Document 2gkarxeVVLn03KGe0wjDwde5

High-Dose Therapy for Refractory Multiple Myeloma: Improved Prognosis With Better Supportive Care and Double Transplants By David H. Vesole, Bart Barlogie, Sundar Jagannath, Bruce Cheson, Guido Tricot, Raymond Alexanian, and John Crowley One hundred and thirty-fivepatients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 t o 100 mg/m2(MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m2 or thiotepa 750 mg/m2 andautologous bonemarrow transplant (ABMT) ( ~ 3 0 %plasma cells; 21 patients); melphalan 200 mg/m2 (MEL200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as adouble-transplant program (67 patients; 42 have completed and 3 are stillawaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% t o 25% with MEL 100 and TB1 regimens, but less than 1% with MEL 200, mainly becausesevere neutropenia (<500/pL) was shortened t o less than 1week due t o infusion of PBSC and use of growth factor therapy. Low PS-microglobulin (p2M) levels S 2.5 mg/ L and MEL200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these t w o parameters, threerisk groups were defined: 29 good-risk patients with low P2M receiving MEL 200 had thebest outcome, with median dura- tions ofEFS of 37 months and projectedOS of r43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high P2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (allP < .0001). Further analysisthat excluded treatment as a variable identifiedhigh P2M and resistant relapse as the two major adverse prog- nostic factors, one of which was present in 80% of the 135 patients. Among these 108high-risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy usingthe double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease. 0 1994 by The American Society of Hematology. MULTIPLE MYELOMA (MM) remains an incurable malignancy.' Recent efforts have been devoted to after high-dose cyclophosphamide (HDCTX) priming with GM-CSF." evaluating dose intensification to the point of bone marrow We now report our collective experience in 135 patients (BM) ablation requiring hematopoietic stem cell supp~rt.~.' with refractory MM, receiving intravenous melphalan at 90 These approaches were initially piloted in patients with re- or 100 mg/m' without transplant (MEL 100);TB1 witheither fractory myeloma4*'and are currently being evaluated in melphalan 140 mg/m2 or thiotepa 750 mg/m' with ABMT earlier disease (TBI); and melphalan 200 mg/m' (MEL 200) supported with Our group had previously observed, in a trial with total both PBSC and ABMT, withthe intent to administer two body irradiation (TBI, usually 850 cGy) with either melpha- successive transplants within 6 months. Those MEL 200 lan 140 mg/mz or thiotepa 750 mg/m2 and autologous BM patients not achieving at least a partial remission (PR) (see support (up to 30%plasma cells), that patients with resistant below) or relapsing after one transplant with MEL 200 were relapse hadan especially dismal prognosis, whereas those offered melphalan 140mg/m2and TB1for their second trans- with primary unresponsive disease fared as well as those plant or an allogeneic transplant iftheyhad a compatible with sensitive myeloma receiving such high-dose therapy sibling donor. Prognostic factor analysis identified a low for response con~olidationO.~ver the past S years, we have pretransplant /32-microglobulin level (P2M) level (52.5 mg/ developed a double-transplant procedure using both periph- L) and primary unresponsive MM (rather than resistant re- eral blood stem cells (PBSC) and autologous BM transplant lapse) as two independent parameters associated with supe- (ABMT) together with granulocyte-macrophage colony- rior event-free survival (EFS) and overall survival (OS). stimulating factor (GM-CSF)." PBSC had been collected When treatment was included in the analysis as a variable, low P2M and MEL 200 emerged as the two most important From the Division of Hematology/Oncology and Arkansas Cancer Research Center, Universitoyf Arkansas for Medical Sciences, Little Rock, AR; the National Cancer Institute, Rockville, MD; University of Texas, M.D. Anderson Cancer Center,Houston, rX; and the Fred Hutchinson Cancer Research Center, Seattle, WA. favorable features, permitting identificationof three risk categories. These results support the hypothesis that further intensification of therapy to the point of a double transplant effects further tumor-mass reduction, and hence, extends remission and survival times. Submitted January 10, 1994; accepted March 28, 1994. Supported in partbyGrantNo. CA 55819from the National PATIENTS AND METHODS Cancer Institute, and the American Cancer Society. The diagnosis of MM used standard criteria." All patients had Address reprint requests to Bart Barlogie, MD, University of Ar- resistant MM as defined by disease progression (greater than 25% kansas for Medical Sciences, Division of Hematology/Oncology, increase in myeloma protein concentration in serum andor 24-hour 4301 W Markham, Slot 508, Little Rock, AR 72205. Bence Jones proteinuria) despite adequate doses of salvage therapy The publication costsof this article were defrayedin part by page usually with at least three cycles of high-dose dexamethasone (DEX) chargepayment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.section 1734 solely to pulsing or vincristine, doxorubicin, and dexamethasone (VAD).I3.I4 Primary unresponsiveness implied failure of ever having responded indicate this fact. with 275% tumor cytoreduction; resistant relapse was defined as a 0 1994 by The American Society of Hematology. relapse from a prior remission ( ~ 7 5 %regression) that failed to 0006-4971/94/8403-0012$3.00/0 respond to DEX or VAD. 950 Blood, VOI 84, NO3 (August 1). 1994: PP 950-956 HIGH-DOSE FOR M M ~~~~~~ Parameter ~~ 100 ~ ~ Table 1. High-Dose Therapy for Refractory M M Patient Characteristics (N = 135) MEL TBI* MEL 200 Plt P2 Total (N) .5Age > 50 57% .8 > l 2 Mos of Prior Rx B2M > 2.5 mg/L 6p7r%e-Tx LDH > 170 U/L pre-Tx Resistant relapse 47 47% 51% 81% 85% 49% 21 .4 ,00876% 76% 67% 67 54% 52% 57% ,007 .2 21% .4 36% .2 .006 .4 .0001 .01 850 cGy with melphalan 140 mg/m2or thiotepa 750 mg/m2. t PI, MEL 100 vTBI; p2, TB1 v MEL 200; p3, MELlOO v MEL 200; p4, combined MEL IOOnBl v MEL 200. P3 .9 .0001 .2 951 P4 .3 .01 .0001 .03 Table 1 summarizes patient characteristics in the three different treatment groups. MEL 100 included 14 patients receiving 90 mgl m' and 9 patients receiving 100 mg/m'of intravenous melphalan between 1985 and 199015;since 1989,24 additional patients receiving melphalan 100 mg/m2were supported with GM-CSF at a dose of 250 &m' subcutaneously.'6None of the MEL 100patients received transplant support. T B 1 (850 cGy; with melphalan 140 mg/m', 18 patients; with thiotepa 750 mg/m', 3 patients) was evaluated between 1985 and 1990 in 21 patients with ABMT that contained 530% plasma cells! On a per-kilogram body-weight basis, at least 1.0 X IO' mononuclear cells and 1.5 X 10`` CFU-GM were required. MEL 200 was administered to 67 patients between 1990 and 1993 with the intent of a double transplant within 6 months." Of the 67 patients, 39 had received prior DEX or VAD and alkylating agent regimens such as melphalan-prednisone (22 patients), VMCP-VBAP (9 patients), or VBMCP (M2 protocol, 8 patients). Four had received only alkylating drugs and 24 only DEX or VAD. Among the 41 patients with primary unresponsive MM, 68% had been refractory for greater than 6 months and 37% for greater than 12 months. With MEL 200, PBSC had been collected after administration of high-dose cyclophosphamide at 6 g/m' followed by daily subcutaneous administration of GM-CSF at 250 @m2, as previously described". In addition, 62 of the 67 patients also had autologous BM harvested, usually within 6 weeks from HDCTX administration. A first cycle of MEL 200 was administered in two doses of 100 mg/ m` each on days -3 and -2, followed on day 0 by infusion of PBSC and BM, followed on day + l by daily subcutaneous injection of GM-CSF 250 &m' until hematopoietic recovery (granulocytes greater than 2,OOO/pL on 3 successive days). Three to 6 months later, a second autotransplant was scheduled. The decision as to proceeding with a second transplant depended on the quantity and quality of available hematopoietic stem cells and tolerance of the first transplant. Eleven patients with PBSC less than 4 X lo8and autologous marrow less than 2 X 10' were given only one autotransplant with MEL 200. The remaining 56 patients with PBSC greater than 6 X 10' andor autologous BM greater than 3 X 10' were candidates for two autotransplants. In the absence of relapse, 24 patients achieving PR (see below) received a second cycle of MEL 200. When the first transplant with MEL 200 failed to effect at least PR or relapse ensued after PR, melphalan 140 mg/ m' plus TB1 850 cGy (11 patients) or 1020 cGy (7 patients) was given. Currently, 3 patients are eligible for their second autotransplant, 3 declined further therapy and 3 died after the first cycle of MEL 200 (toxicity, 1 patient; recurrent MM, 2 patients). Five other patients went on to allogeneic transplant using HLA-identical sibling donors after busulfan 14 m a g and cyclophosphamide 120 m a g . Ofthe 67 patients receiving MEL 200, two autotransplants were actually administered to 31 patients (46%) within 6 months, and to 42 (63%) within 1 year. Considering the five additional allotransplants, altogether, 70% received 2 transplants. All patients provided written informed consent to the investigational treatment according to institutional policies. Supportive care measures included prophylactic antibiotics with either oral ciprofloxacin or trimethoprim-sulfamethoxazole.Recombinant human erythropoietin at a dose of 10,OOO U subcutaneously thrice weeklywas used in over 50% of the 67 patients receiving MEL 200. Platelet transfusions were administered when platelets dropped below 2O,OOO/pL andpackedredblood cells were transfused when hemoglobin decreased to levels below 8 g/dL. Upon completion of hematopoietic recovery, 42 of 67 MEL 200 patients received posttransplant interferon a2b (IFNa2b) at an initial dose of 3 X lo6U/m' thrice weekly subcutaneously until disease progres- sion. I F N was discontinued because of undue toxicity in about one third of patients. Response was defined as partial when patients achieved 275% tumor-mass reduction including decrease in Bence Jones proteinuria to less than 100 mg per day and in BM plasmacytosis on aspirate and biopsy examination to less than 5%. A complete remission (CR) required the absence, in bothserum and urine, of monoclonal protein on immunofixation analysis as well as a normal BM aspirate and biopsy including the absence of monoclonal plasma cells on DNA/ cytoplasmic Ig flow cytometry''. Early death referred to any deaths within 60 days of high-dose therapy. EFS and OS are reported from initiation of high-dose therapy. An "event" was defined as disease relapse or death caused by MM or other causes. Statistical methods included chi-square tests for comparison of rates"; Kaplan-Meier estimates of relapse-free and overall survival curves''; and log-rank testz0for comparison of curves. Multivariate analyses were done using Cox regression models." Variables examined before autotransplant included age, p2M, lactate dehydrogenase (LDH), Ig isotype, duration of prior therapy, primary resistance versus resistant relapse, as well as the type of high-dose therapy applied. A test for treatment differences, adjusting for prognostic factors, is sometimes called an analysis of covariance." Results with MEL 200 were examined on an intent-to-treat basis. RESULTS The three treatment groups differed markedly in four prognostic parameters (Table 1). Compared with the other patients, those receiving MEL 200 had a significantly lower incidence of LDH and 82M elevation, resistant relapse and greater than 12 months of prior therapy. These data indicate accrual of more favorable patients with resistant MM in recent years. Figure 1 depicts the clinical outcome according to treatment regimen. Table 2 compares EFS and OS in primary refractory disease and resistant relapse. Noteworthy are the short median durations of EFS and OS withboth MEL 100 and TB1 of 7-6 months among patients with resistant relapse, which were extended withMEL 200 to 17 months for EFS (P = .0007) and to 21 months for OS (P =.OM).Primary unresponsive MM had comparable prognosis withTB1 and MEL 200: median EFS was 7-3 years, 952 1 .o EVENT-FREE SURVIVAL A TB1 2110 24 8 16 0.8 1 .o 0.8 z 0 0.6 lK B 0 g 0.4 z 2 0.6 lK B 0 E 0.4 VESOLEET AL OVERALL SURVIVAL 0.2 0.0 1.1.1.1.1.I.I. 24 12 36 4a 60 72 a4 MONTHS FROM TREATMENT 0.2 W, 0.0 1.1.1.1.1.111. 24 12 36 413 60 72 a4 MONTHS FROM TREATMENT Fig 1. Clinical outcome in refractory myeloma accordingto treatment regimens.Superior event-free ( l e f t ) and overall survival (right) after MEL 200 compared with TB1 and MEL 100 regimens (for details, see text). whereas the median survival was 66 months with T B 1 and has not been reached at 43 months with MEL 200. CR rates of 10% to20%were noted with MEL 200 in both the primary unresponsive and resistant relapse groups. Early mortality ( 5 2 months) was only 1% with MEL 200 as opposed to 19% with MEL 100 and 24%with TB1 ( P = .002), mainly as a result of shortened granulocytopeniawith cyclophosphamide-primed PBSC added to ABMT (Fig 2). Several pretreatment variables affected EFS and OS (Table 3). Low P2M, primary unresponsive disease, low LDH, less than 12 months of prior therapy, and younger age ( 5 5 0 years) were all favorable features. In addition, the treatment regimen influenced prognosis markedly: MEL 200 effected median durations of EFS and OS of 21 and 43+ months, respectively, which were much longer than the 5 and 7 months with MEL 100 and the 8 and 16 months with T B 1 regimens. Less than 1 year of prior therapy was the only significant parameter associated with higher CR rate. Because of the difference in several major prognostic variables among the three treatment groups (see Table l), a multivariate regression analysis of pretreatment features was performed, which adjusts for these disparities and helps define those parameters independently affecting outcome (Table 4). Including treatment as a variable, low P2M level and Regimen MEL 100 TB1 MEL 200 Table 2. High-Dose Therapy for RefractoryMyeloma: Effect of Treatment Regimen (N = 135) Primary Unresponsive Resistant Relapse N %ED I P ) %CR ( P ) 24 21 a 17 t t 23 4 70 29 14 36 (.07) L041 41 2 + 26 0 10 19 Median mos EFS ( P ) 4 5 os ( P ) 7 7 L0071 7 43i 21 LO11 HIGH-DOSE THERAPY FOR MM Granulocytes > 500/p1 1.o 953 Platelets > 50,0OO/pl 1.o 0.8 5 0.6 F K E2 0g 0.4 l i0.2 0.8 2 0.6 L g 0g 0.4 D N Median Davq 23 21 mMEL 200 67 14 0.2 Grow N MediaDnavs e TBI 21 34 BMEL 200 67 18 D = .OoOl D = .07 0.0 0.0 12 24 36 48 48 96 144 192 240 288 336 DAYS FROM TRANSPLANT DAYS FROM TRANSPLANT Fig 2. Hematopoieticrecovery after PBSC + ABMT + GM-CSF (MEL200) versus ABMT alone(TBI).Significently faster granulocyte recovery with PBSC added to autologous BM in support of MEL 200 than with BM autografts alone givenwith TBI. Table 3. Intensive Therapy for RefractoryMyeloma (N = 135): Prognostic Factors Parameter N %ED (P) %rPR %CR (PI EFS (PI B2M s2.5 mg/L >2.5 mg/1L4 45 413 90 '1 Unresponsive 72 8 Resistant re1l4apse 63 MEL 100 19 TB1 MEL 200 47 21 24 L7) 67 LO004) Age s50 >50 53 Mos from DX 36 65 70 8 16 14 S12 20 >l2 57 16 5 78 15L06) LDH S 170 U/L 45 >l70 U1/4L 66 8 69 5523 50 51 51 40 76 58 49 53 L07) 58 8 11 8 6 10 12 12 7 L04) 2151 9 35 7 LOO011 2: (.00041 5 (.3) 21 (.0007) L03) 18 (.OS) Abbreviations: PR, partial remission; DX, diagnosis. os (PI 1 2LO001) 47 15 L00031 7 16(.4) L05) 2 43 15 L0071 l6(.2) 954 TreatmeWntithout EFS Parameter (PI B2M c 2.5 mg/L (.0001) Primary unresponsive (.0007) LDH c 170 U/L (.03) Age =S 50 (.3) Abbreviations: DX, diagnosis. Table 4. Multivariate Analysis of Favorable Variables as Variable Treatment With OS Parameter ( P ) B2M c 2.5 mg/L (.0001) Primary unresponsive 1.006) c 1 2 mos from DX ( . l ) Age 5 50 (.2) EFS Parameter ( P ) B2M c 2.5 mg/L (.0001) MEL 200 (.0001) Primary unresponsive (.004) Age 5 50 (.04) VESOLE ET AL as Variable OS Parameter ( P ) B2M c 2.5 mg/L (.0001) MEL 200 (.002) c 1 2 mos from DX (.008) Age I50 (.05) therapy with MEL 200 were the two most important favorable parameters for both EFSand OS. EFS wasalso superior with primary unresponsive MM and age 550, whereas OS was prolonged with less prior therapy and younger age. The dominant favorable roles of both low P2M and MEL 200 recognized on multivariate analysis led us to use these two variables to define different risk groups among patients with refractory MM. The 29 patients who both exhibited low P2M and received MEL 200 had the best outcome (good risk); 54 patients with either low P2M or receiving MEL 200 constituted an intermediate risk group, whereas those 52 with high P2M and not receiving MEL 200 had a dismal prognosis (poor risk) (Table 5 and Fig 3). A second strategy was applied to address the imbalance in prognostic factors, which were significantly more favorable in the MEL 200 group compared with MEL 100/TBI (now referred to as "no MEL 200") (see Table I). Multivariate regression analysis without treatment as a variable showed, for both EFS and OS, low P2M and primary unresponsive MM (rather than resistant relapse) to be the two most significantvariables associated with favorable outcome (Table 4). This was true for all 135 patients and the subgroups receiving MEL 200 or no MEL 200. The good-risk group of 27 patients exhibiting both favorable features had significantly lower mortality (0% v 14%) and longer EFS and OS than the remaining 108 subjects (37 v 8 months and 66 v 16 months, respectively) (Table 6). When treatment was examined (MEL 200 v no MEL 200) in the good- and poor-risk categories, MEL 200 provided superior outcome with lower early mortality and longer EFS and OS compared with no MEL 200, especially in the poor-risk category (less than 2 favorable variables), constituting 80% of all patients (Table 6). Landmark analyses at 1 and 2 months after high-dose therapy showed that poor-risk patients receiving MEL 200 fared better than those in the no MEL 200 group (Table 7). This implies that improved outcome with MEL 200 was not simply related to better supportive care with PBSC and hematopoietic growth factors, but to greater tumor cytoreduction accomplished with two transplants. DISCUSSION This report represents the largest series of intensive therapy for MM administered in the setting of refractory disease, using progressively more intensive therapy and improved supportive care. The high early mortality of about 25% with TB1 was virtually eliminated in the MEL 200 group, mainly as a result of rapid hematopoietic engraftment with PBSC added to ABMT with hematopoietic growth factors. In support of this conclusion was the observation of a similarly low mortality among the 42 second-transplant recipients in the MEL 200 group, whether MEL 200 was applied twice (no death among 24 patients) or TB1 was added (one death among 18 patients). MEL 200 also prolonged EFS and OS markedly, especially among patients with resistant relapse. In adjusting for the heterogeneity in patient and disease characteristics present among the three treatment groups, multivariate regression analysis was applied that identifiedlow P2M, reflecting low tumor mass, and MEL 200 (rather than TB1 or MEL 100) as the twomost important independent favorable features associated with prolonged EFS and OS. On the basis of these two features, three risk groups could be identified with markedly different prognoses. A superior outcome after MEL 200 was confirmed by a separate multivariate analysis that excluded treatment as a variable and identified lowP2M and primary unresponsive MM as principal favorable parameters (Table 4). Among the 80% of patients in the poor-risk category (less than two favorable features; Table 6), MEL 200 was superior to the remaining therapies bothwith lower mortality and marked extension of EFS andOS. Longer EFS and OS in patients with primary refractory MM as opposed to resistant relapse was partly explained by fewer months of prior treatment before highdose therapy in the former group (median of 10 months v 33 months with resistant relapse, P = .Owl).However, as shown by multivariate analysis of pretreatment variables, Table 5. Clinical Outcome According to p2M and MEL 200 16 5 Risk Parameters Good 29 B2M c220.05 and MEL 4 Interme6diate 54 B2M2c002.5 or MEL 3 Po1o0r 23 B522M > 2.520a0nd no MEL P .04 N %ED 43 0 37 %CR 21 .002 Median mos EFS os f ,0001 .0001 HIGH-DOSE THERAPY FOR MM Event-Free Survival RISK N EventIDead 1.o 29 7 A INTERMEDIATE 54 38 52 50 .m01 0.8 955 Overall Survival RISK l .o 29 @GOOD N Dead 6 A INTERMEDIATE 54 26 0.8 z g 0.6 k B 0 K 0.4 z g 0.6 L B 0 0.4 0.2 0.2 0 43828142 98674620 MONTHS FROM TREATMENT 0.0 L 0 12 438264 60 72 84 MONTHS FROM TREATMENT J 96 Fig 3. Event-free and overall survival dMered markedly accordintgo p2M levels beforehighdosetherapy andthe specific regimen applied. Good-risk patients hadB2M S 2.5 mglL and received MEL 200; intermediate risk waosbserved in the presanw of one of these two favorable variables; poor risk was notedwith high p2M and when other regimens were applied (MEL100 or TBI). the type of resistance was the principal feature, whereas differences in prior therapy duration did not retain independent significance (Table 4). The major observation of this investigation is that further dose intensification with MEL 200 with tandem autotransplants was successfully applied to 63%of patients within 1 year and resulted in extended EFS and OS, independent of other well-recognized favorable prognostic variables, such as low P2M. These results support the concept of "more is better" for myeloma, confirming our contention that resistance of therapy can be overcome by increasing dose intensity as approached with tandem transplants. The use of cyclophosphamide-primed PBSC and hematopoietic growth factors assured rapid hematopoietic engraftment, thereby reducing the incidence of serious infections and virtually eliminating mortality. Based on the greater efficacyof tandem autotransplants in patients with refractory MM, a similar approach is currently under investigation in recently diag- Favorable Variables" Table 6. Prognosis According to Pretreatment Variables andthe Influence of Therapy Median mos Treatment N %ED ( P ) %CR EFS ( P ) os I f ) 2 MEL 200 19 0 No MEL 200 a0 16 39+ 43+ 0 20 L031 66 (.6) <2 MEL 200 No MEL 20203 B2M S 2.5 mg/L, primary unresponsive MM. 48 60 (.001) 13 8 25 (.001) 956 VESOLEETAL Table 7. One- and Two-Months Landmark Analysis Unfavorable Group Median mos Landmark m. Treatment MEL 200 No MEL N %ED ( P ) %CR EFS (P) OS (P) 47 0 13 19 25 53 15 1.005) (.0001) B (.006) m. MELZOO 41 0 NoMEL200 47 0 B2M > 2.5 mg/L and/or resistant relapse. 13 19 25 11 LO002) 12 (.04) nosed patients. Timely administration of two autotransplants was feasible in about 80% of these patients, resulting in CR rates exceeding 50% and 3-year projections for EFS and OS of 75% and 80%, re~pectively.'~ A considerable relapse rate is still being observed after tandem autotransplants. It is unknown whether these relapses are the consequence of inadequate tumor cytoreduction or caused by tumor cells contaminating BM and PBSC transplants, or a combination of the two. Future studies will be directed toward the infusion of tumor-free transplants in combination with a more intensive preparative regimen for the second transplant that includes high-dose melphalan and TBI. ACKNOWLEDGMENT The authors greatly appreciate the technical assistance of Sandy Thompson-Mattox, Dwayne Bracy, and Lela Vaught, as well as the secretarial help provided by Christina Bewley and Madeline Scallan. REFERENCES 1. Barlogie B, Alexanian R, Jagannath S: Plasma cell dyscrasias. J Am Med Assoc 268:2946, 1992 2. Barlogie B, Jagannath S: Autologous bone marrow transplantation, in Forman, SJ, Blume KG, Thomas ED (eds): Bone Marrow Transplantation. Boston, MA, Blackwell, 1994, pp 754 3. Ballester OF: Allogeneic bone marrow transplantation for multiple myeloma. Semin Oncol 2067, 1993 4. Jagannath S, Barlogie B, Dicke KA, Alexanian R, Zagars G, Cheson B, LeMaistre FC, Smallwood L, Pruitt K, Dixon DO: Autologous bone marrow transplantation in multiple myeloma: Identification of prognostic factors. Blood 76:1860, 1990 5. 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