Document b5eLwjxnOMROn6x9L95BJXQoD

Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Treatment Strategies for Plasma Cell Myeloma Lon Smith and Raymond Alexanian CA Cancer J Clin 1985;35;214-220 DOI: 10.3322/canjclin.35.4.214 This information is current as of September 8, 2010 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://caonline.amcancersoc.org To subscribe to the print issue of CA: A Cancer Journal for Clinicians, go to (US individuals only): http://caonline.amcancersoc.org/subscriptions/ CA: A Cancer Journal for Clinicians is published six times per year for the American Cancer Society by Wiley-Blackwell. A bimonthly publication, it has been published continuously since November 1950. CA is owned, published, and trademarked by the American Cancer Society, 250 Williams Street NW, Atlanta GA 30303. (American Cancer Society, Inc.) All rights reserved. Print ISSN: 0007-9235. Online ISSN: 1542-4863. TreatmentStrategiesfor PlasmaCell Myeloma Lon Smith, M.D. Raymond Alexanian, M.D. Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) Introduction Multiple myeloma accounts for one per cent of all malignant tumors and causes the death of about 7,000 individuals in the United States each year. During the past 20 years, the frequency of diagnosis has increased, complications have been better controlled, and a variety of drug combi nations have been evaluated. We summa rize some of the major advances regarding the choice of initial therapy, the role of unmaintained remission, and the treatment available for resistant disease. Localized and Indolent Myeloma Solitary plasmacytoma of bone and indo lent multiple myeloma represent two vari ants of plasma cell dyscrasias that should be considered separately. Each entity re quires a different approach to staging and treatment.' Approximately five percent of patients with plasma cell myeloma have a solitary lesion, which is defined by one area of bone destruction with no bone marrow Dr. Smith is a former Fellow in Medical On cology at The University of Texas M.D. An derson Hospital and Tumor Institute in Houston, Texas. Dr. Alexanian is Professor of Medicine in the Department of Hematology at The University of Texas M.D. Anderson Hospital and Tumor Institute in Houston, Texas. plasmacytosis and no disease complica tion, such as anemia or hypercalcemia. At our institution, only one half of these pa tients had a serum or urine myeloma pro tein. In all patients, the IgG or IgA serum peak was less than 1.6 gm/lOO ml, Bence Jones protein excretion was less than 500 mg/day, and normal immunoglobulin lev els were preserved. When treated with 4,000 rad, most patients showed a marked diminution of the myeloma protein level. Eventual progression to overt multiple myeloma has occurred in two thirds of pa tients who present with a solitary bone le sion; the remaining one third have probably been cured. Another five percent of patients have indolent myeloma. These patients are asymptomatic, but do show changes typ ical of multiple myeloma"monoclonal globulin peaks above 4 gm/lOO ml, mar row plasmacytosis, and occasionally lytic bone lesions. Diagnosis often follows de tection of an elevated serum protein on routine chemical survey. Such patients have been followed without treatment provided that serial electrophoretic studies are ob tained every two to three months. Treat ment should be initiated when there is a clear upward trend in myeloma protein and calculated tumor mass. About one half of patients have shown such slow elevations in myeloma protein that chemotherapy has been deferred for more than two years. As is true for patients with indolent lym phoma, the delay in treatment has not af 214 CA-A CANCERJOURNALFORCLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) fected the long-term outcome.' These IgG peak from four to two gm/lO0 ml con patients are eligible for one of the various forms more closely to a 75-percent reduc interferons now available. tion in tumor mass. While low monoclonal IgG peaks are Staging of Overt Multiple Myeloma best assessed from the routine serum elec trophoresis, low monoclonal IgA globulins Clinical features that correlate with mea sured tumor mass and survival have been used to define a clinical staging system for multiple myeloma.2 We have refined this system to make the staging of patients more quantitative and more relevant to the clin ical outcome (Table 1). We recognize that factors other than tumor load may contrib ute to anemia and hypercalcemia. Less em phasis has been placed on defining the extent of lytic lesions or bone demineral ization since this variable is excessively are frequently obscured by normal globu lins. For this reason, igA peaks below 2,000 mg/lOO ml should be evaluated serially from direct quantitations. All of these fac tors are considered in a simple computer program that includes the serum myeloma protein component, albumin, hemoglobin, and body weight. Data obtained in this way permit the calculation of monthly changes in tumor mass from an arbitrarily assigned value of 100 percent at the start of therapy. Serial changes in each patient's tumor subjective and often leads to the overstag ing of individual patients. The degree of marrow plasmacytosis, the level of serum About two thirds beta2 microglobulin, and the levels of nor of relapsing patients and about mal immunoglobulins also contribute to a one third of unresponsive @ more consistent staging of individual pa tients. patients achieved a 75-percent reduction in tumor mass Approach to Treatment from a vincristine Adriamycin-dexamethasone Before chemotherapy is begun, optimal combination. control of reversible medical complica tions, such as overt infection, is desir able. Treatment should not be delayed for mass can be plotted and, when viewed in hypercalcemia, particularly since the the context of sequential therapies or no therapeutic regimen always includes treatment follow-up, serve as invaluable corticosteroids. For patients with severe aids in the management of these patients. vertebral fracture pain, at least one course For patients undergoing initial treat of chemotherapy is useful before local ra ment at our institution, response is defined diation therapy is considered, unless the by a 75-percent reduction in calculated tu radiation therapy is required for spinal cord mor mass and/or disappearance of Bence compression. Jones protein. Less strict criteria, such as The effectiveness of chemotherapy a 50-percent reduction, will result in a should be monitored with serial measure 20-percent higher response rate. For pa ments of the serum myeloma protein con tients responding to combination therapies, centration and/or Bence Jones protein such as vincristine-cyclophosphamide excretion. The true degree of tumor re Adriamycin-prednisone (VCAP), the onset duction will be underestimated if consid of remission is usually rapid so that the eration is not given to the changing catabolic tumor-halving time is less than four months rate for different IgG levels, the reduction (median 1.5 months). Thus, a stable serum of plasma volume with therapy, and the peak during the first few months usually possible effect of normal background glob indicates that a remission will probably ulin in the calculation of tumor mass never occur. When Bence Jones protein is change.5 When the data are corrected for present, either as the only abnormality or these factors, a reduction in a monoclonal in combination with a serum peak, con VOL. 35, NO. 4 JULY/AUGUST 1985 215 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) clusions can be reached even earlier. Within two months, Bence Jones protein excretion was reduced by 50 percent in all patients who achieved a 75-percent reduction in tu mor mass as defined by changes in their serum peak.6 The failure to reduce Bence Jones protein by 50 percent within this pe riod identified resistant patients. Therapeutic Choices In 1969, the Southwest Oncology Group reported that four-day courses of mel phalan and prednisone given at six-week intervals reduced myeloma tumor mass by 75 percent in about 45 percent of patients.7 Since this development, progress in con trolling the disease has been limited. The The most important predictor of prolonged survival is the occurrence of response; the pretreatment tumor mass is a secondary factor. major drug combinations that have been evaluated include combinations of differ ent alkylating agents with or without a ni trosourea compound, and combinations of an alkylating agent with Adriamycin and/ or vincristine. Following reports that patients with myeloma resistant to melphalan might re spond to either cyclophosphamide or a nitrosourea, several treatment centers eval uated combinations of different alkylating agents with or without a nitrosourea, such as BCNU. However, combinations such as melphalan-cyclophosphamide-prednisone, or the same drugs plus BCNU, did not consistently improve the results in com parison with melphalan-prednisone. In contrast, a favorable experience was reported with a combination of vincris tine-melphalan-cyclophosphamide -BCNU prednisone (the M-2 protocol) in a study at Memorial Sloan-Kettering Cancer Cen ter.8 Using a reduction of 50 percent in myeloma protein as the criterion for re sponse, the authors concluded that 78 per cent of 81 patients responded, compared with only 33 percent of 46 patients in a historical control group treated with either melphalan or melphalan-prednisone. The median survival for patients on the M-2 protocol was significantly longer (38 months) than the median survival of the control group (15 months). Many questions have been raised about this trial. About 70 percent of the patients were designated as having high tumor mass, even though anemia and hypercalcemia oc curred only half as frequently as at other centers, where about 40 percent of patients had high tumor mass. The apparent supe riority of the M-2 protocol, when compared with other trials using similar drugs at dif ferent doses, is unexplained. Considering the conflicting results, no convincing and reproducible gain seems evident from com binations of different alkylating agents, with or without a nitrosourea. When Adriamycin became available, the drug was evaluated in combination with other agents. No differences in response or survival were found from combinations of alkylating agents, Adriamycin, and prednisone compared with melphalan prednisone alone. Slightly superior results were obtained, however, when more recent studies combined vincristine-Adriamycin prednisone with either an alkylating agent or a nitrosourea.9 Among 256 patients evaluated at our institution between 1974 and 1980, the response rate was 58 percent for patients who received combinations containing both vincristine and Adriamy cm, compared with 42 percent for patients for whom one or both of these drugs were omitted.9 The onset of remission occurred more rapidly among patients receiving the vincristine-Adriamycin combinations. Yet, the median survival time was similar at 30 months whether or not patients received vincristine and Adriamycin as part of the early treatment program. Most patients resistant to melphalan prednisone received Adriamycin-contain ing regimens later in their course, and many then achieved their first or second remis sion. These observations suggest that the outcome in patients without severe com plications (for example, low tumor mass) 216 CA-A CANCER JOURNAL FOR CLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) HI TumorMo.. On. of the Following Hemoglobin <8.5 gm!100 ml without renal failure or hypoferremia Calcium> 11.5 mg/100 mI* without bedridden status Supporting Features Often Present: Marrow plasmacytosis> 40 percent on flow cytometry or suspension smears in most patients gM <20 mg/100 ml or lgA <40 mg!100 ml or lgG <400 mg/100 ml in about half the patients Serum beta2 microglobulin > 8.0 mg/liter without creatinine> 1.8 mg/100 ml in about half the patients Low Tumor Mom.-. All of the Following Hemoglobin> 10.5 gm/100 ml, unless other factors causing anemia + Calcium < 11.0 mg/100 ml* + lgG or gA peak <5.0 gm/100 ml + Serum beta2 microglobulin <4.5 mg/liter Supporting Features Often Present: Marrow plasmacytosis < 20 percent on flow cytometry or suspension smears in most patients 1gM > 50 mg/100 ml and gA> 100 mg/100 ml and lgG > 750 mg/100 ml in about half the patients IntermedIate Tumor Mom.. AUOtherPatients ~Correccatlecdium(mg/100 ml) = serum calcium (mg/i00 ml)s"erum albumin (gm/i00 ml) + 4.0. VOL 35, NO 4 JULY/AUGUST 1985 217 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) may be the same when the initial treatment consists of melphalan-prednisone only, provided that vincristine-Adriamycin pro grams are always used later in the disease course. Unfortunately, many patients treated initially with melphalan-prednisone never receive Adriamycin later, when their disease is progressing. We favor the use of VCAP combinations as part of the initial treatment in all patients because of the higher response rate and the opportunity to stop or change therapy after the maximum tumor reduction. Remission Maintenance Early studies showed no advantage for maintenance therapy in patients who achieved a 75-percent reduction in tumor mass, in comparison with no treatment un til relapse.' The median duration of un maintained remission in more recent trials has been 14 months in those who achieved disappearance of their abnormal protein and six months in those with a persistent serum peak.' When relapse occurs in either group, about one half achieve a 50-percent re duction in tumor mass when therapy is re sumed. In those who fail to respond by these criteria, myeloma protein either re mains stable or rises slowly for many months. Thus, unmaintained remission follow-up seems appropriate for those re sponding patients in whom the myeloma protein has disappeared following 12 months of treatment (20 percent of the total patient population) or in whom a markedly reduced serum myeloma protein remains stable following 24 months of treatment (10 percent of the total patient population). This approach is not advisable for patients who have not responded with a reduction of 75 percent in tumor mass or for whom regular follow-up is not possible. In previous studies, acute leukemia de veloped in about six percent of our re sponding patients treated indefinitely with alkylating agents. With the elimination of procarbazine from our treatment pro gram and the reduced use of melphalan, especially in patients followed on no ther apy, this frequency has been reduced to about one to two percent in recent years. Prognosis No clinical features have consistently pre dicted response to chemotherapy. The fre quency of response is similar for patients regardless of the initial tumor burden. Re cently, flow cytometric measurements have indicated that patients with a high RNA content in plasma cells have a greater like lihood of response than those with a lower content.3 The most important predictor of prolonged survival is the occurrence of re sponse; the pretreatment tumor mass is a secondary factor. Table 2 demonstrates that longevity is determined primarily by the residual number of plasma cells after an optimal program of chemotherapy. For this reason, projections of prognosis in indi vidual patients should be deferred until several months after the start of chemo therapy. Resistant Multiple Myeloma All patients who achieve remission even tually relapse if they do not die of another cause. Occasionally, the pattern of relapse may involve a rising Bence Jones protein or progressive bone lesions and soft tissue tumors even with no change in the mye loma protein level. Such occurrences often presage the development of a more ag gressive disease course and may be asso ciated with new clones apparent in flow cytometry studies. For this reason, patients in remission should be followed with pe riodic measurements of Bence Jones pro tein and bone films (lateral skull and anteropostenor pelvis) in addition to reg ular assessments of their abnormal glob ulin. The onset of relapse is followed by a median survival time of only nine months unless remission is achieved. In the past, chemotherapy has not been very effective for patients with melphalan resistant myeloma. Response rates were about 25 percent in patients treated with nitrosourea-Adriamycin combinations. Re cent experience suggests a role for more intensive courses of glucocorticoids. Hou wen et al reported responses in about 25 percent of patients with refractory mye loma who had received weekly courses of 218 CA-A CANCERJOURNALFORCLINICIANS Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) 4A5lUl npreastipeonntssive'81528Improved' 22 Intermediate 31 *202428Responsive324558 Inc1l9u8d1e.s< 189 patients treated with VCAP combinations from 1974 to patie5n0ts-wpeitrhcent reduction of tumor mass (excludes three percent of weeekas)r.ly50-7d5e-paethrcentwithin four reduction of tumor mass. 1 I I vindesine and prednisone.'2 In further trials at our institution, no patient responded to vindesine alone, but about one fourth achieved significant tumor reduction from frequent pulses of prednisone, either alone or in combination with vindesine. About one half of patients then responded when prednisone pulses were combined with vincristine and Adriamycin.'3 These encouraging results prompted us to design a vincristine-Adriamycin-dexa methasone (VAD) regimen.'4 Dexametha sone was substituted for prednisone in a dose that provided a fourfold increase in glucocorticoid effect. Vincristine and Adnamycin were given over four days by continuous infusion to provide slowly cy cling cells with prolonged exposure. About two thirds of relapsing patients and about one third of unresponsive patients achieved a 75-percent reduction in tumor mass. These results were superior to those described for any group of patients with myeloma re fractory to alkylating agents. When considered in the context of our previous experience with pulse predni sone, the results suggest that glucocorti coids provide a dose-dependent antitumor action. This finding has been overlooked for many years and should be exploited in all patients with myeloma, as well as in those with closely related lymphoma. Dexamethasone pulses alone have been especially useful in myeloma patients undergoing radiation therapy or in those severely thrombocytopenic from marked bone marrow infiltration. The future as sessment of steroid receptors on plasma cells may identify those patients most likely to benefit. New Directions Several new approaches to the therapy of myeloma patients are currently under in vestigation. Based on the success of the VAD regimen for patients with refractory myeloma, higher doses of glucocorticoids should be included in the treatment of pre viously untreated patients. Studies are in dicated that offer patients under the age of 55 in early relapse reinduction treatments with high doses of chemotherapy and au VOL 35, NO 4 JULY/AUGUST1985 219 Downloaded from caonline.amcancersoc.org by on September 8, 2010 (American Cancer Society, Inc.) tologous bone marrow rescue. Interferon has been studied exten sively in clinical trials at this institution. About one fourth of previously untreated patients have achieved a 50-percent reduc tion in tumor mass with leukocyte inter feron, either with an impure preparation from Finland or with a purified interferon prepared by recombinant DNA techniques. Only about 10 percent of patients resistant to melphalan have achieved a similar re sponse. These results do not support a role for interferon as a single agent, but they offer promise that leukocyte or other in terferons might improve the results in com bination with other agents. Hemibody irradiation as a consolida tion treatment for patients in remission is under study at several institutions, but de finitive results are not available. When the variables that affect remission time were controlled, no obvious gain resulted fol lowing the treatment of a small number of patients at our institution. Cisplatinum has been effective in one murine model of myeloma and warrants further investiga tion in patients with refractory disease. While recent trials with high-dose cytosine arabinoside or spirogermanium have not been encouraging, very high doses of mel phalan have achieved some success in se lected patients.'5 No consistent gain has resulted from the use of BCG or levamisole as part of an immunotherapy consolidation program. Clinical research over the last 20 years has clarified the heterogeneity of disease features and the clinical course of patients with multiple myeloma. The physician must consider whether the patient needs any chemotherapy at all (e.g., localized or in dolent myeloma), the choice of the initial therapy, the indications for no-treatment follow-up, the sequence of drug combi nations for progressive disease, and then the application of selected new agents. Rigorous attention to the changing mass of the tumor from serial electrophoretic stud ies, the rational projection of outcome based on prognostic factors, and knowledge of improved therapies are all essential for op timal care. References 1. Alexanian R: Localized and indolent mye loma. Blood 56:521"525,1980. 2. Dune BGM, Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and sur vival. Cancer 36:842"854, 1975. 3. Barlogie B, Alexanian R, Gehan E, et al: Marrow cytometry and prognosis in myeloma. J Clin Invest 72:853"861,1983. 4. Scarife JH, Anderson H, Palmer MK, et al: Prognostic significance of pretreatment serum beta2 microglobulin levels in multiple myeloma. Eur J Cancer Clin Oncol 19:1361"136149, 83. 5. Salmon SE: Immunoglobulin synthesis and tumor kinetics of multiple myeloma. Semin Hematol 10:135"144,1973. 6. McLaughlin P, Alexanian R: Myeloma pro tein kinetics following chemotherapy. Blood 60:851"855, 1982. 7. Alexanian R, Haut A, Khan AU, et al: Treat ment for multiple myeloma. Combination che motherapy with different melphalan dose regimens. JAMA 208:1680" 1685, 1969. 8. Lee BJ, Lake-Lewin D, Meyers JE: Inten sive treatment of multiple myeloma, in Wiernik PH (ed): Controversies in Oncology. New York, John Wiley & Sons, 1982, pp 61"79. 9. Alexanian R, Dreicer R: Chemotherapy for multiple myeloma. Cancer 53:583"588,1984. 10. Alexanian R, Gehan E, Haut A, et al: Un maintained remissions in multiple myeloma. Blood 51:1005"1011, 1978. 11. Gonzalez F, Tnijillo JM, Alexanian R: Acute leukemia in multiple myeloma. Ann Intern Med 86:440"443,1977. 12. Houwen B, Ockhuizen T, Marrink J, et al: Vindesine therapy in melphalan-resistant mul tiplemyeloma. EurJ Cancer 17:227"231, 1981. 13. Alexanian R, Yap BS, Bodey GP: Pred nisone pulse therapy for refractory myeloma. Blood 62:572"577, 1983. 14. Barlogie B, Smith L, Alexanian R: Effec tive treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353"1356, 1984. 15. McElwain TJ, Powles RL: High-dose in travenous melphalan for plasma-cell leukaemia and myeloma. Lancet 2:822"824,1983. 220 CA-A CANCERJOURNALFORCLINICIANS