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Keywords:

  • multiple myeloma;
  • chemotherapy;
  • clinical trials

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The effectiveness of melphalan plus dexamethasone (M-Dex) with melphalan plus prednisone (MP) as induction therapy and dexamethasone with observation as maintenance therapy was compared in 585 older patients with multiple myeloma. Randomization to the M-Dex arm was stopped as a result of an analysis performed which met a predetermined event-related criterion. Of 466 patients randomised to MP or M-Dex, no differences were detected in the respective median progression-free survivals (PFS) [1·8 vs. 1·9 years; Hazard Ratio (HR) = 0·88, 95% CI 0·72–1·07; P = 0·2] or overall survivals (OS) (2·5 vs. 2·7 years; HR = 0·91, 95% CI 0·74–1·11; P = 0·3). Of the initial 585 patients, 292 remained evaluable for maintenance therapy. Patients randomised to maintenance dexamethasone had a superior median PFS (2·8 years vs. 2·1 years; HR = 0·61, 95% CI 0·47–0·79; P = 0·0002). No difference in median OS was detected (4·1 years vs. 3·8 years; HR = 0·88, 95% CI 0·65–1·18; P = 0·4). The maintenance therapy results were robust when analysed by using two additional methodologies. Dexamethasone did not improve clinical outcome when combined with melphalan during induction; maintenance dexamethasone improved PFS, but this did not translate into a detectable survival advantage.

While high dose therapy with autologous stem cell transplantation has become the standard of care for many patients with multiple myeloma (Attal et al, 1996; Imrie et al, 2002; Child et al, 2003), randomised trials have largely excluded patients with important co-morbidities and those older than 65 years, the median age of myeloma diagnosis. For these patients, melphalan plus prednisone (MP) has been the most widely used treatment strategy (Myeloma Trialists’ Collaborative Group, 1998) and has remained a reference for comparison with other non-transplantation options (Hernandez et al, 2004; Facon et al, 2006; Palumbo et al, 2006). A retrospective analysis (Salmon et al, 1994) suggested that the dose and duration of steroid therapy may influence outcomes of myeloma patients and a phase II study suggested that pulsed high-dose dexamethasone may yield responses comparable with those seen with MP (Alexanian et al, 1992). These data led the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) to conduct MY.7, which is a phase III trial comparing induction therapy with melphalan plus dexamethasone (M-Dex) to MP, and maintenance therapy with dexamethasone to observation, in previously untreated myeloma patients.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Study design

This non-blinded randomised-controlled trial was conducted by the NCIC CTG in 37 Canadian centres. Patients were randomised to one of four treatment arms: induction treatment with MP or M-Dex and maintenance management with observation or dexamethasone, as shown in Fig 1. Stratification was by Salmon–Durie disease stage (Durie & Salmon, 1975), serum creatinine level and treatment centre. In 1996, a stratification variable was added by incorporating the intended use of a bisphosphonate. The objectives of the trial were to compare the overall survival (OS) of previously untreated patients, with symptomatic myeloma, who were treated with induction chemotherapy consisting of MP or M-Dex and to compare the OS of patients, who did not demonstrate progressive disease with induction therapy, who were then observed with no further treatment or who received dexamethasone as maintenance therapy. This report describes the final analyses of both the induction and maintenance questions.

image

Figure 1.  Design and conduct of the National Cancer Institute of Canada Clinical Trials Group MY-7 Trial. A total of 585 eligible patients were evaluated. Initially, patients were randomised to one of four treatment arms. An interim analysis evaluating induction therapy was conducted in November 2000; 408 patients were assessed and no differences in outcomes between induction therapies were detected. Randomization to induction therapy that included dexamethasone was therefore closed in January 2001, after entry of 466 patients; the final analysis of induction therapy included these patients and is based on the data base locked in August, 2004 (results described in current report). Of the 585 patients randomised to maintenance therapy at the time of trial registration, 292 did not have disease progression during induction therapy and were included in the primary analysis evaluating maintenance therapy.

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The process for patient randomization was concealed, and performed by using a computer generated dynamic minimization technique (Pocock & Simon, 1975) conducted at the central office of the NCIC CTG. All participating centres received approval from their local research ethics boards and written informed consent was obtained from all participants. Data were held and analysed by the NCIC CTG.

Eligibility and evaluation of patients

Five hundred and ninety-five patients with previously untreated, symptomatic stage I or stages II–III myeloma using the Salmon–Durie classification (Durie & Salmon, 1975) were randomised. Inclusion criteria included histological confirmation of myeloma by biopsy of a plasmacytoma or bone marrow plasmacytosis of at least 10% and a measurable serum monoclonal paraprotein of IgA, IgG, IgD or IgE type, or urinary excretion of at least 1·0 g of monoclonal light chain protein in 24 h. Patients with marrow plasmacytosis of <10% were eligible if a measurable serum or urine paraprotein was present and associated with at least one osteolytic bone lesion. Patients were ineligible if they had a comorbid condition that, in the opinion of the treating physician, precluded the use of protocol therapy; had a history of cancer other than for adequately treated squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or cancer that was treated more than 5 years before study entry and considered cured; or, had confirmed peptic ulcer disease within 2 years of study entry. Patients were permitted to receive up to a total dose of 120 mg of dexamethasone (or steroid equivalent) for urgent complications, such as spinal cord compression, prior to randomization.

Baseline assessments included a history and physical examination, complete blood count, biochemical profile of liver and renal function, serum protein electrophoresis, immunoglobulin quantification and either immunoelectrophoresis or immunofixation and beta-2-microglobulin (if available), quantification of 24-h urinary total protein and monoclonal light chain excretion, chest radiograph, radiographic skeletal survey, and bone marrow aspirate and biopsy evaluation. Laboratory testing was required within 21 d of randomization; radiographs were required within 28 d of randomization.

Among the 595 randomised patients, 10 (1·7%) were subsequently considered ineligible (Fig 1). The remaining 585 patients were included in this report. The primary analyses of the induction and maintenance questions were conducted according to the modified intention-to-treat principle that includes all eligible patients. As described below, given the complexity of addressing two questions within the same trial, additional analyses evaluating the maintenance question comparing dexamethasone with observation were performed to assess the robustness of conclusions reached with the primary analysis.

Treatment protocol

All treatment was with oral medication. The dose of melphalan was 9 mg/m2 for 4 d every 28 d; if after two treatment cycles, a stable or rising monoclonal protein was observed and nadir neutropenia of <0·5 × 109/l was not observed, doses were escalated by 3 mg/m2 with subsequent cycles. The prednisone dose was 100 mg per day for 4 d every 28 d; induction doses of dexamethasone were 40 mg per day for 4 d every 14 d for the first 84 d (3 treatment cycles) and then every 28 d with remaining cycles. Patients were to receive twelve 28-day cycles of therapy; doses of melphalan and corticosteroid were attenuated or deleted according to a predetermined schedule based on the observed treatment-related toxicities. Patients who did not demonstrate disease progression after completing induction therapy were, as per their initial allocation, either observed or received dexamethasone 40 mg per day for 4 d every 28 d until experiencing dose-limiting toxicity or progressive myeloma. Patients with a response to treatment that was deemed by the attending physician to be satisfactory, and who subsequently experienced progressive myeloma, were retreated with their assigned induction treatment; if the initial response to therapy was unsatisfactory, patients received subsequent therapy off study.

Following completion of three treatment cycles in the initial 129 patients, a 19% incidence of grade 3 or greater infections was observed in the 63 patients randomised to M-Dex (Shustik et al, 1997). Subsequent patients allocated to M-Dex received prophylactic cotrimoxazole or ciprofloxacin on days 15–24 of their first three treatment cycles.

Assessment of response and definition of study outcomes

Patients underwent monthly clinical assessments and measurements of routine haematological and biochemical parameters including serum and, if applicable, 24–h urine monoclonal paraprotein levels. Bone radiographs were obtained as clinically indicated. Treatment-related toxicity was assessed monthly.

The primary outcome for both the induction and the maintenance questions, OS, was measured from the time of randomization until the time of death from any cause. Secondary outcomes included response to treatment, progression-free survival (PFS), and treatment-related toxicity. Best response to treatment was categorised as responder, stable non-responder or progressive disease. Patients must have received a minimum of four cycles of induction treatment to be evaluable for a response assessment. Criteria for response included a reduction in the serum monoclonal paraprotein by at least 50% and a reduction in the 24-h urine excretion of monoclonal light chain by at least 90%. Each criterion required that the reduction be observed on two separate measurements taken at least 4 weeks apart. Criteria for progressive disease included an increase in the serum monoclonal paraprotein to least 50% above the baseline value, or 10 g/L above the nadir value, an increase in the 24-h urinary monoclonal light chain excretion to >100% above baseline or by more than 2 g/24 h above the nadir value, the development of hypercalcemia despite chemotherapy, the unequivocal development of a new lytic bone lesion, or a progressive cytopenia in conjunction with increasing marrow plasmacytosis. Patients who did not meet the criteria for either a response or progressive disease were classified as stable non-responders. Those patients who were responders or stable non-responders at the end of cycle 12 were eligible for maintenance management. PFS was measured from the time of randomization until meeting one of the above criteria of progressive disease. Treatment-related toxicity was graded by using the National Cancer Institute Common Toxicity Criteria version 2.0 (http://ctep/info.info.nih.gov/reporting/ctc.html).

Statistical analyses

The trial was designed to detect an improvement in median OS of 1·5 years (4·5 vs. 3·0 years; hazard ratio [HR] 1·5) with induction therapy that included M-Dex. With a power of 80% and a two-sided 5% level test, it was determined that at least 196 deaths would need to be observed and would require accrual of 450 patients over 4·5 years with one additional year of follow-up. In order to detect an improvement in median OS of 1·75 years (5·25 vs. 3·5 years; HR 1·5) with maintenance dexamethasone, and with a power of 80% and a one-sided 5% level test, it was determined that a minimum of 162 deaths would need to be observed and would require accrual of 600 patients in order to have about 360 patients included in the maintenance study. It was anticipated this accrual would require 6 years with two additional years of follow-up. Interim analyses were planned for both the induction and maintenance therapies when 50% of the required events had occurred. Distributions of OS and PFS between treatment arms were calculated with the life-table method of Kaplan and Meier (1958) and compared by the log-rank test stratified by the variables used in the randomization process. (Mantel, 1966). The Cox regression model (Cox, 1972) was used to study the treatment effect when adjusted for baseline factors. Although a one-sided test of statistical significance was initially chosen to determine the sample size for the maintenance question, all comparative analyses are reported by using a two-sided test of statistical significance.

Analysis of trials testing two interventions that occur in sequence are potentially complex (Byar et al, 1990; Girling et al, 2003; Pater & Crowley, 2006). Limitations may be observed if a sequential process of randomization is utilised, as benefits seen with an intervention tested in the first randomization may be distorted (i.e. exaggerated) if the intervention tested in the second randomization is also beneficial. For instance, in our trial, were M-Dex to be more effective than MP, more patients would have been potentially eligible to receive maintenance dexamethasone; if maintenance dexamethasone had further improved outcome, the magnitude of any benefit seen with M-Dex would have been exaggerated. We considered that interpretation of this risk would be facilitated by performing the randomization to both study questions at the time of trial registration. In doing so, it was possible for a secondary analysis to be performed to identify the best treatment sequence resulting from the induction and maintenance therapies.

As patients with progressive disease during induction therapy cannot provide meaningful information to answering the maintenance question, the primary analysis of this question was performed by using the modified intention-to-treat principle, and thus included only eligible patients, including meeting the eligibility criterion that there be no disease progression during the induction therapy. To find the best treatment sequence, a secondary planned analysis comparing all four treatment groups was performed. Finally, in order to test whether our conclusions were robust, we performed a tertiary unplanned analysis that included all randomised patients, including those with disease progression during the induction phase.

Trial conduct

The trial was activated in June 1995, and closed to accrual in July 2003. Two analyses of induction therapy (MP vs. M-Dex) were performed. A first protocol-specified analysis was performed in November 2000 and was based on a locked database from May 2000, after 408 patients were accrued and 196 deaths were observed. No differences in PFS or OS were detected between treatment groups; greater toxicity was observed in patients allocated to receive M-Dex (Shustik et al, 2001). The protocol was therefore amended to assign all further patients to induction therapy with MP and either observation or dexamethasone during the maintenance phase; at the time of implementing this amendment, 466 patients had been randomised to receive MP or M-Dex. The data base for these 466 patients was cleaned and locked in August 2004, analysed in April 2005, and forms the basis for the induction analysis reported below.

There were two analyses of maintenance therapy. After the first planned interim analysis was reviewed by the Data and Safety Monitoring Committee of the NCIC CTG, a recommendation was made to continue accrual to the full-planned sample size. The second analysis was performed after entry of 585 eligible patients (466 who had been randomised to M-Dex or MP and 118 who received MP alone as induction therapy) and 164 deaths in the maintenance group had been observed. Of these 585 patients, 292 were eligible for assessment of observation or maintenance therapy with dexamethasone. The data base for this analysis was cleaned, locked and analysed in May 2004. Figure 1 summarises the enrolment and study flow.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Analysis of induction therapy

The analysis of induction therapy included 466 patients; 234 were allocated to receive MP and 232 to M-Dex. Baseline characteristics were well balanced between the randomised groups (Table I). The median age (70·9 years) reflected the older population of patients who would not have been considered for stem cell transplantation and thus treated with induction therapy that included melphalan; 95% of patients had stages II–III disease. The median duration of induction therapy was 12 months in patients randomised to MP and 11·6 months in those receiving M-Dex. The median cumulative dose of melphalan was greater in the M-Dex group (768 mg vs. 648 mg).

Table I.   Baseline characteristics of the final induction analysis cohort at randomization.
CharacteristicMP Arms 1 & 2 n = 234 (%)M-Dex Arm 3 & 4 n = 232 (%)Total n = 466 (%)
  1. MP: melphalan + prednisone; M-Dex: melphalan + dexamethasone.

Age – years
 Median71·270·870·9
 Range41·4–90·641·9–8841·4–90·6
Gender – no. (%)
 Male100 (43)88 (38)188 (40)
 Female134 (57)144 (62)278 (60)
Myeloma protein – no. (%)
 IgG144 (62)147 (63)291 (62)
 IgA66 (28)66 (28)132 (28)
 IgD1 (0)1 (0)2 (0)
 >1 class3 (1)4 (2)7 (2)
 Light chain only20 (9)14 (8)34 (8)
Durie–Salmon stage – no. (%)
 Stage I13 (6)11 (5)24 (5)
 Stage II57 (24)54 (23)111 (24)
 Stage III164 (70)167 (72)331 (71)
Serum creatinine – no. (%)
 (≤175 μmol/L)198 (84)197 (85)395 (85)
 (>175 μmol/L)36 (15)35 (15)71 (15)
Serum calcium – no. (%)
 (<2·6 mmol/L)193 (82)195 (84)388 (83)
 (≥2·6 mmol/L)38 (16)36 (15)74 (15)
 Not done3 (1)1 (0)4 (1)
Serum albumin – no. (%)
 (<35 g/L)118 (50)123 (53)241 (52)
 (≥35 g/L)111 (47)103 (44)214 (46)
 Note done5 (2)6 (3)11 (2)
Beta2-microglobulin – no. (%)
 (≤204 nmol/L)18 (8)22 (9)40 (9)
 (>204 nmol/L)133 (57)131 (56)264 (57)
 Not done83 (35)79 (34)162 (35)

At the time of final analysis, 374 patients were eligible for assessment of response. Ninety-two patients received fewer than four cycles of induction therapy for a variety of reasons and were not evaluable for response. Responses were more common in patients receiving M-Dex (57% vs. 48%; P = 0·05). With a median follow-up of 5·2 years, no differences in PFS or OS have been detected (Fig 2). Three hundred and sixty-six (79%) patients had died and 417 (89%) had experienced disease progression or died without documented disease progression. The median PFS was 1·8 years in those randomised to MP vs. 1·9 years in the M-Dex group (HR = 0·88, 95% CI 0·72–1·07; P = 0·2). The median OS was 2·5 years in those randomised to MP vs. 2·7 years in the M-Dex group (HR = 0·91, 95% CI 0·74–1·11; P = 0·3).

image

Figure 2.  Outcomes of 466 patients treated with melphalan + prednisone or melphalan + dexamethasone. No differences in progression-free survival (2A) or overall survival (2B) were detected between the randomised groups.

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Among the non-haematological toxicities, significantly more infections (47% vs. 35%; P = 0·01), including grades 3–4 infections (15% vs. 9%; P = 0·03), were seen in patients receiving the M-Dex. Significant differences in other non-haematological toxicities were not observed. Among the haematological toxicities, significantly more grades 3–4 neutropenia (64% vs. 53%; P = 0·004) and thrombocytopenia (39% vs. 27%; P = 0·01) were seen in patients receiving the MP.

Analysis of maintenance therapy

Of the 292 patients included in the primary analysis of maintenance therapy, baseline characteristics were balanced between the randomised groups (Table II). The median age was 70·8 years, 83% of patients had stages II–III disease and, because of earlier closure of the M-Dex arm, only 42% of patients had received this induction therapy. No difference in the cumulative amount of prior melphalan therapy was noted; patients allocated to observation had received a median of 768 mg vs. 744 mg in patients receiving the dexamethasone. The median duration of maintenance dexamethasone therapy was 14·4 months with a median total cumulative dose received of 2160 mg.

Table II.   Baseline characteristics of maintenance cohort at randomization.
CharacteristicObservation n = 147 (%)Dexamethasone n = 145 (%)Total n = 292 (%)
Age – years
 Median70·271·548–85
 Range41–9170·841–91
Gender – no. (%)
 Male81 (55)84 (58)61 (42)
 Female66 (45)165 (57)128 (43)
Myeloma protein – no. (%)
 IgG91 (62)91 (63)182 (62)
 IgA48 (33)36 (25)84 (29)
 IgD0 (0)1 (1)1 (0)
 >1 class1 (0)5 (3)6 (2)
 Light chain only7 (5)12 (8)10 (7)
Durie–Salmon stage – no. (%)
 Stage I9 (6)14 (18)23 (8)
 Stage II42 (29)38 (26)80 (27)
 Stage III96 (65)93 (64)189 (65)
Serum creatinine – no. (%)
 (≤175 μmol/L)133 (90)132 (91)265 (91)
 (>175 μmol/L)14 (10)13 (9)27 (9)
Serum calcium – no. (%)
 (<2·6 mmol/L)131 (89)121 (83)252 (86)
 (≥2·6 mmol/L)16 (11)23 (16)39 (13)
 Not done0 (0)1 (1)1 (0)
Serum albumin – no. (%)
 (<35 g/L)83 (56)73 (50)156 (53)
 (≥35 g/L)64 (44)72 (50)136 (47)
Beta2-microglobulin – no. (%)
 (≤204 nmol/L)14 (10)19 (13)33 (11)
 (>204 nmol/L)85 (58)75 (52)160 (55)
 Not done48 (33)51 (35)99 (33)
Response status at completion of induction – no. (%)
 Responders120 (82)113 (78)233 (80)
 Stable non-responders27 (18)32 (22)59 (20)

With a median follow-up of 5·1 years, 171 (59%) patients had died and 227 (78%) had experienced disease progression or died without documented disease progression. The median PFS was superior in patients randomised to maintenance therapy with dexamethasone (2·8 vs. 2·1 years; HR = 0·61, 95% CI 0·47–0·79; P = 0·0002). This difference did not translate into a detectable difference in OS; the median OS was 4·1 years in those randomised to dexamethasone vs. 3·8 years in the observation group (HR = 0·88, 95% CI 0·65–1·18; P = 0·4) (Fig 3).

image

Figure 3.  Outcomes of 292 patients treated with maintenance dexamethasone therapy or observed. Patients allocated to maintenance therapy with dexamethasone had superior progression-free survival (3A). No difference in overall survival (2B) was detected between the randomised groups (3B).

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There were more non-haematological toxicities experienced by patients receiving maintenance therapy with dexamethasone. Specifically, there was more hyperglycemia (44% vs. 27%; P = 0·003) and infection (40% vs. 27%; P = 0·02). No differences in other non-haematological or haematological toxicities were detected.

A planned secondary analysis was performed by using a log-rank test to assess the differences in OS and PFS among the four treatment arms in the 466 patients who were randomised before the analysis that resulted in closure of the M-Dex induction arms. As shown in Table III, these results were consistent with the primary analysis. Superior PFS (P = 0·0008) was observed in the treatment arms receiving the maintenance therapy with dexamethasone, but no difference in OS was detected (P = 0·4).

Table III.   Secondary analysis of induction and maintenance therapies by treatment arm.
Induction treatment armMaintenance therapy armMedian PFS (years)Median OS (years)
  1. PFS, progression-free survival; OS, overall survival.

Melphalan + prednisoneObservation1·382·31
Melphalan + dexamethasoneObservation1·622·73
Melphalan + prednisoneDexamethasone2·132·73
Melphalan + dexamethasoneDexamethasone2·072·76
  P = 0·0008P = 0·4

Finally, an unplanned tertiary analysis was performed to evaluate a strategy of maintenance therapy determined prior to induction therapy. This analysis included all 585 patients, including those with disease progression during the induction therapy. The median PFS was superior in patients randomised to maintenance therapy with dexamethasone (2·04 vs. 1·59 years; HR = 0·71, 95% CI 0·59–0·85; P = 0·0002); no difference in OS was detected (medians of 2·73 vs. 2·44 years; HR = 0·90, 95% CI 0·74–1·09; P = 0·28).

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The primary treatment of patients with myeloma is determined by their baseline characteristics. Younger patients, and those without important comorbidities, are treated with protocols that include high-dose therapy with melphalan and autologous stem cell transplantation (Attal et al, 1996; Imrie et al, 2002; Child et al, 2003) while others are treated with conventional dose chemotherapy. A large individual patient-data meta-analysis (Myeloma Trialists’ Collaborative Group, 1998) demonstrated that treatment with MP was as effective as more complex and toxic regimens. Strategies tested to improve outcomes of patients treated with conventional dose therapy have included modifications in the steroid component of induction therapy and use of active agents as maintenance treatment.

Our trial, with 466 patients analysed for induction, is the largest to report results of a randomised comparison of MP with M-Dex. Similar results to ours were observed in two previously reported trials (Hernandez et al, 2004; Facon et al, 2006). Hernandez et al (2004) compared the outcomes of 201 older patients; the dose of dexamethasone in their M-Dex regimen was 20 mg/m2 on days 1–4 every 4 weeks. While no differences in overall response rate were detected, more complete responses were seen in patients receiving M-Dex. This did not translate into any detectable advantage in event-free survival or OS. Similarly, Facon et al (2006) compared the outcomes of 240 older patients randomised to MP or M-Dex whose data were extracted from a four-arm trial that also included testing of dexamethasone alone and dexamethasone plus interferon. Dexamethasone was given as 40 mg/d on days 1–4, 9–12 and 17–20 every 6 weeks. Again, more responses were observed in M-Dex patients, but no differences in PFS or OS were detected. Both our trial and that of Hernandez et al (2004) reported more frequent infections in patients receiving the M-Dex. Based on the weight of these data, treatment with M-Dex for induction cannot be recommended.

Previously reported-randomised trials testing the continuation of MP (Belch et al, 1988) and interferon (Myeloma Trialists’ Collaborative Group, 2001) as maintenance therapies described superior durations of disease control, but failed to detect clinically important improvements in OS. In contrast, a Southwest Oncology Group (SWOG) randomised trial involving 125 patients (Berenson et al, 2002), that compared maintenance therapy with alternate day prednisone, 50 mg vs. 10 mg, observed significant prolongation of median PFS (14 vs. 5 months; P = 0·003) and a borderline difference in median OS (37 vs. 26 months; P = 0·05) with the higher dose treatment. Our inability to duplicate these OS results may reflect differences in patient eligibility criteria, less frequent scheduling of dexamethasone, or statistical variation associated with the relatively small sample size of the SWOG study.

Our trial includes a design complexity in that we addressed treatment questions regarding both induction and maintenance therapy. When trials include multiple questions addressing interventions that occur in sequence, there is a potential for one question to influence the results of the other question (Byar et al, 1990; Girling et al, 2003; Pater & Crowley, 2006). Specifically, there is a potential risk that the magnitude of any benefit seen with an intervention tested in the first randomization may be distorted (i.e. exaggerated) if this benefit results in more patients becoming eligible for a second intervention and having this second intervention further alters outcomes. We recognised this potential in designing our trial and therefore conducted the randomization to maintenance therapy as part of the process of trial registration. This approach would facilitate an evaluation of the robustness of conclusions reached by permitting an ability to perform a comparison of the four randomised groups. Such an approach was not required when evaluating the induction question, as no differences between the induction groups were either detected or suggested.

This trial design made evaluation of the maintenance therapy question more complex, as many patients randomised at the time of trial registration to maintenance therapy would subsequently become ineligible for this intervention because of earlier disease progression. A potential for bias in determining the eligibility for providing maintenance therapy might therefore result. We have accounted for this potential risk through several mechanisms. Firstly, all patients eligible for maintenance therapy (i.e. those with no disease progression during induction therapy) were included in a primary analysis on an intention-to-treat basis and not on the basis of whether maintenance therapy was provided. Secondly, the baseline characteristics of the two maintenance strategy groups were assessed for balance and no differences, including no differences in initial treatment assignment, were evident. Thirdly, we reached the same conclusions with a preplanned secondary analysis that assessed all four potential treatment allocations, and an unplanned tertiary analysis that included all randomised patients (including those not eligible for maintenance therapy because of progressive disease during induction therapy). We therefore regard our conclusion that maintenance therapy with dexamethasone improves PFS as one that is robust.

The unreliability of response rate and duration as a predictor of OS has been observed with the testing of newer anti-myeloma agents. Specifically, in two trials comparing maintenance therapy with thalidomide following the autologous transplantation, significant differences in PFS did not translate into superior OS (Attal et al, 2005; Barlogie et al, 2006). It is therefore important that maintenance therapies with newer drugs including bortezomib and lenalidomide be formally tested in randomised trials. Combining these latter agents with dexamethasone, which we have demonstrated to have potentially important activity in the maintenance setting, warrants further study.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This work was completed by the National Cancer Institute of Canada Clinical Trials Group, which is supported by the National Cancer Institute of Canada and the Canadian Cancer Society.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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