIVE GROWTH CONTROL MECHANISMS IN PATIENTS WITH PLASMA CELL NEOPLASMS Benign Monoclonal Immunoglobulinopathy The plasma cell disease benign monoclonal immunoglobulinopathy (BMI) has been classified as a controlled proliferation of a single clone of immuno globulin-producing cells (6). In this disorder, a clone of plasma cells (pre sumably derived from a single cell) expands until the population reaches a certain size (as many as 5 X 1011 cells), and then remains stable for many years. This is the commonest disorder responsible for a serum M-protein (45) and has been found in 1% of adults over the age of 25, 3% over 70, and 19% of nonagenarians (46). Progression of BMI to myeloma has been reported (47) but is uncommon. Hamburger & Salmon (48) were able to grow colonies of plasma cells from the marrow of 34 of 41 untreated or relapsing myeloma patients, 2 of 2 patients with macroglobulinemia, and 2 of 3 patients with BMI. Plasma cell colonies were not recovered from any of the marrow cultures of 10 patients without a plasma cell disorder, nor

PLASMA CELL MYELOMA

439


from one patient with reactive plasmacytosis. Thus, in BMI there appears to be a population of cells capable of producing an M-protein and of forming colonies of plasma cells in vitro, as myeloma cells do. This population expands to a certain cell number and then remains stable for many years. The major difference from myeloma is that the growth of the monoclone is controlled in BMI, so that a progressive increase in cell number and the development of plasmacytomas or osteolytic lesions does not occur. Myeloma Remissions In some ways the status of patients during treatment-induced remissions resembles that of patients with BMI. The M-protein level falls progressively during remission-induction to reach a plateau, and then remains stable throughout the remission. The duration of this stable phase is not prolonged by maintenance therapy. Some of these remissions persist for unusually prolonged periods. The remission that has lasted for more than eight years following 225 rads of total body irradiation (17) has been mentioned. In addition, I have observed unmaintained remissions of five years in a patient with IgG kappa myeloma, and in a patient producing only lamda light chains that has continued six years after melphalan was discontinued. Moreover, at least one long remission of more than five years has been reported following only one course of melphalan in a kappa light-chain disease patient (49). The persistence of an M-protein throughout these remissions, and the demonstration that 12 of 24 remission marrows con tained myeloma stem cells capable of forming colonies of plasma cells (48), indicates that the myeioma clone persists but is controlled during remis sions. In both BMI and myeloma remissions there are large monoclonal popula tions of plasma cells (greater than 1010 cells) that remain stable for pro longed periods. Myeloma stem cells capable of forming colonies of plasma cells are present in both BMI and remission marrows. Unmaintained myeloma remissions last for variable periods, from a few months to many years, with a median duration of 11 months (41). A recurrence of progres sive, uncontrolled growth of myeloma cells ends the remission in most myeloma patients. In contrast, progression from the stable monoclone in BMI to myeloma is uncommon. Suppressor T Cells Paglieroni, MacKenzie & Caggiano (50) provided evidence that suggests that myeloma marrow contains a population of suppressor T cells. These investigators tested the reaction of autologous peripheral blood lym phocytes (PBL) against marrow cells in the one-way mixed leukocyte reac tion. PBL did not respond to unfractionated myeloma marrow cells. There

440

BERGSAGEL

was a strong reaction of PBL to purified myeloma cells, which could be suppressed by myeloma marrow lymphocytes. The removal of E-rosette forming cells from the marrow lymphocyte fraction removed the suppressor cells, and return of the E-rosette-forming cells restored suppressor activity. This is the evidence for the presence of suppressor T cells in myeloma marrow.


Growth Control Mechanism Hypothesis

Further studies of the marrows of treated myeloma patients, and of BMI patients, suggest a possible growth control mechanism to explain the stable state of the monoclone during myeloma remissions and in BMI (SO). Sup pressor cells were not found in the marrows of BMI patients, and appeared to be reduced in the marrows of myeloma patients following treatment. It is possible that the suppressor T cell activity demonstrated in the marrow of myeloma patients represents part of a growth control mechanism. The hypothesis can be formulated as follows. Progressive, uncontrolled growth of the monoclone occurs only in the presence of marrow suppressor T cells (e.g. untreated or relapsing myeloma). It remains stable in patients with BMI, in whom suppressor T cells are not demonstrable in the marrow. Suppressor T cells appear to be reduced in the marrow of treated myeloma patients; possibly those who achieve prolonged,stable remissions are those who have the greatest reduction in suppressor T cells. Relapse occurs as suppressor T cells regenerate, and a progressive increase in myeloma growth rate occurs as the suppressor T cell population expands. A quantita tive assay for suppressor T cells would facilitate the testing of this hypothe sis.

SUMMARY Studies during the past two decades have clarified the tumor biology of plasma cell neoplasms, identified the progonostic factors, and established a useful clinical staging system. The response rates and survival of myeloma patients treated with new agents and drug combinations are only minimally better than those achieved with melphalan and prednisone. The failure of more intensive treatment to improve survival, and the lack of a correlation between myeloma cell-kill and survival, suggests that the beneficial results of treatment may not be due to an effect of therapy on the myeloma cell mass. Alternate hypotheses are required to explain the effect of treatment on plasma cell neoplasms. One alternate hypothesis holds that treatment re duces a population of suppressor T cells in myeloma patients and allows a growth control mechanism to be reestablished. This growth control mecha-

PLASMA CELL MYELOMA

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nism maintains the myeloma cell number stable until suppressor T cells regenerate sufficiently to allow the monoclone to grow again. If research provides further support for a growth control mechanism in patients with plasma cell neoplasms, therapeutic research should be aimed at correcting the faulty control mechanisms, rather than at trying to reduce the tumor plasma cell number.


Literature Cited

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Plasma cell myeloma: biology and treatment.

Orbital plasma cell myeloma.

Case report of plasma cell myeloma.

Paraproteinemic corneal deposits in plasma cell myeloma.

Extracellular crystals in plasma cell myeloma.

[Plasma cell myeloma in the stomach?].

Towards Stratified Medicine in Plasma Cell Myeloma.

Changing treatment paradigms for patients with plasma cell myeloma: impact upon immune determinants of infection.

Plasma cell sarcoma complicating a case of multiple myeloma.

Ultrastructure of a plasma-cell myeloma in the mandible.

A challenging diagnosis: crystal-storing histiocytosis in plasma cell myeloma.

Plasma cell leukaemia with alpha-interferon therapy in myeloma.

Disseminated plasma cell myeloma presenting as massive pleural effusion.

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma.

Plasma cell morphology in multiple myeloma and related disorders.

Non-secretory multiple myeloma presenting as primary plasma cell leukaemia.

Concomitant lymphoplasmacytic lymphoma and plasma cell myeloma, a diagnostic challenge.

14q+ marker chromosomes in multiple myeloma and plasma-cell leukaemia.

Biphenotypic plasma cell myeloma: two cases of plasma cell neoplasm with a coexpression of kappa and lambda light chains.

Chance identification of synchronous hairy cell leukemia and plasma cell myeloma in a potential HSC donor.

relapsed multiple myeloma with vincristine, mitoxantrone and dexamethasone (VMD protocol)

Renal cell carcinoma and plasma cell myeloma: Unique association and clinical implications.

Letter: Treatment of myeloma.

Anti-myeloma activity of MELK inhibitor OTS167: effects on drug-resistant myeloma cells and putative myeloma stem cell replenishment of malignant plasma cells.