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Keywords:

  • bone marrow transplant;
  • high-dose treatment;
  • myeloma;
  • survival;
  • novel treatment

Summary

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

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7·47 years for responders (CR and PR) versus 4·89 years for non-responders; P = 0·035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7·4 years in CR group versus 5·3 years in non-CR group; P = 0·023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

With the advent of novel chemotherapeutic agents, such as thalidomide and its analogues (Singhal et al, 1999; Richardson et al, 2002; Anderson, 2003; Schey et al, 2004) and more recently the proteosome inhibitor bortezimib (Richardson et al, 2003), responses have been observed in myeloma patients who are refractory to standard modalities of treatment. Given these findings, the potential use of these drugs in first or second-line therapy for patients with myeloma is a natural aim in the effort to augment initial responses. However, the rationale use of these novel options requires a full understanding of the basis for current best therapeutic practice in terms of depth, rate and duration of response with respect to each treatment stage, and its impact on disease-free survival. To date, ‘standard treatment’ has involved infusional chemotherapy followed by high-dose melphalan (HDM) with stem cell support for fitter patients (Bjorkstrand et al, 1995; Fermand et al, 1995; Harousseau et al, 1995; Bensinger et al, 1996; Powles et al, 1997; Raje et al, 1997; Desikan et al, 2000; Harousseau & Attal, 2002). Evaluating the impact of this two-stage approach on clinical outcome is a crucial first step in developing the evidence base for the incorporation of new agents. Of particular importance is the significance of remission status following the induction regime and following HDM, and the long-term outlook as a function of response at both of these stages. Clinical studies thus far have conflicted in their findings (Lahuerta et al, 2000; Rajkumar et al, 2000; Alexanian et al, 2001) with complete response (CR) status post high-dose, translating into a survival advantage in some, but not all, published series. Here, we report on a large series of previously untreated myeloma patients who were treated with infusional chemotherapy followed by HDM. The impact of responses to induction chemotherapy and at 3 months following high-dose treatment with respect to long-term outlook was assessed with a view to develop a predictive model.

Patients and methods

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

Study design

A total of 383 consecutive patients with previously untreated multiple myeloma were entered into the transplant programme at the Royal Marsden Hospital between 1985 and 2004. The diagnosis of multiple myeloma was according to standard criteria (Durie & Salmon, 1975). All patients had at least stage I disease and were therefore considered eligible for treatment. Induction therapy was delivered with the aim of getting all patients to a high-dose procedure and maximizing responses following each stage of treatment. Eligibility for high dose was considered at the time of maximum response to induction therapy; patients with a good performance status (Eastern Cooperative Oncology Group performance score < 2) were considered candidates for high-dose treatment. Clinical data including Beta2microglobulin (B2M), full blood count, biochemistry, serum and urine paraprotein and bone marrow histology was collected prospectively according to a standard protocol and recorded on a computerized database. Follow-up was at 2-months interval. Responses to induction protocols at the time of maximum response and at 3 months following high-dose treatment were recorded in addition to mortality data.

Treatment schedule

A standard induction protocol was used consisting of cycles of infusional CVAMP chemotherapy (0·4 mg vincristine and doxorubicin 9 mg/m2 by continuous i.v. infusion for 4 d, methylprednisolone 1·5 g i.v./p.o. for 5 d and cyclophosphamide 500 mg i.v. on days 1, 8, 15 and repeated for every 3 weeks). One further cycle of chemotherapy was delivered following attainment of a maximum response. The median number of cycles delivered was five. Following maximum response plus one, patients considered eligible for a high-dose procedure underwent a peripheral blood progenitor or bone marrow stem cell collection using granulocyte colony-stimulating factor 12–16 μg/kg without cyclophosphamide priming. Those with adequate (>2·0 × 108/kg) mononuclear cells proceeded to receive 200 mg/m2 melphalan with autologous stem cell support. Those with inadequate stem cell collections received 140 mg/m2 melphalan. The dose of melphalan was not modified according to renal function (Sirohi et al, 2001). Patients able to tolerate interferon as maintenance therapy received interferon alpha on a thrice-weekly basis in doses of up to 5 million units s.c. Most patients received bisphosphonates throughout their management, initially sodium clodronate but more recently zoledronic acid.

Response evaluation

The response criteria have been described before (Gore et al, 1989) and the requirement for CR included an absence of the original monoclonal paraprotein in serum/urine by serum/urine electrophoresis maintained for a minimum of 8 weeks, <5% plasma cells on bone marrow biopsy and stable skeletal survey. This definition did not require a negative serum/urine immunofixation result. Partial response (PR) was defined by a 50% reduction in the serum paraprotein and 50% reduction in marrow infiltration in non-secretory disease, sustained for 4 weeks. In this study, patients were identified as non-responders (NR) if they did not meet the criteria for CR or PR after at least two cycles of CVAMP treatment.

Statistical methods

Correlations between demographic factors at presentation and responses to treatment were analysed using the chi-squared test for categorical variables and the Kruskal–Wallis test for numeric variables. The influence of demographic factors at presentation or responses to treatment, on outcome after treatment was determined using the log-rank test to produce Kaplan–Meier survival curves. For the likelihood of CR after HDM, events were censored at the time of next treatment. P-values were determined for all comparisons and were considered significant when <0·05. The Cox multivariate regression method was used to determine the influence of demographic factors at presentation on outcome after HDM. All analyses were performed according to an intention-to-treat method.

Results

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

Patient characteristics

The 383 patients in the study had a median age of 54 years (range, 35–78 years) The majority of patients were immunoglobulin-G (IgG) (219), 64 patients were IgA, four patients were IgD and two patients were IgM. There were 94 patients with light chain or non-secretory myeloma. The median haemoglobin at presentation was 11 g/dl (range 7·5–13 g/dl), median creatinine 100 μmol/l (range 52–230 μmol/l), and median albumin 36 g/l (range 19–40 g/l). B2M levels were stratified according to the criteria proposed in the International Staging System (ISS) (Greipp et al, 2003) as follows: B2M of <3·5 mg/l, B2M of >5·5 mg/l and values between these ranges. The majority of patients (296) had a B2M of 3·5–4 mg/l, 58 patients had a B2M of <3·5 mg/l and 29 patients had a B2M >5·5 mg/l.

Predictors of survival at presentation

Several clinical parameters at presentation were predictive of patients responding poorly to induction chemotherapy (Table I). In particular, patients who died during this phase of treatment were, on average, older with higher creatinine, lower albumin, lower haemoglobin and high B2M (>8·0 mg/l) levels in comparison with other groups of patients. Presentation B2M, creatinine, haemoglobin and albumin levels were identified as powerful predictors of response to CVAMP. Univariate analysis identified age >54 years, B2M >3·65 mg/l and serum creatinine >91 μmol/l as being significantly associated with a reduced overall survival (OS). Of these, B2M demonstrated the greatest significance (P = 0·001). On multivariate analyses of outcome after HDM, B2M was the most significant variable, increasing the probability of death by 1·8 in the group with a B2M >3·65 mg/l at presentation. The likelihood of relapse was increased by 1·6 for the same cut-off value.

Table I.  Comparison of patient characteristics at presentation, according to response to induction chemotherapy.
Clinical parameters (median)CRPRNRDiedP-value
  1. CR, complete response; PR, partial response; NR, non-responders; BJP, Bence–Jones protein.

  2. *Results of highly significant P-values.

Age (years)515453·5580·024
Calcium (mmol/l)2·352·382·392·440·632
Creatinine (μmol/l)9389911270·001*
Albumin (g/l)393536330·002*
Hb (g/dl)12·51111·39·30·000*
B2M (mg/l)2·83·83·48·00·000*
IgA, g/l (%)14 (22)30 (47)15 (23)5 (8)0·1
IgD, g/l (%)1 (25)3 (75)000·1
IgG, g/l (%)27 (12)130 (59)47 (22)15 (7)0·1
IgM, g/l (%)01 (50)1 (50)00·1
Non-secretory/BJP only (%)16 (17)40 (43)29 (31)9 (9)0·1

Response to induction therapy

There was a 66% overall response rate following treatment with CVAMP (CR 15%, PR 51%, NR/minimal response (MR) 26%, 8% died during induction therapy, Fig 1). These responses compare favourably with published series, with the majority of responses being PR with similar dexamethasone-based regimes. A total of 282 patients went on to have HDM and an analysis of OS for patients at maximum response to CVAMP showed a significantly better outcome for responders (median OS, 6·4 years for responders versus 4·1 years for NR; P = 0·0085, Fig 2A). In order to determine the most significant time point of the predictive value of treatment response, we analysed the effect of response on outcome after each successive course of CVAMP. This reached statistical significance after three courses of therapy (252 patients had three or more courses of CVAMP; median OS 7·5 years for responders versus 4·9 years for NR P = 0·035) (Fig 2B). The median survival of patients receiving induction chemotherapy but not proceeding on to HDM was poor at 10 months and alternative novel treatments for this group may improve this outcome.

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Figure 1. Response to treatment and mortality at each stage of the high-dose approach.

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Figure 2. (A) Overall survival for responders and non-responders to CVAMP assessed at maximum response to CVAMP. (B) Overall survival for responders versus non-responders to CVAMP assessed after three cycles of CVAMP.

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Response to HDM

Of the 282 patients who went on to receive HDM, 253 (90%) received 200 mg/m2 and 29 (10%) received 140 mg/m2. Reasons for not receiving HDM included early death and patient preference. Patients with an inadequate response to CVAMP (NR/MR) were much more likely to have melphalan 140 mg/m2 than responders (CR, PR) P = 0·00001. Of the 214 responders, 202 (94%) received melphalan 200 mg/m2 compared with 51 of the 68 NR (75%). Response to CVAMP was predictive of response to HDM (P < 0·00005), and the likelihood of achieving CR after HDM was significantly greater in those who achieved a response to induction therapy. The majority of responders were in PR post induction (51%) and the administration of HDM was associated with an 80% probability of attaining a CR. In total, 50% of patients receiving HDM achieved a CR (Fig 1), which compares favourably with other published series (Attal et al, 1996; Davies et al, 2001; Child et al, 2003). Of the 68 patients who failed to achieve a response to induction therapy and went on to receive HDM, 52 (76%) demonstrated a response to HDM, suggesting that a lack of response to CVAMP should not necessarily preclude HDM as a treatment option. However, new strategies to improve response rates within this group prior to the administration of HDM are likely to impact on progression-free survival (PFS).

Influence of year group on OS after first high-dose therapy

Using an intention-to-treat principle, the median OS for all patients was 5·1 years (Fig 3A) with a median follow-up of 8 years. In order to assess the influence of treatment year on outcome, the OS of patients was examined according to 5-year cohorts from 1985 to 2004 (Fig 3B). The numbers of patients in each year group were comparable. The median survival for the 1985–89 cohort was 4·6 and 5·4 years for the 1990–94 cohort. The median survival for the other two cohorts has not yet been reached. A significant trend to improved outcome was noted from 1995 onwards (P = 0·015). At an average of 4 years from first HDM, 80% of the 2000–04 group were alive in comparison with 70% of the 1995–99 group and 50% of those treated in the previous decade. This is likely to reflect better supportive care, the availability of new antimicrobial agents and the switch from bone marrow to peripheral progenitor cell as a source of stem cells, with faster engraftment times and shorter periods of neutropenia with its associated risks.

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Figure 3. (A) Overall survival for all patients in the study according to the intention-to-treat analysis. (B) Overall survival after first high-dose treatment according to the year group.

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Response at 3 months following high-dose therapy

Maximum responses to HDM were of a similar order to published series (50% CR, 10% PR, 34% NR/MR and 6% deaths, Fig 1) (Attal et al, 1996; Davies et al, 2001; Child et al, 2003). Most of these responses had occurred within 3 months following HDM and in order to examine the influence of extent of response on long-term outcome, we plotted Kaplan–Meier survival curves from 3 months following HDM. At this point there were 260 surviving patients. The achievement of a CR following HDM translated into a better PFS and OS and this difference was maintained for the duration of long-term follow-up. The median OS in the CR group was 7·4 years and 5·27 years in the non-CR group (P = 0·023) (Fig 4A). A 10–15% difference in OS was noted, was maintained on long-term follow-up and was also present in each of the year cohorts studied, showing the predictive value of assessing disease status at 3 months. Failure to achieve CR was significantly associated with a greater probability of progressive disease, with a median time to progression of 3·8 years for those in CR versus 1·87 years for the non-CR group (P = 0·0001) (Fig 4B). These findings highlight the need for intervention with new therapeutic measures for this patient group, to improve response status and hence overall outcome.

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Figure 4. (A) Overall survival according to response status at 3 months posthigh-dose. (B) Probability of progressive disease after first high dose as a function of complete response status at 3 months posthigh-dose.

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For those patients who failed to respond to induction therapy but went on to receive HDM, outcome following HDM was correlated with response to the high-dose treatment, with CR status post high-dose translating into a survival advantage in comparison with those not achieving CR. B2M was the only factor shown to significantly influence outcome at 3 months post-HDM for patients who had a sub-optimal response to induction therapy. A subanalysis of survival difference according to the dose of melphalan (200 mg/m2 vs. 140 mg/m2) used showed a significantly improved outcome for patients receiving 200 mg/m2 melphalan with a median survival of 7·1 years for those receiving 200 mg/m2 and 2·6 years for those receiving melphalan 140 mg/m2 (P < 0·00001).

Discussion

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

This analysis underlines the heterogeneity of myeloma in terms of biological behaviour and, with the introduction of novel treatment approaches, emphasizes the importance of identifying discriminators at an early stage to predict those who will respond poorly to standard therapy. Much in the same way that risk stratification has been usefully adopted in acute leukaemia and high grade lymphoma, profiling of patients with myeloma using some of the clinical parameters we have identified in this study, will help to stratify patients, allowing those in a poor risk group to be considered for novel therapeutic agents or more aggressive strategies, such as mini-allogeneic transplantation.

This analysis is one of the few reports of long-term outcome for myeloma patients treated with HDM, spanning just less than two decades. These results are comparable with, if not better than, outcomes in other published series with good long-term outcomes (median survivals of approximately 5 years) and a significant proportion of patients (35%) still alive at 10 years although a plateau in survival was not reached (Harousseau et al, 1995; Alegre et al, 1998). A number of studies have confirmed the superiority of HDM compared with conventional chemotherapy (Blade et al, 1996, 2000, 2001; Vesole et al, 1999) The Intergroupe Francais du Myelome 90 (Attal et al, 1996) was the first randomized trial showing better response rates, which translated into a survival benefit, and was subsequently confirmed in the larger Medical Research Council (MRC) VII study (Child et al, 2003). This current data set suggests that survival following HDM has significantly improved over the last decade, as has the safety of the approach, permitting most patients access to autologous transplantation. However, if this therapeutic approach is to be optimized, with the introduction of newer agents, it is essential to understand the effect of response on outcome of each component of the treatment. In particular, it is important to define whether the attainment of a CR is the desired aim for each stage of therapy. This can only be carried out on data sets like this, which have long follow-up and have paid close attention to the collection of response data prospectively.

Even at presentation a subset of patients can be identified who have adverse parameters, including a high B2M and low serum albumin, reflecting more aggressive disease and poorer performance status, and have a significant mortality during the induction phase. This is in keeping with the proposed prognostic factors identified in the ISS, which highlights a B2M value of >5·5 mg/l as a criterion for identifying stage III disease with poor outcome (median survival 29 months), and a serum albumin of <35 g/l as an important factor reflecting a poorer baseline status. Our analysis also identified creatinine, haemoglobin and albumin levels as powerful predictors of survival at outset. It may be argued that the patients with poor presentation prognostic variables should be offered novel therapies at diagnosis as they have a high chance of death during induction therapy, however, our data and previous data from the MRC trials (Maclennan et al, 1992) would suggest that, as many of these patients can be rescued, a change in strategy later during induction therapy but prior to HDM may be a more appropriate time point.

Analysis of the data carried out with the aim of defining the stage at which response should be assessed identified a group of patients who have not responded after three cycles of induction chemotherapy as having a worse outlook. The significance of response to induction therapy becomes more powerful after further courses of therapy have been delivered and maximum response has been reached (P = 0·0085 at maximum response versusP = 0·035 after three cycles). Thus by carefully monitoring response to therapy at an early stage, after the third cycle of chemotherapy (9 weeks of treatment), it is possible to identify a powerful discriminatory factor at an early stage of the disease process when a change in strategy is appropriate. This result also suggests that treatment should be delivered with the aim of getting maximum numbers of responses before HDM and that maximizing response at this stage is important. The addition of novel agents at this stage in the treatment regime may offer a way of salvaging NR early. Interestingly, our results are in keeping with work published by other groups and demonstrate that patients with unresponsive disease at induction can be salvaged with HDM with the achievement of high response rates (Vesole et al, 1999). However, in light of our findings, which underscore the importance of achieving a CR pre-HDM, this is probably not the most appropriate strategy to improve OS and the use of a novel agent, such as a bortezomib combination, to maximize response during the induction phase would seem logical rather than relying on HDM alone.

The response after HDM and achievement of CR at 3 months were also prognostically important, with differences in both PFS and OS for patients in CR. The impact of attaining a CR was independent of the initial response to CVAMP, further suggesting that attainment of a CR after HDM should be a major therapeutic aim. A number of other studies have demonstrated the advantage of achieving CR after high-dose therapy (Davies et al, 2001). For patients not achieving a CR at this time point, it may be argued that further treatment should be offered either as a full treatment schedule or as a maintenance strategy.

This analysis demonstrated that depth of response to induction treatment and HDM were correlated with both OS and PFS, suggesting that a two-stage response assessment will enable risk profiling to identify NR to induction therapy at an early stage and to define patients not in CR following HDM. Both of these groups may be suitable candidates for novel agents. Our data would argue that, in addition to the more traditional prognostic markers, such as B2M, albumin and haemoglobin levels, a prognostic system to identify patients that would benefit most from novel therapies should incorporate treatment response, given that many patients destined to relapse early after the first high dose cannot always be identified at presentation using the traditional markers. Although cytogenetical data was not assessed in this study, several publications have demonstrated the adverse prognostic impact of chromosome 13 abnormalities, particularly deletion of 13q14, which would be an additive factor in risk stratification (Tricot et al, 1997; Zojer et al, 2000; Facon et al, 2001; Kaufmann et al, 2003; Shaughnessy et al, 2003). A temporal profile could therefore be established, enabling subgroups of patients to be streamlined according to their perceived risk of relapse at each time point along a standard protocol. We are now using the treatment model outlined in Fig 5, which identifies significant temporal windows for the incorporation of novel agents in the treatment of new patients with myeloma. The most beneficial treatment strategy for these patients has yet to be decided; however, we have chosen to evaluate drugs with specific-targeted effects, such as bortezomib and immunomodulatory drugs either alone or in combination, with the aim of increasing CR rate at each stage and improving overall survival.

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Figure 5. Proposed risk stratification model for incorporating novel therapies. MINI ALLO, mini allogeneic transplant.

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Acknowledgements

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

Supported by the Bud Flanagan Leukaemia Fund and the Jenny Bidwell Research database.

References

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