Between July 2002 and October 2005, 147 patients with newly diagnosed, symptomatic, or progressive MM were registered, of whom 143 were eligible and 142 started induction therapy. The characteristics of these 142 patients are typical of the past trial experience in SWOG. The median age was 57 years (range, 23 to 66 years); 83% were white, and 61% were men. Immunoglobulin isotypes included IgG in 62%, IgA in 15%, and only light chain in 11%. None had IgD myeloma; 12% had nonsecretory disease. Serum levels of B2M and C-reactive protein (CRP) exceeded 3.5 mg/dL in 44% and 0.8 mg/dL in 17%, respectively. ISS distribution included 48% of patients with ISS 1, 30% with ISS 2, and 22% with ISS 3. Anemia (ie, hemoglobin < 10 g/dL) was present in 37%, and renal function impairment (ie, creatinine > 2 mg/dL) was present in 6%. Hypercalcemia (ie, serum calcium > 10 mg/dL) was rare (13%), and elevation of LDH (ie, > 190 U/L) was noted in 29%. Cytogenetic abnormalities were recorded in 42% of 81 patients who had such information available. Bone marrow plasmacytosis that exceeded 30% was present in 67%.
B depicts a CONSORT flow diagram that accounts for all patients enrolled and initiated in successive protocol phases, the present status of each, and the reason for study removal of each. Registration to PBSC collection occurred in 111 patients, a first transplantation was performed in 103 (73%), and a second transplantation was performed in 82 patients (58%). Ninety-one percent of second transplantations were performed within 4 months from the first application. Seventy-nine patients (56%) proceeded to maintenance, of whom 65 have since come off study.
Of 111 patients who underwent PBSC collection, 88% collected the PBSC quantity required to perform two transplantations (ie, ≥ 4 × 106 CD34 cells/kg), and 74% received two transplantations. The inability to proceed to second transplantation was due to low PBSC yield (which permitted single transplantation only in seven and no transplantation in two patients) and to patient or physician choices in seven and two patients, respectively. The excellent tolerance afforded timely application within a 4-month interval of a second transplantation in 91% of those who received this intervention.
One treatment-related death was observed during induction and one during the maintenance phase. Overall, grades 3 to 4 toxicities were observed in 59% during induction, 40% during PBSC collection, 90% with first transplantation, 94% with second transplantation (predominantly hematologic), and 69% during the maintenance phase of the trial. Infectious complications occurred in two thirds of patients during each of the two transplantation phases. The incidence of deep vein thrombosis decreased from 26% when THAL 100 mg was given to the first 23 patients to 9% as a result of reduction of the starting THAL dose to 50 mg, with weekly increments of 50 mg as tolerated to a maximum of 400 mg (P
Twenty-seven percent reported neurologic toxicity of grade 3 or higher during THAL-prednisone maintenance.
Response and Survival Outcomes
The proportions of patients who achieved various response levels relevant to the four treatment phases of the trial are depicted in A. Thus, at the end of induction therapy, 66% had achieved at least PR, including 14% who qualified for REM, 22% for VGPR, and 5% for CR status. The respective values for first post-transplantation and second post-transplantation time points were 79% and 81% for PR, 60% and 63% for REM, 48% and 53% for VGPR, and 11% and 12% for CR. Finally, at the end of the first year of maintenance, 87% qualified for PR, including 80% for REM, 72% for VGPR, and 22% for CR status. The cumulative proportions of patients who attained PR and CR over time are portrayed in B, which demonstrates ultimate levels of PR and CR of 77% and 15%, respectively; the median times to reach PR and VGPR status were 3 and 14 months, respectively, whereas the median has not been reached for CR. Counted from the onset of the respective response levels, 58%, 63%, and 77% were estimated to remain without recurrence 4 years after achievement of PR, VGPR, and CR status, respectively (C). During the median follow-up of 37 months, 15 patients have remained on study; 74 have remained event free; and 98 are alive, with 4-year estimates of 50% and 64% (A). Examination of baseline prognostic variables and of post-therapy events (ie, response) and interventions (ie, first and second transplantations) as time-dependent covariates revealed ISS stage and LDH to be independently and significantly associated with both OS and EFS ( and ). The combined presence of ISS stage 1 and normal LDH identified 44 patients with an outstanding prognosis; only one patient died, whereas 10 suffered an event, which contrasts with poor outcomes among the three remaining combination subsets (B). Whereas PR and VGPR did not independently affect OS and EFS, timely application of the second transplantation reduced the hazards of both death and any event by 80% and 69%, respectively. By applying a 4-month landmark analysis, 24-month survival and event-free survival rates were 91% and 75%, respectively, when two transplantations had been applied, as opposed to 70% and 49% in the remaining participants who had received just one cycle of high-dose therapy in that time frame (C). Among patients who achieved less than VGPR status after the first transplantation, the post-landmark OS (and EFS, data not shown) was superior when such patients had received a second transplantation rather than moving on to maintenance without additional high-dose therapy (OS: P = .04; EFS: P = .03; D). In addition, for EFS, there was a strong trend for those already in VGPR to have superior outcome when a second transplantation had been applied (P = .06). The improved outcome after a second transplantation for patients who had less than VGPR after the first transplantation could not be explained by an upgrade in the response level: among patients with less than VGPR at the time of first transplantation, 36% of patients (14 of 39) achieved at least VGPR status after the second transplantation, which was not different from the 23% (three of 13) when such second intervention had not been applied (P = .3608). The baseline characteristics of patients who received or did not receive two transplantations within the 4-month landmark were similar (data not shown); the observed superior OS after two transplantations when VGPR had not been attained was likely due to the therapeutic intervention.
Fig 2. Response. (A) Cumulative best response by treatment step: The proportions of patients who achieved partial response (PR) and complete response (CR) status increased from 60% and 1% at the end of induction to 79% and 5% after the first transplantation (more ...)
Fig 3. Overall and event-free survival outcomes. (A) All patients: The 4-year estimates of survival and event-free survival were 64% and 50%, respectively. (B) Overall survival according to International Staging System (ISS) stage and lactate dehydrogenase (LDH). (more ...)
Univariate Analyses of Baseline and Time-Dependent Post-Therapy Variables Associated With OS and EFS
Multivariate Analyses of Baseline and Time-Dependent Post-Therapy Variables Associated With OS and EFS
In line with our stated protocol objectives, we also compared survival outcomes on this S0204 trial with those previously observed in S9321. S0204 affected OS and EFS, which were superior to outcomes observed in S9321, both when all patients were considered (A and B) and when the analysis was restricted to 121 patients in S0204 and 363 in S9321 who had been matched on ISS stage and LDH as the two key variables associated with outcomes in S0204 (C and D). The time on study was significantly longer than had been the case for S9321; thus, at 24 months, 79% of patients had remained on S0204 compared with only 15% on S9321 (E), which strongly suggests better tolerance of S0204.
Fig 4. Comparisons of this tandem transplantation trial S0204 and a previous Intergroup trial S9321. (A) Overall survival (all patients) was superior on S0204 trial compared with the Intergroup trial S9321. (B) Event-free survival (all patients) was superior (more ...)