Document Lp6Z2Z94N2q0NVrk3ezr09wbb

Limited Value of Myeloablative Therapyfor Late Multiple Myeloma By Raymond Alexanian,Meletios Dimopoulos,Terry Smith, Kay Delasalle, Bart Barlogie, and Richard Champlin The utility of myeloablative therapy supported by autologous bone marrow (BM) or blood progenitor cellswas assessed in 49 patients with multiple myeloma who had received at least 1 year ofprior chemotherapy. Outcomes were compared with those of similarpatients who did not receive intensive treatment primarily forsocioeconomic reasons. Among patients with disease in resistant relapse despite treatment with vincristine-doxorobucin bycontinuous infusionwith pulse dexamethasone (VAD), a 6 1% response rate was associatedwith a median remissiontime of 5 months. After primary resistancefor more than 1 year, 6 of 15 patients responded and the overall survival was similar to that of control patients. For patients with melphalan-resistant disease that responded to VAD, the remission time was similar to that of control patients. Current myeloablative treatments supportedbyautologous B M or blood stem cells were useful to very few patients with multiple myeloma after the first year of chemother- apy. 0 1994 by The American Societoyf Hematology. IN RECENT YEARS, many patients with multiple myeloma resistant to standard therapieshave received myeloablative treatment supported by autologous bone marrow (BM) or blood stem cell tran~plantation."B~ecause of the high risk ofserious complications, such treatments have usually been limited to patients younger than 60, with good performance, and without serious medical complications. Most reports have included patients in diverse phases of disease, and none have compared results with those of similar patients who did not receive intensive therapy. Recent analyses have shown encouraging results in patients with primary resistant disease or in patientswho have responded to initial c h e m ~ t h e r a p y .A~b.l~ative regimens may be less useful during later phases of disease. In this report,we evaluate the results of myeloablative treatment supportedby autologous BM or blood stem cellsin specificcategories of patients during late phases of multiple myeloma. MATERIALSAND METHODS Patients. Between January 1986 and April 1993, 49 patients with multiple myeloma received intensive, myeloablative therapy supported by autologous marrowor blood stemcells at least 1 year after initial chemotherapy. Nonewere older than 62, had a Zubrod performance status other than 0 or I , or had serious cardiac, pulmonary, or renal impairment. An age limit of 62 was chosen after treatment-related deaths occurredin four of five patients aged 63 to 69. The median age was 52, and key prognostic features are summarized in Table 1. All received intensive therapy after at least two courses of vincristine-doxorobucin by continuous infusion with pulse dexamethasone (VAD).6The myeloma was relapsing despite VAD in 23 patients (resistant relapse), was resistant to primary treatment for more than 1 year in 15 patients (prolonged primary resistance), and was consolidated during remission after successful VAD treatmentof resistant disease in 1 I patients (lateremission). From [he University of Texus M.D. Anderson Cunrer Center, Houston. Submitted hi ly 25, 1993;acceptedSeptember 20, 1993. Supported inpart by thReobert Hompe MyelomaResearch Fund. Address reprint requeststo RaymondAlexanian, MD, B1o,xUniversity of TexasM.D. Anderson Cancer Center, Houston. TX 77030. The publication costs ofthis article were defrayed in part by page charge payment. This urticle must therefore be hereby marked "advertisement" in accordance with18 U.S.C. section 1734 solely to indicate thisfact. 0I994 by TheAmerican Society ofHernutology. 0006-4971/94/8302-0028$3.00/0 Approval for these studies was obtained from the Institutional Review Board, and written informed consent was provided according to the Helsinki Declaration. Treatment. Treatment for 26 patients consisted of a combination of melphalan (140 mg/m2) and total body irradiation (850 cGy TBI) as described previously':thiotepa (750 mum2)was substituted in five patients when intravenous melphalan was unavailable for 9 months; since 199I , a combination ofthiotepa (750 mglm'), busulfan (10 mg/kg), and cyclophosphamide(120 mg/kg) wasadministered to 18 patients3(Table l). Either autologous BM or blood stem cells collected by leukapheresis were infused intravenously within 48 hours after completion of TB1 or highdose chemotherapy. BM consisted of at least 2 X IO8 nucleatedcells/kg and I X IO4 granulocyte-macrophage colony-formingunit/kg; blood stem cells were givento five recent patients with greaterthan 20%marrow plasmacytosisor an inadequate marrow harvest and consisted of at least 2.5 X 10' nucleated cells/kg and 3 X IO6 CD34+ mononuclear cells/kg. All patients received prophylactic antibiotics, initially trimethoprim, sulfamethoxaa l e , and ketoconazole in a protected-environment room; since 1989, they received vancomycin, norfloxacin, fluconazole,and acyclovir in a private room. Previous reports have considered the times to granulocyte and platelet recovery,the toxicity,and the causes of treatmentrelated death.'" All responding patients were maintained on interferon-a ( 1 to 2 million units/mz, three times weekly) withdexamethasone (20 m@* each morning, for 4 days each month). Stuging and response'. Plasma cell tumor mass was defined in each patient as high, intermediate, or low by standard rite ria.'.^ Thus. high tumor mass required either Hgb less than 8.5 g/dL or serum calcium greater than I I .5 mg/dL; intermediate tumor mass was defined by Hgb between 8.5 and 10.5 g/dL or serum myeloma protein greater than 4.5 g/dL with normal serum calcium; low tumor mass required both Hgbgreater than 10.5g/dL and serum myeloma protein less than 4.5 g/dL. Clinical response was defined as a 75% reduction of serum myeloma protein production, disappearance of Bence Jones protein, and reduction of marrow plasmacytosis to lessthan 55k9Complete remission required the disappearance of serum monoclonal globulin on immunofixation studies. Seven patients (14%) died of treatment-related complications and were considered unresponsive. Control putic.nls. For each of thethree disease phases under study, control patientswere identified who also received VAD and met the eligibility criteria for myeloablative therapy, but did not receive such treatment. Most patients were contemporary with the transplanted patients and either refused intensive treatment, were denied coverage of the procedure by their insurance company, or were ineligible for TB1 because of prior radiotherapy to the spine; 31 additionalpatients (39%) received VAD withoutsubsequent transplant during the3 years before activation ofthe transplant protocol. As in patients who received intensive therapy, control patients were 62 years old or less, had Zubrod performance status Of0 or I. were free of serious cardiac, pulmonary or renal dysfunction. 512 Blood, Vol83, No 2 (January 15). 1994:pp 51 2-516 MYELOABLATIVE FOR MYELOMA 513 Table 1. Clinical Featuresof PatientsWho ReceivedMyeloablativeor Standard Therapy Resistant Relapse Primary Resistance Late Remission Transplant Control Transplant No.patients age Median Pre-VADstatus Tumor mass Hig7h Intermediate Low BzM(mg/L) and (median Median months 1st therapy-transplant 1st therapy-VAD Ablative therapy Melphalan-TB1 Thiotepa-TB1 TBC Stem cell source Marrow Blood 23 14 52 (38(-3601) 33 11 15 52 52 (-4612) - 62) 4 4 15 14 3.1 (1.(31-.395- ) 29 20 14 1 8 23 0 10 16 3.6 14) - 37 - - - - 0 96 68 2.8 (1.6 - 8.8) 18 8 8 0 7 11 4 Abbreviations: BzM, Betagnicroglobulin;TBC, Thiotepa busulfan cyclophosphamide. Control 32 55 (22- 62) 0 18 3.3 (1.4-6.7) - 10 - - - Transplant 50 (43- 62) 0 3 8 2.6 (1.7 - 6.5) 34 27 4 4 3 10 1 Control 49 (30- 62) 0 3.5 (2.2 - 6.4) 42 - - - and would have received a transplant-supported treatment if that procedure had been possible. Only patients wholived at least 3 months after VAD were included, because that was the minimum interval between VADand intensive therapy. All patients who met the criteria for control patients were included for comparison with the 49 transplanted patients. Because the disease stage was low or intermediate before VAD for those who receivedintensivetherapy for primary resistant disease or during late remission, controls in these categorieswere limited to those with the same disease stages. For each treatment group, age and major prognostic factors were similar for patients who receiveda transplant-supportedtreatment or were continued on VAD (Table 1). Statistical analysis. The Kaplan-Meier method was usedto calculate survival and remission distributions, and differences were compared by a Wilcoxon test. Survivawl as measured fromthe initiation of intensive therapy, and from the onset of VAD therapy for comparisonsbetween transplant and control groups. Remission time was calculated fromthe onset of a 75% reduction of myeloma protein synthesisto the first objective sigonf relapse. RESULTS Resistant relapse. Intensive therapy induced responses in 6 1% of 23 patients with disease relapsing despite VAD. Treatment-related deaths occurred in four patients (17%), none achieved a complete remission, and the median survival was 8 months. When all patients are considered, the median remission was 3 months ( 5 months for responding patients) and no patient respondedfor more than 15 months (Fig 1). Inall responding patients, the remission time after transplant was shorter than the first remission. Despite the slightlyless advanced disease among transplanted patients (Table l ) ( P = .l@, survival after prior VAD was similar to that of 33 control patients (Fig I). Re- sponse rates and remission times were the same regardless of the degreeofplasmacytosisin transplanted marrow (range,0%to 25%). Primary resistance greater than I year. Among 15 pa- tients with primary resistant disease for at least l year, there were two treatment-related deaths, six patients responded, and none achieved a complete remission. Among the six responding patients, the median remission was I7 months. Although four patients responded for more than 1 year, survival after VAD was similar for comparable patients who did or did not receive myeloablativetreatment (P= .47)(Fig 2). Transplanted BM contained 1 1% to 20%plasma cells in five patients, among whom one patient responded for 16 months; with fewer plasma cells or with blood stem cell transplant, 5 of 10patients responded ( P = .26). Consolidation oflate remission. Eleven patients with resistant or relapsing diseaseresponded to VAD and received myeloablative consolidation treatment at least 1 year after initial chemotherapy. BeforeVAD, the disease was unresponsive to standard therapy in three patients and had been relapsing in eigphat tients. Intensivetherapy was givena median of 3 months after the onset of remission (range,1 to 5 months), and there was one treatment-related death. Complete remissionwas confirmed in 4 of 10 patients with evaluable data in comparison with 1 of 14 control patients (P = .05);two additional transplanted patients showed greater than 75%decrease of residual tumor mass and four patients had less marked reductions. Low levels onformal IgM ( 4 0 mg/dL) doubled to the normal range in three of six patients with evaluabledata who receivedintensivetherapy, in comparison withone of nine control patients ( P = .IO). 514 100 Remission Survival ALEXANIAN ET AL .g- 50 .-v) v) E B .C- W C ;0) 20 +Transplant Fig 1. (Left) Remissiontime 10 .I 2460 20 40 60 of 2 3 patients with relapsing disease after myeloablative After Ablative Therapy After VAD therapy.(Right)Survival after VAD of transplantedand 3 3 Months of Treatment patients. control Among those who received myeloablative therapy, the median total remission time was 12 months, similar to the 7 months of comparable patientsmaintained on VAD (P= .16) (Fig 3). Only one transplanted patient responded for more than 2 years. In all patients with re- lapsing disease, the remission time after transplantwas shorter thanthe first remission; survival afterVAD was similar for comparable patients who did or did not re- ceive intensive treatment (P= .36). Transplanted mar- row contained less than 10%plasma cells in all patients Remission l .CC>-D 3 Survival - VAD -VAD +Transplant - -. l L - Fig 2. (Left)Remission time of 15 patients with primary resistanmt yeloma after myeloablative therapy. (Right) Survival after VAD of transplanted and 32 control patients. I 10 20 30 20 After Ablative Therapy Months of Treatment 40 60 After VAD 80 MYELOABLATIVE THERAPY FOR MYELOMA 100 515 Fig 3. (Left) Remission times of 11 patients after a sequence of VAD salvage and myeloablative therapies, and of 15 control patients. (RightS) urvival after VAD of same groups of patients. 10 20 After VAD 40 20 40 After VAD Months of Treatment 60 and therewas no relation between the degroeef marrow plasmacytosis and outcome. DISCUSSION In recent years, myeloablative treatments supported by autologous BM or blood stem cells have been given to many patients with multiple Regimens have varied and patients have been treated in different phases of disease, with the primary focus on the feasibility of the procedure and thefrequency of remission. Myeloablative therapy with autologous transplanthas been considered to be more effective in patients treated during thefirst year after diag- nosis although controlled studies have not yet been con- d u ~ t e d . ~Th, ~e r,o~le of intensive therapy in patientslater in the disease course has not been critically assessed. We ex- amined the efficacy of this procedurein three groupsof pa- tients in late phases of disease who received two different, but similarly effective, myeloablative treatment^.'.^ Patients were studied during resistant relapse, after at least l year of primary resistance, and during a VAD-induced remission of melphalan-resistant disease. Results were compared with those of similar patients who qualified for marrow trans- plantation inall respects but were denied treatment primar- ily for socioeconomic reasons. Because they continued to receive standard care, such patients appeared to provide a suitable comparison group for the patients who received in- tensive regimens. Their clinical features, response, and sur- vival time were similar to those observed in previously re- ported trials with VAD for resistant myeloma.6.10." Undetected selection factors may have excluded some pa- tients from either of our study groups, thereby biasing the outcomes; butwe believe that such effects would have been small. The age, medical status, andtumor mass of the matched groups of patients were similar for each disease phase. This comparison provided some insight on the po- tential value of myeloablative therapy for patients in late phases of multiple myeloma. Patients with myeloma in resistant relapse hada very poor outcome consistent with a previous report by Jagan- nathet Whereas the myeloma was often sensitive to treatment, responses were brief and thesurvival short. The outcome was similar to that of comparable patients who were maintained on standard treatments until death. This experience was similar to the poor results observed in pa- tients with large cell lymphoma during resistant relapse.12 One explanation for the initial sensitivity but early relapse could be the evolution with time of more resistant and pro- liferative sub clone^.'^ Myeloma patients with relapsing dis- ease have a higher growth fraction and greater numbers of colony-forming cells on in vitro culture studies,l4,If5eatures that could explain the short remission and rapid tumor re- growth despite intensive therapy. Patients with multiple myeloma and a long duration of primary resistance had a low response rate, approximately one half of that observed in similar patients who were treated duringthe first year of disease. This observation was consistent with an increase in the proportion of drug-resis- tant cells over time,12."similar to previous experiences with VAD treatment of melphalan-resistant myeloma.6 The in- creased resistance to intensive therapy was not explained by known prognostic factors, such as plasma cell hypodiploidy or high-serum lactate dehydrogenase.l6," Whereas several 516 ALEXANIAN ETAL patients responded for more than 1 year and derived meaningful benefit, overall survival was not improved in comparison with control patients. Myeloablative treatment supportedby autologous BM or blood stem cells during late remission further reduced the myeloma, but remission and survival times were similar to those of control patients. Even when the disease was most limited before intensive treatment, recurrences occurred within 2 years in virtually all patients. Thus, myeloablative treatment using mixtures of current drugs, or with total body irradiation, was helpful to very few patients during late phases of multiple myeloma. Further study of intensive therapy should be reserved for patients earlier in their disease course, either for primary resistant disease or during a remission that is likely to be short after initial chemotherapy." ACKNOWLEDGMENT The authors thanAknita Kuo and ManSeullivan for the analyses and Rose Guevara for excellent secretarial assistance. REFERENCES 1. Barlogie B, Alexanian R, Dicke K, Zagars G, Spitzer G, Jagannath S, Honvitz L: High-dose chemoradiotherapy and autologous bone marrow transplantationfor resistant multiple myeloma. Blood 70:869, 1987 2. Jagannath S, Barlogie B, Dicke K, Alexanian R, Zagars G, Cheson B, LeMaitre F, Smallwood L, Pruitt K, Dixon D: Autologous bone marrow transplantation in multiple myeloma: Identification of prognostic factors. Blood 76: 1860, 1990 3. Dimopoulos M,Alexanian R, Przepiorka D, Hester J, Andersson B, Giralt S, Mehra R, van Besien K, Delasalle K, Reading C, Deisseroth A, Champlin R: Thiotepa,busulfan, and cyclophosphamide: A new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma. Blood 82: 2324,1993 4. Fermand J, Chevret S, Levy Y, Miclea J, Tsapis A, Gerota J, Benbunan M, Brouet J: The role of autologous bloodstem cells in support of high-dose therapy for multiple myeloma. Hematol Oncol Clin North Am 6:45 I , 1992 5. Harousseau J, Milpied N, Laporte J, Collombat P, Facon T, Tigarid J, Casassus P, Guilhot F, lfrah N,Gandhour C Double intensive therapy in highrisk multiple myeloma. Blood 79:2827, 1992 6. Alexanian R, Barlogie B, Dixon D: High dose glucocorticoid treatment for resistant multiple myeloma. Ann Intern Med 105:8, 1986 7. Dune B, Salmon S: A clinical staging system for multiple myeloma. Cancer 36:842, 1975 8. Alexanian R: Diagnosis and management of multiple myeloma, in Wiernik P, Canellos G, Kyle R, SchifferC (eds):Neoplastic Diseases of the Blood (ed 2). New York, NY, Churchill Livingstone, l99 I , p 453 9. McLaughlin P, Alexanian R: Myeloma protein kinetics following chemotherapy. Blood 60% I , 1982 10. Alexanian R, Barlogie B, GuttermanJ: Alpha interferon combination therapy for resistant myeloma. Am J Clin Oncol 14: 188.1991 I 1. Dimopoulos M, Delasalle K, Champlin R, Alexanian R: Cyclophosphamide and etoposide therapy with GM-CSF for VADresistant multiple myeloma. Br J Haematol83:240, 1993 12. Philip T, Armitage J, Spitzer G, Chauvin F, Jagannath S, Cahn J-Y, Colombat P, Goldstone A, Gorin N, Flesh M, Laporte J-P. Maraninchi D, Pic0 J, Body A, Anderson C, Schots R, Biron P, Cabanillas F, Dicke K: High-dose therapy and autologous bone marrow transplantation after failure ofconventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 316:1493, 1987 13. Goldie J, Coldman A: A mathematic model for relating the drug sensitivity of tumors totheir spontaneousremission rate. Cancer Treat Rep63: 1727, 1979 14. Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow S: The growth fraction of human myeloma cells. Blood 57:333, 1981 15. Takahashi T, Lim B, Jamal N, Tritchler D, Lockwood G, McKinney S, Bergsagel D, Messner H: Colony growth and self renewal of plasma cell precursors in multiple myeloma. J Clin Oncol 3:1613, 1985 16. Barlogie B, Alexanian R, Dixon D, Smith L, Smallwood L, Delasalle K: Prognostic implications oftumor cell DNA and RNA content in multiple myeloma. Blood 66:338, 1985 17. Dimopoulos M, Barlogie B, Smith T, Alexanian R: High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 115:93I , l99 1