Document pev934QE8m3eGbXEX2XOvB7Kw

Myeloma Protein Kinetics Following Chemotherapy By Peter McLaughlin and Raymond Alexanian The effects of chemotherapy were evaluated in 43 multiple myeloma patients with high monoclonal globulin levels in both serum and urine. In responding patients. Bence Jones protein excretion declined more rapidly and markedly than the serum myeloma protein. Bence Jones protein excretion was reduced by 50% within 2 mo in responders. remained unchanged in nonresponders. and declined with a slow halving time of 2-7 mo in patients with partial disease I N MOST PATIENTS with multiple myeloma, changes in serum myeloma protein production rate have provided the best available index of tumor mass change from chemotherapy.'2 The utility of systematic Bence Jones protein (BJP) quantitations in defining remission and relapse has been less clear, primarily because the relation of changing BJP excretion to variations in tumor mass has not been defined. Thus, the significance of a specific reduction in BJP excre- tion following chemotherapy is unknown. Such knowl- edge would also provide a more realistic appraisal of remission and relapse in the 20% of myeloma patients with light chain excretion as their only protein abnor- mality. This study evaluated serum myeloma proteins and Bence Jones protein excretion simultaneously in a large number of patients receiving chemotherapy. Results indicated that a rapid and marked decline of BJP excretion provided the earliest evidence that a remission would develop, sometimes months before definitive changes in the serum myeloma protein had occurred. With rare exceptions, the eventual magni- tude of tumor reduction was predicted from the rate of BJP decline during the first 2 mo of treatment. MATERIALS AND METHODS The records of 525 consecutive, previously untreated patients with multiple myeloma referred to the University of Texas M.D. Ander- son Hospital between September 1965 and December 1980 were reviewed. Only patients with both serum myeloma protein exceeding 2.0 g/dl and BJP excretion greater than I .0 g/day were eligible for study. Only those patients with at least 4 myeloma protein measure- ments in both serum and urine for at least 6 mo following the start of chemotherapy were analyzed. Patients with renal abnormalities (i.e., BUN >40 mg/dl or 24-hr urinary albumin > I g) were analyzed separately. Among patients with marked albuminuria, those with a urine monoclonal component of the same electrophoretic mobility as the serum myeloma protein were excluded because light chain excretion could not be quantitated. All patients received intermittent courses of an alkylating agent with prednisone, many also receiving vincristine and doxorubicin in accordance with specific protocols.3 Changes in the serum myeloma globulin concentration were measured from the electrophoretic strip in patients with IgG and high lgA peaks, and from the direct immunoglobulin quantitation in patients with IgA monoclonal globulins falling to less than 2.0 g/dl. control. Three patients with clinical resistance to treat- ment showed atypical protein changes and progressively more Bence Jones protein excretion relative to their serum monoclonal component. Serial measurements of Bence Jones protein excretion provided an early and reliable index of tumor mass change in patients with multiple myeloma. Variations in myeloma tumor mass were calculated from changes in serum myeloma protein production rate using techniques described previously. .2 BJ P excretion/day was determined simultaneously from the product of the 24-hr urine protein excretion and the percent light chain globulin on urine electrophoresis. Patients were classified into three response groups depending on the magnitude of reduction in serum myeloma protein production as an index of tumor mass change, as described previously.'2 Respond- ers eventually reduced serum myeloma proteins by at least 75%, "improved" patients by 50%-74%, and nonresponders showed less than a 50% reduction. The response of three atypical patients was difficult to classify and these patients were analyzed separately. Survival was calculated from life-table calculations with statistical comparisons by the Wilcoxon technique. RESULTS Because of the specific pretreatment and serial myeloma protein measurements required, the analysis was limited to those 43 patients who had complete data for at least 6 mo. The clinical features of these patients are summarized in Table 1 . In these selected patients with high monoclonal globulin levels in both serum and urine, the median serum peak was 4.7 g/dl and the median BJP was 2.1 g/day. Since the kinetics of serum myeloma protein and BJP change in the I 2 patients with renal disease were similar to those without renal abnormalities for each response category, these patients were included in the analysis. In each patient, the percentage change in BJP excretion following chemotherapy was compared with the percentage decline in serum myeloma protein production as the primary index of tumor mass change.' As indicated in Fig. I, 16 of 20 responding patients reduced serum myeloma protein by 50% within 2 mo, the serum peak disappearing from the electrophoretic strip in 4 of these patients. All respond- ing patients showed a rapid reduction of BJP excretion From the University of Texas M.D. Anderson Hospital and Tumor Institute, Houston, Texas. Submitted July /3, 198/: accepted May 20, 1982. Address reprint requests to Peter McLaughlin. M.D. . Depart- ment of Medicine. M.D. Anderson Hospital and Tumor Institute. 6723 Bertner Avenue, Houston, Texas 77030. 1982 by Grune & Stratton, Inc. 0006-497//82/6005--0008$O/ .00/0 Blood, Vol. 60, No. 4 (October), 1982 851 852 Table 1 . Clinical Features of Patients No. of patients Medianage No. Hb <8.5 g/dl No. calcium > 1 1 .5 mg/dl No. BUN >40 mg/dl No. high tumor mass Median survival (mo) Myeloma proteins No.lgGpeak Median g/dl No.lgApeak Median g/dl Median BJP excretion (g/day) #{149}Thr patients with atypical Responsive 20 57 4 2 3 8 48 14 4.8 6 4.7 2.0 Improved 9 60 2 1 1 4 23 7 4.6 2 6.4 2.5 changes were excluded. Unresponsive 11 55 1 0 1 5 12 6 5.6 5 4.4 2.2 by at least 50% within 2 mo and by 90% to less than 200 mg/day within 4 mo. Among 4 patients with very slow declines in serum myeloma protein (i.e., halving time 4-8 mo), all showed a more rapid decline of BJP RESPONDERS McLAUGHLIN AND ALEXANIAN excretion, with a halving time of 0.5-2 mo; the serum peak concentration had declined by only 1 59o-3O% by the time that BJP excretion had been reduced by more than 50%. Unresponsive patients showed a different pattern of myeloma protein change (Fig. 1). None of the 1 1 unresponsive patients reduced either the serum my- eloma proteins or BJP excretion by 50%, a clear plateau in BJP excretion being evident in all within 4 mo of treatment. In "improved" patients, myeloma proteins fell in a pattern intermediate to that found in responsive and unresponsive patients (Fig. 2). All reduced their serum myeloma protein by 50%-74% and their BJP by more than 50%, but BJP excretion declined slowly with a median halving time of 4 mo (range 2-7 mo). BJP disappeared eventually in 2 "improved" patients but persisted at more than 250 mg/day in the remaining 7 (Fig. 2). The median survival times for responders, improved patients, and nonresponders were 48, 23, and 12 mo, RESPONDERS a, > C a, E Ca a, a, 0. 0 C 0 C) V 0 0. C a, 0 0. Ca NON-RESPONDERS E 0 a, (I) a, g 100 NON-RESPONDERS E I- a, Cl) 50 1 2 34 5 5 1 50 0 1 234 567 Months Of Treatment Fig. 1 . Upper panels indicate responders, showing the slower fall in serum myeloma protein (left) compared to the rapid decline and disappearance of urine Bence Jones protein (right). Lower panels show absence of change in unresponsive patients. CHEMOTHERAPY AND MYELOMA PROTEIN KINETICS 100% C 0 a,. .a, 50% I-> a,- .E a,, 0 I-, a,.,- >. Tumor Mass Improved Patients 100% 50% 20% UrIne Bence Jones Protein 853 Fig. 2. `improved" urine BJP (right). 10 15 5 Months Of Treatment patients showed less marked reductions of tumor mass to 25%-50% of control (left) with slow reductions of respectively. The survival for responders was signifi- cantly better than that for the combined group of nonresponders and improved patients (p < 0.01). Insufficient patients were available to define whether responders with very rapid reduction of myeloma pro- teins lived longer than slow responders. The rate of BJP reduction was compared among the three different response groups whose tumor mass response had been defined from the serum myeloma protein data. Figure 3 shows clear separations in the rate of BJP decline for each response category that were obvious within several months of treatment. Three patients showed atypical protein changes. One responder had an unusually slow fall of BJP, which paralleled a very slow, but eventually marked, fall of the serum IgA component (Fig. 4C). One patient had an initial reduction of the serum IgG peak by 50%, with a rapid reduction of BJP to 200 mg/day within 2 wk (Fig. 4A); early clinical relapse with enlarging subcutaneous and pleural tumors were then associated with rapid elevations of both protein compo- nents. Both of these patients were atypical only in the speed of their protein changes. One other atypical patient had persistent urinary BJP despite a decline in the IgG peak by 75% (Fig. 4B). In this patient, only the persistent BJP identified him as a nonresponder. These patients had most clinical features similar to those of the other patients. However, two were hypercalcemic with a high tumor mass, and the serum peak was less than 3.2 g/dl in all, in comparison with the median of 4.8 g/dl for all other patients. The kinetics of protein reduction were also evalu- ated in 35 consecutive patients who produced only BJP that had disappeared following identical chemother- apy programs. The clinical features of myeloma had resolved and the patients were considered in remission. As in responding patients with serum myeloma pro- teins, the BJP halving time was less than 2 mo in all. However, more than 4 mo of treatment was required in 10 patients before BJP disappeared from the urine, and all had very high pretreatment excretion levels (median 10 g/day). In one patient with 26 g/day of lambda light chain excretion, disappearance of BJP excretion occurred only after 1 8 mo of treatment. DISCUSSION While a reduction in serum myeloma protein has been an accepted measure of the total tumor response,"2 the significance of a specific decline in Bence Jones protein excretion (BJP) has been less clear. The role of BJP was evaluated from serial assessments of both serum and urine protein markers in a large number of patients with both abnormalities who received a standard program of chemotherapy. Changes in Bence Jones protein excretion provided the earliest index of either a marked plasma cell reduction 854 100 ci - 2 0> (I) C 04) 1) CE a, 0 Ca 5#{149}.. 04)0 C McLAUGHLIN AND ALEXANIAN 10 I 2 3 4 56 Months Of Treatment Fig. 3. Degree of BJP decline serum myeloma protein reduction. several months. as a percent of the pretreatment value in the three response categories defined from the degree of A rapid reduction occurred only in responding patients. while nonresponders were recognized within or a resistance to chemotherapy. Thus, BJP excretion was reduced rapidly and disappeared in responding patients, but persisted at more than 50% of the pretreatment value in all nonresponders, differences that were obvious within several months of treatment. Patients with an intermediate tumor reduction showed slower and usually less complete reduction of Bence Jones protein than achieved in responders. BJP changes correlated well with other accepted criteria of remission, even in the presence of renal failure and/or nephrosis, and patients responding by this criterion had longer survival times. The failure to reduce BJP by 50% within 4 mo after the start of chemotherapy identified patients with therapeutic resistance in whom different treatments should be instituted early, espe- cially when advanced disease is present and the prog- nosis is poor.4 Each of the infrequent exceptions to this pattern appeared to be clinically resistant to chemo- therapy and showed progressively less heavy chain and more light chain production per cell in the manner described by Hobbs.5'6 More frequent measurements of Bence Jones protein excretion, such as weekly after the start of chemotherapy, might have confirmed response and resistance trends even earlier in some patients. Such data could also clarify the important question of whether the speed of protein reduction has any correla- tion with prognosis. The rapid metabolism of Bence Jones protein proba- bly accounts for its prompt elimination from the urine following a marked reduction of the myeloma cell population. The half-life for heavy chain immuno- globulins ranges from 6 days for IgA to 23 days for IgG components, and their catabolism is largely inde- pendent of the kidney.7 In contrast, the half-life of Bence Jones protein is less than I day, and the kidney is the major site of catabolism.8'9 Since the capacity for CHEMOTHERAP' AND MYELOMA PROTEIN KINETICS 855 THREE ATYPICAL PATIENTS a, .2a, > C aa, a, a, a. 0 C .2 . 1::N\ a, a, 0 C a, 0 a. a, E >,0 a, -I,///,////,/,// 10 O 3'O Months Of Treatment 4O Fig. 4. Lower panel indicates an atypical patient with slow declines and eventual disappearance of both urine BJP (dotted line) and IgA myeloma protein (solid line). With relapse. only BJP excretion increased markedly. Upper right panel shows a patient with a marked reduction of serum myeloma protein but little change in urine BJP (dotted line). Upper left panel indicates an atypical patient with a temporary fall in urine BJP (dotted line) that was followed by early progression of both protein markers and of multiple tumor masses. renal catabolism may exceed 30 g/day in some mye- loma patients with high production levels, the urinary excretion of Bence Jones protein presumably repre- sents the excess production that escapes renal catabo- lism. Thus, the disappearance of urinary BJP reflects a less marked decline of total BJP production and of the myeloma cell mass than does a comparable decline in serum myeloma protein production. In patients with Bence Jones protein excretion as their only abnormality, precise criteria for remission have been difficult to define. Some centers have defined remission as a 50% reduction in BJP excretion, while others have required disappearance. No studies have considered the rates of protein change or the time to disappearance as a factor. Our studies indicated that only patients with a rapid rate of BJP reduction "responded" in terms of a 75% reduction of serum myeloma protein production. Because some patients may have a very high basal BJP excretion, especially when Bence Jones protein constitutes the only abnor- mality, the eventual disappearance of BJP may require many months of chemotherapy. Those patients with slow reductions should be considered resistant to chemotherapy and should be offered promising new agents, especially if they are symptomatic. Some of our patients had atypical BJP changes following chemotherapy the serum monoclonal despite a marked decline of component. Later BJP eleva- tions with disease progressionwere sometimes than the increments in the abnormal serum greater protein. These patterns were similar to those of Hobbs, who proposed the concept of "Bence Jones escape" to indicate the emergence of a more primitive plasma cell subclone with less ability to produce or assemble intact immunoglobulins.5'6 Presumably even more dedifferen- tiation occurred in those uncommon relapsing patients whose disease progressed with only bone destruction and/or soft tissue tumors, of the original myeloma described several patients but without any protein. Suchman with an aggressive recurrence et al. have terminal phase of multiple myeloma with less differentiated plasma cells.'#{176S}uch atypical relapse patterns empha- size the importance of monitoring serial changes of myeloma proteins, bone lesions, and bone marrow plasmacytosis throughout a patient's course, since changes in any of these features may herald disease progression. ACKNOWLEDGMENT The authors are indebted to Kay Delasalle, who assisted with the analyses. REFERENCES 1 . Salmon SE: Immunoglobulin synthesis and tumor kinetics of multiple myeloma. Semin Hematol 10:135-147, 1973 2. Alexanian R, Salmon 5, Bonnet i, Gehan E, Haut A, Weick i: Combination therapy for multiple myeloma. Cancer 40:2765-2771, 1977 3, Alexanian R, Salmon 5, Gutterman J, Dixon D, Bonnet i, Haut A: Chemoimmunotherapy for multiple myeloma. Cancer 47:1923-1929, 1981 4. Alexanian R, Balcerzak 5, Bonnet J, Gehan E, Haut A, Hewlett i, Monto R: Prognostic factors in multiple myeloma. Cancer 36:1 192-1201, 1975 5. Hobbs JR: Monitoring myelomatosis. Arch Intern Med 135:125-130, 1975 6. Hobbs iR: Growth rates and responses to treatment in human myelomatosis. Br i Haematol 16:607-617, 1969 7, Solomon A, Waldmann TA, Fahey JL, McFarlane AS: Me- tabolism of Bence Jones proteins. J Clin Invest 43:103-117, 1964 8. Wochner RD, Strober W, Waldmann TA: The role of the kidney in the catabolism of Bence Jones proteins and immunoglobu- lin fragments. i Exp Med 126:207-221, 1967 9. Miettinen TA, Kekki M: Effect of impaired hepatic and renal function on [I's'] Bence Jones protein catabolism in human subjects. Clin Chim Acta 18:395-407, 1967 10. Suchman AL, Coleman M, Mouradian JA, Wolf DJ, Saletan 5: Aggressive plasma cell myeloma: A terminal phase. Arch Intern Med 141:1315-1320, 1981