The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483–487.
High-dose therapy with autotransplants leads to improved survival compared to standard-dose therapy in patients with multiple myeloma.1 We have previously shown that high complete remission (CR) rates (over 40%) can be achieved with tandem autotransplants in previously untreated patients. In a pair-mate analysis, this approach (termed ‘Total Therapy’) led to a significantly higher CR, overall survival (OS) and event-free survival (EFS), when compared to a matched cohort of patients treated with conventional-dose therapy on Southwest Oncology Group trials.2 In these initial studies, patients who failed to achieve a partial remission (PR) after the first transplant (Tx-1), received high-dose melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen for the second autotransplant (Tx-2). Even in this primary unresponsive group of patients, a second high-dose cycle induced a CR in 10% and PR in 55%. Among patients achieving ⩾PR after Tx-1, Tx-2 utilizing MEL-200 led to attainment of CR in 38%, resulting in an increase in the cumulative CR rate on an intent-to-treat basis from 24 to 43%. With the hypothesis that the benefit of more dose-intense conditioning with MEL-TBI or MEL-CY may be even more effective in the patients responding to Tx-1, we applied these regimens to 43 patients achieving ⩾PR after Tx-1. In this study, we have compared the outcome of patients attaining ⩾PR after Tx-1 and receiving MEL 200 + cyclophosphamide for Tx-2 (group 1) or Mel 140 + TBI (group 2) with a matched group of patients receiving MEL 200 as conditioning for Tx-2 (group 3). Each group was evaluated for treatment response, survival, engraftment kinetics and toxicities.
Patients and methods
Forty-three myeloma patients achieving at least a PR after Tx-1 with MEL 200, received Tx-2 within 12 months of Tx-1 following conditioning with a combination of melphalan 140 mg/m2 and total body irradiation (1125 cGy) (n = 24; group 2) or melphalan 200 mg/m2 and cyclophosphamide 120 mg/kg (n = 19; group 1). MEL-CY was employed in patients who could not receive TBI due to prior irradiation, availability of matched siblings for allotransplant or patient choice. Control pair mates (n = 43) matched for all relevant prognostic factors (cytogenetics, B2M, months of prior therapy, Tx-2, Ig isotype and CRP) were identified from 450 patients receiving tandem autotransplant, with melphalan 200 mg/m2 (group 3). Patient characteristics of all three groups in terms of age, stage, isotype, sensitivity to induction therapy (>50% reduction in paraprotein), response to Tx-1 and prognostic factors such as β-2-microglobulin levels, cytogenetics and extent of prior therapy are shown in Table 1. Peripheral blood stem cell (PBSC) procurement was performed following high-dose cyclophosphamide with growth factors, except nine patients who had stem cell collections following high-dose G-CSF (10–16 μg/kg) alone. All patients received the first autotransplant following conditioning with MEL-200.
MEL-200 was administered in two doses of 100 mg/m2 on days −3 and −2 followed by PBSC infusion on day 0. Patients responding to Tx-1 (⩾PR) underwent a second autotransplant with either MEL-TBI or MEL-CY following recovery from the transplant, generally within 6 months of Tx-1. Patients receiving MEL-CY received melphalan 100 mg/m2 on days −5 and −4, cyclophosphamide 60 μg/kg was infused over 4 h on days −3 and −2 and PBSC were infused on day 0. Patients conditioned with MEL-TBI received melphalan 140 mg/m2 as a single dose on day −4, TBI was given in nine fractions days −3 to −1 for a total dose of 1125 cGy. The dose of irradiation to the lungs was limited to 800 cGy. PBSC were infused on day 0. All patients received either GM-CSF (250 μg/m2) or G-CSF 5 μg/kg from day +1 until granulocyte recovery (granulocytes >2000 × 3 days). Supportive measures included prophylaxis with ciprofloxacin, fluconazole and acyclovir. Platelets were transfused when platelet counts dropped below 20000 cells/μl and packed red cells were transfused for hemoglobins <8 gm/dl. A complete response (CR) required the absence of monoclonal protein in both serum and urine on immunofixation analysis and attainment of normal bone marrow aspirate and biopsy with <1% light chain restricted plasma cells on flow cytometry, on at least two successive occasions >2 months apart. PR implied a ⩾75% tumor-mass reduction including a normal bone marrow aspirate and biopsy and in case of Bence Jones proteinuria, reduction to <100 mg per day. Early death refers to any death within 60 days of high-dose therapy.
Overall survival (OS) and event-free survival (EFS) curves were estimated from the day of second transplant by the product-limit method (Kaplan–Meier) and compared using the log-rank test. Endpoints for event-free survival were relapse, disease progression >25% or death. Overall survival compilations only used death date for an endpoint. Cox regression analysis was used to compare OS and EFS of the three groups. Chi-square tests were used to compare patient characteristics between patient groups. A stratified log-rank test was used for the matched comparison between the groups. Multivariate regression analysis was performed using any prognostic factor that attained significance on univariate examination, also including the conditioning regimen as a variable to evaluate independence over all other prognostic factors. All P values are two-tailed.
Lymphocyte recovery was compared between two groups (groups 1 and 2, combined, and group 3) using a random coefficient model and chi-square tests. The random coefficient model assumes the regression model for each subject is a random deviation from some population model. The relationship between lymphocyte count and time was assumed to be linear for each subject. The mathematical form of the model is given below. Yij = A + B* time + c* group = D* group* time + aI + bI * time + eij. A, B, C and D are the fixed effects portion of the model and aI, bI and eij are the random effects part of the model. The C coefficient represents the difference in intercepts between the treatment groups, while D represents the difference in slopes between the two groups.
Forty-three patients achieving at least a PR following Tx-1, underwent Tx-2 with MEL-CY (n = 19; group 1) or MEL-TBI (n = 24; group 2). Forty-three controls who achieved ⩾ PR and received MEL 200 were identified among 450 patients receiving tandem transplants with melphalan alone (group 3). The three groups were well matched (P > 0.4) for all relevant pretransplant characteristics (Table 1). Efficacy, in terms of attainment of CR, was comparable, 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0). Early (60 day) mortality of 8% in group 2 was higher compared to 0% in groups 1 and 3 (P = 0.07). Despite identical response rates, EFS (median: 27, 15, 61 months) and OS (median: 39, 25 and 76 months) were significantly inferior among patients receiving more intensive regimens (groups 1 and 2) (P = 0.001). EFS (P = 0.09) and OS (P = 0.1) were not significantly different between groups 1 and 2 (Figure 1). Non-hematological toxicities were comparable between patients receiving melphalan (group 3) and more intensive regimens (groups 1 and 2), stomatitis ⩾ grade II, 60 vs 70% (P = 0.4), fever ⩾38.3°C for more than 3 days, 21 vs 23% (P = 0.8) and pneumonia/sepsis in 24 vs 24% (P = 1.0). Engraftment kinetics was also similarly comparable between patients receiving melphalan alone (group 3) or more intensive regimens (groups 1 and 2). The median days to recovery of granulocytes to 0.5 × 109 cells/l (11 and 10 days, P = 0.05) and platelets to 50 × 109 cells/l (14 and 15 days, P = 0.6) were not significantly different in groups 1 and 2 compared to group 3.
Multivariate regression analysis was performed on all 86 patients including conditioning for Tx-2 as a variable in addition to univariately significant pre-transplant prognostic indicators. Favorable prognostic indicators for EFS were serum β-2-microglobulin ⩽2.5 mg/l prior to the first transplant, MEL-200 for Tx-2, ⩽12 months of prior therapy and favorable cytogenetics. Favorable features for overall survival included serum β-2-microglobulin ⩽2.5 mg/l, MEL-200 for Tx-2 and ⩽12 months of prior therapy (Table 2).
As immunological recovery is considered important for maintenance of remission, we evaluated the recovery of lymphocytes in patients receiving melphalan alone (group 3) compared to more intensive regimens (groups 1 and 2). The proportion of patients recovering lymphocyte counts to at least 1.0 × 109 cells/l was higher in group 3 after 60 days (P < 0.05) (Table 3). Similarly the projected lymphocyte count was also higher in group 3 (P < 0.001) over the first year after the transplant. The number of CD34-positive cells/kg infused, which could potentially affect lymphocyte recovery, was comparable between patients receiving melphalan alone (group 3) and the more intensive regimens (groups 1 and 2; median: 7.6 vs 4.4 × 106, P = 0.2).
We have previously shown that tandem use of high-dose therapy with autotransplantation led to a progressive increase in the rate of CR, an important first step to achieving durable responses. In this study we examined if an increase in the dose intensity of the conditioning regimen for the second autotransplant could lead to higher CR rates or improved survival in responding patients, a subset most likely to benefit from dose escalation. However, the addition of TBI or cytoxan to melphalan for Tx-2 in these patients did not lead to higher CR rates. On the contrary, the survival of patients receiving MEL-TBI or MEL-CY was significantly inferior to that of a matched cohort treated with tandem MEL-200.
The reasons why the addition of TBI or cyclophosphamide to high-dose melphalan did not improve CR rate or survival are not entirely clear but illustrate the importance of melphalan as the most active single agent in this disease. As a single agent, cyclophosphamide at a maximum tolerated dose of 6–7 g/m2 produces far less tumor cytoreduction than melphalan at 140–200 mg/m2.3 In several phase II studies, results with or without TBI have been comparable.4567891011 Similarly, a case-control study showed excessive morbidity and no added benefit with the addition of total body irradiation.12 The IFM as a study is currently addressing this issue in a randomized trial. TBI is also associated with significant morbidity, particularly in older individuals, as evidenced by 8% early deaths in patients receiving TBI in this study. The reduction of melphalan dose to 140 mg/m2 in TBI-containing regimens may have played a role in the outcome, yet cannot be addressed in the scope of this subgroup of patients. In a recent analysis of EBMT registry data on autotransplants in 903 patients with myeloma, non-TBI-based conditioning regimens were associated with an improved outcome, which supports our findings.13 On multivariate analysis, MEL-200 for second autotransplants emerged as a significant favorable variable for both OS and EFS in this study. Taken together, these data suggest that MEL-200 alone may represent the optimal regimen for second autotransplants in myeloma patients responding to the first autotransplant.
High-dose regimens for conditioning in allotransplants incorporate TBI and cyclophosphamide as marked immunosuppression is necessary in addition to cytoreduction. However, incorporation of these in autotransplants may result in unwanted and potentially disadvantageous immunosuppression. Additionally, total body irradiation has been shown to depress the regional recovery of TH1 subset in a murine model.14
Several lines of evidence, both laboratory and clinical, suggest the importance of immunoregulatory mechanisms in control and outcome in MM.1516171819 Powles et al20 have observed significant relationships between lymphocyte recovery and the probability of relapse in acute myeloid leukemia patients receiving allografts. To define immune recovery, we plotted the recovery of the total lymphocyte count from the number of days from the second high-dose therapy (see Figure 2 and Table 3). Lymphocyte recovery was superior in patients receiving high-dose therapy with melphalan alone. The impaired lymphocyte recovery in more intensely conditioned patients, wherein duration of remission was shortened, suggests a possible role for immunologic recovery in remission maintenance. Additionally, this study also suggests the need for an in-depth study of relationships between conditioning regimens and immune reconstitution. This becomes more critical when post-transplant immune manipulations such as idiotype vaccination and dendritic cell infusions are employed.212223
High-dose therapy, mostly melphalan based with autotransplantation leads to improved survival compared to standard-dose therapy in myeloma. However, the only randomized trial comparing conventional therapy to high-dose therapy (IFM-94) employed melphalan in combination with TBI. Timing (early vs late) and number (one vs tandem) of autotransplants and optimal conditioning regimens are currently under investigation.2425 Our data indicate that choice of conditioning regimens may be an important variable that may influence outcome in these trials. Recently, the French Myeloma Intergroup (IFM) reported preliminary results of a clinical trial comparing single autotransplants using MEL-TBI with a tandem approach using melphalan 140 mg/m2 for first autotransplants, followed by MEL-TBI for second autotransplants. At 2 years of median follow-up, there were no significant differences in the two arms in terms of CR rate or survival. While mature data from this trial are awaited, a surprising finding was the lack of increment in the CR rate following second autotransplant in the double autotransplant arm, which is in direct contrast to the data from our Total Therapy experience and may reflect the differences in conditioning regimens in these trials.
In conclusion, these data suggest that conditioning with MEL-TBI or MEL-CY for second autotransplants within 1 year in patients responding to first autotransplant is feasible, but does not improve CR rates and may lead to an inferior outcome when compared to MEL-200. Choice of conditioning regimens may therefore be an important variable affecting the outcome of tandem autotransplant trials. Based on these data, we recommend MEL-200 as the conditioning regimen of choice for both first and second autotransplants in responding patients. It seems unlikely that further intensification of pre-transplant cytoreductive therapy will lead to an improved outcome in these patients. Efforts to maximize post-transplant cytoreduction utilizing immunologic approaches, maintenance chemotherapy or other novel approaches are worthy of pursuit in an attempt to improve survival.262728
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This work was supported in part by CA55819 from the National Cancer Institute, Bethesda, MD.
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