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Keywords:

  • multiple myeloma;
  • bortezomib;
  • complete response;
  • clinical benefit;
  • minimal response

Summary

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24·1 vs. 6·9/6·4 months) and TTAT (27·1 vs. 13·6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3·8 vs. 2·3 months), TTAT (8·7 vs. 6·2 months), TTP (4·9 vs. 2·8 months) and OS (24·9 vs. 18·7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.

Quality of response to therapy in patients with multiple myeloma is becoming recognised as a key determinant of long-term outcome (Attal et al, 1996; Harousseau et al, 2006). The adoption of high-dose melphalan therapy plus autologous stem cell transplantation (HDT-ASCT) for selected patients has resulted in substantial increases in quality of response, in terms of response rates and rates of complete response (CR), compared with conventional chemotherapy regimens in the front-line setting (Attal et al, 1996; Barlogie et al, 1997; Child et al, 2003). This has been accompanied by improvements in outcomes reflective of clinical benefit, including progression-free survival (PFS), event-free survival (EFS) and overall survival (OS) (Attal et al, 1996; Barlogie et al, 1997; Child et al, 2003). Numerous studies in the front-line setting have demonstrated that quality of response, notably CR, or CR plus near CR (nCR) or very good partial response (VGPR) is prognostic for long-term outcome and clinical benefit. CR, CR/nCR or CR/VGPR following HDT-ASCT have been associated with prolonged PFS, EFS and OS (Attal et al, 1996; Bladéet al, 2000; Alexanian et al, 2001; Harousseau et al, 2006; O’Shea et al, 2006; Wang et al, 2006; Cavo et al, 2007). CR and CR/VGPR have been shown to be prognostic for OS in patients not proceeding to HDT-ASCT (Hussein et al, 2006; Kyle et al, 2006; Wang et al, 2006). Some studies have indicated that CR or quality of response post-induction therapy but pre-HDT-ASCT may also result in prolonged PFS and OS (Alegre et al, 1998; Majolino et al, 1999; O’Shea et al, 2006; Wang et al, 2006).

New front-line regimens incorporating recently introduced agents have been shown to produce high response rates and high rates of CR (±nCR/VGPR) compared with standard induction therapies, as reviewed by Richardson et al (2007a). This increased quality of response may translate into clinical benefit in terms of improved PFS/EFS and prolonged OS, both in patients proceeding to HDT-ASCT and in those not receiving a transplant. In addition, the elevated rates and quality of responses may result in additional clinical benefit by, for example, prolonging the length of time off-treatment prior to clinical relapse with therapies administered for a finite duration; indeed, prolonged time off-treatment has been suggested to be more important to patients than time to progression (TTP) or PFS (Durie et al, 2006; Richardson et al, 2008).

Novel-agent-based regimens are also demonstrating substantial activity, including high rates of CR (±nCR/VGPR), in patients with relapsed and/or refractory multiple myeloma (Richardson et al, 2007a) and so may offer increased clinical benefit in this setting as well as prolonging postrelapse survival (Kumar et al, 2008), particularly among those patients achieving higher quality responses. Bortezomib (VELCADE®, Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge, MA, USA and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA) was recently approved for the treatment of multiple myeloma based on the phase 3 VISTA trial; this expands the existing indication to include previously untreated multiple myeloma patients. Previously, the approval was based on the results of the international, randomised phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of single-agent bortezomib compared with high-dose dexamethasone in patients with relapsed multiple myeloma; bortezomib was shown to offer a significantly longer TTP, higher response and CR rates, and superior OS compared with dexamethasone (Richardson et al, 2005). Indeed, bortezomib is the only single agent to have shown a survival benefit in patients with relapsed multiple myeloma. In an updated analysis of the APEX trial, after median follow-up of 22 months, median OS was 29·8 months with bortezomib versus 23·7 months with dexamethasone, despite >62% of dexamethasone patients crossing over to receive bortezomib (Richardson et al, 2007b). The overall response rate in the bortezomib arm was 43%, including 15% CR/nCR, and median TTP was 6·2 months (Richardson et al, 2007b).

Here, we report an exploratory cohort analysis of the bortezomib arm of the APEX study assessing the relationship between quality of response and clinical benefit, as assessed by treatment-free interval (TFI), time to alternative therapy (TTAT), TTP and OS, in patients treated with bortezomib. The aim was to determine whether achieving a high quality response with bortezomib was prognostic for improved clinical benefit in terms of time off-treatment (TFI and TTAT), TTP and OS. The use of TFI and TTAT reflects recommendations in the International Uniform Response Criteria to report time to re-treatment in order to differentiate between disease progression according to response criteria (defined by relative or absolute changes in M-protein level, among other measures) and clinical (i.e. symptomatic) disease progression warranting therapy (Durie et al, 2006). This represents the first analysis of the impact of quality of response on clinical benefit conducted within the context of a phase 3 trial in the relapsed setting.

Materials and methods

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

Patients and study design

Details of the APEX study have been published previously (Richardson et al, 2005). Patients on the bortezomib arm (n = 333) received 1·3 mg/m2 on days 1, 4, 8 and 11 for eight 3-week cycles and then on days 1, 8, 15 and 22 for three 5-week maintenance cycles. Patients were evaluated every 3 weeks for 39 weeks, then every 6 weeks until disease progression and subsequently every 3 months for survival (Richardson et al, 2005). Response rates and TTP were determined by computer algorithm (and validated by independent review) according to the stringent European Group for Blood and Marrow Transplantation (EBMT) criteria (Bladéet al, 1998), modified to include the category of nCR (CR but immunofixation-positive) (Richardson et al, 2003), a subcategory of partial response (PR).

Review boards at all participating institutions approved the study, and all patients provided written informed consent. The study was conducted according to the Declaration of Helsinki, the International Conference on Harmonisation and the Guidelines for Good Clinical Practice.

Response cohort analysis

The aim of this exploratory, post-hoc cohort analysis of the APEX trial was to assess clinical benefit according to the quality of response achieved with bortezomib therapy. Response and time-to-events data from the updated analysis of the APEX trial (Richardson et al, 2007b) were used. Our analysis did not include patients randomised to dexamethasone, as this arm was halted at a preplanned interim analysis and therefore updated response and clinical benefit data were not available (Richardson et al, 2005, 2007b). A total of 315 patients in the bortezomib arm were evaluable for response.

Clinical benefit was assessed in a total of five response cohorts, defined according to quality of response as follows (with associated M-protein reduction required): CR (100% M-protein reduction, immunofixation-negative); VGPR (≥90% and ≤100% M-protein reduction, immunofixation-positive, i.e. including nCR by modified EBMT criteria; Durie et al, 2006); PR (≥50% and <90% M-protein reduction, i.e. PR by EBMT criteria but excluding VGPR); MR (≥25% and <50% M-protein reduction); and non-response (NR; including no change and progressive disease). Data were also evaluated for patients within the VGPR cohort who did or did not meet the requirements for nCR by modified EBMT criteria.

Clinical benefit was assessed by TFI (time from last dose of bortezomib to first dose of next anti-myeloma therapy), TTAT (time from first dose of bortezomib to first dose of next anti-myeloma therapy), TTP and OS.

Statistical methods

TFI, TTAT, TTP and OS were assessed using Kaplan–Meier methods, and medians and 95% confidence intervals (CI) were calculated. Patients were censored at the date of last contact for TFI, TTAT and OS, and at the date of last disease assessment for TTP. Statistical comparisons were conducted between response cohorts using the Wald chi-square test method. P values <0·05 were considered significant.

Results

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

Among the 315 response-evaluable patients who received bortezomib in the APEX trial, 135 (43%) achieved PR or better. Of these, 27 (9%) achieved CR, 31 (10%) VGPR [including 21 (7%) meeting the criteria for nCR] and 77 (24%) PR. In addition, 21 (7%) achieved MR and the remaining 159 (50%) were non-responders. Baseline demographics and patient characteristics for all the patients and for the five response cohorts are shown in Table I. The proportions of patients with IgA or light chain disease appeared higher in the CR and VGPR cohorts compared with the other cohorts and the overall population, while the proportion of patients with International Staging System (ISS) (Greipp et al, 2005) Stage I disease appeared somewhat higher, and the proportion with ISS stage III was lower, in the CR cohort compared with the other cohorts.

Table I.   Baseline demographics and patient characteristics for all response-evaluable patients treated with bortezomib in the APEX trial and for cohorts defined according to quality of response to bortezomib.
ParameterTotal n = 315Quality of response to bortezomib
CR n = 27VGPR n = 31PR n = 77MR n = 21NR n = 159
  1. *Data missing for 9 patients in total, including 2 CR, 2 VGPR and 5 NR.

  2. †Data missing for 9 patients in total, including 4 PR and 5 NR.

  3. ‡Protocol specified 1–3 prior therapies, but retrospective review found that 14/333 (4%) patients treated with bortezomib had received >3 prior therapies (Richardson et al, 2005).

  4. CR, complete response; ISS, International Staging System; KPS, Karnofsky Performance Status; MR, minimal response; NR, no response (including stable disease and progressive disease, excluding MR); PR, partial response (excluding VGPR); VGPR, very good partial response (including near CR).

Median age (range), years62 (33–84)60 (46–76)63 (38–84)60 (39–79)66 (38–75)61 (33–83)
Male, n (%)180 (57)11 (41)19 (61)43 (56)13 (62)94 (59)
Myeloma type, n (%)
 IgG192 (61)8 (30)11 (35)56 (73)12 (57)105 (66)
 IgA73 (23)10 (37)13 (42)15 (19)6 (29)29 (18)
 Light chain/other50 (16)9 (33)7 (23)6 (8)3 (14)25 (16)
KPS ≥70%, n (%)*290 (95)25 (100)28 (97)74 (96)19 (90)144 (94)
ISS (Greipp et al, 2005) stage, n (%)†
 I133 (43)16 (59)13 (42)35 (48)9 (43)60 (39)
 II96 (31)8 (30)9 (29)19 (26)4 (19)56 (36)
 III77 (25)3 (11)9 (29)19 (26)8 (38)38 (25)
Median number (range) of prior therapies‡2 (1–7)2 (1–5)2 (1–3)1 (1–7)2 (1–3)2 (1–5)

Quality of response and clinical benefit

Table II summarises exposure to bortezomib and clinical benefit in all response-evaluable patients and in the five response cohorts. Overall, patients received a median of six cycles of treatment, and 39% of the patients completed the planned eight 3-week cycles (Richardson et al, 2007b). Patients who achieved any degree of response received a higher median number of cycles of treatment than NR patients, while patients achieving CR received fewer cycles than those achieving VGPR/PR, possibly reflecting protocol-specified criteria for discontinuing treatment (Richardson et al, 2005).

Table II.   Clinical benefit in all response-evaluable patients treated with bortezomib in the APEX trial (n = 315) and according to quality of response to bortezomib.
 Total n = 315Quality of response to bortezomib
CR n = 27VGPR n = 31PR n = 77MR n = 21NR n = 159
  1. *HR = 0·344 (95% CI: 0·159, 0·746), P = 0·007 (vs. VGPR); HR = 0·372 (95% CI: 0·197, 0·702), P = 0·002 (vs. PR).

  2. †HR = 0·358 (95% CI: 0·169, 0·758), P = 0·007 (vs. VGPR); HR = 0·363 (95% CI: 0·189, 0·700), P = 0·002 (vs. PR).

  3. ‡HR = 0·527 (95% CI: 0·312, 0·888), P = 0·016 (vs. NR).

  4. CI, confidence interval; CR, complete response; HR, hazard ratio; MR, minimal response; NE, not estimable, parameter not yet reached; NR, no response (including stable disease and progressive disease, excluding MR); OS, overall survival; PR, partial response (excluding VGPR); TFI, treatment-free interval; TTAT, time to alternative therapy; TTP, time to progression; VGPR, very good partial response (including near CR).

Median cycles of bortezomib received, n68101084
Median TFI (95% CI), months4·8 (3·8, 5·9)24·1* (9·7, 24·4)6·9 (5·5, 11·1)6·4 (4·4, 10·3)3·8 (0·5, 9·7)2·3 (1·4, 3·1)
Median TTAT (95% CI), months10·6 (9·7, 12·8)27·1† (15·2, 32·0)13·6 (10·0, 17·3)14·0 (12·6, 16·1)8·7 (7·0, 13·1)6·2 (4·9, 8·0)
Median TTP (95% CI), months6·2 (5·6, 6·9)9·7 (7·6, 17·7)10·8 (8·1, 14·4)8·5 (7·0, 9·9)4·9‡ (3·9, 6·9)2·8 (2·1, 2·9)
Median OS (95% CI), months29·8 (23·2, NE)NE (NE, NE)NE (23·8, NE)NE (29·8, NE)24·9 (18·9, NE)18·7 (14·9, 22·7)

Patients achieving CR had a significantly longer median TFI (24·1 months) than patients achieving VGPR (6·9 months) or PR (6·4 months); similarly, median TTAT was significantly longer in patients achieving CR (27·1 months) compared with patients achieving VGPR (13·6 months) or PR (14·0 months) (Table II). In contrast, median TTP appeared similar in the CR, VGPR and PR cohorts (Fig 1). Median OS had not been reached in any of these cohorts, but will probably be longer in comparison with the MR or NR cohorts (Fig 2). Within the VGPR cohort, results were similar for the 21 patients meeting the criteria for nCR (100% M-protein reduction) and the remaining 10 VGPR patients (data not shown); however, the small patient numbers prevented meaningful comparison. Patients achieving MR appeared to have prolonged median TFI (3·8 vs. 2·3 months), TTAT (8·7 vs. 6·2 months), TTP (4·9 vs. 2·8 months, Fig 1) and OS (24·9 vs. 18·7 months, Fig 2) compared with non-responders.

image

Figure 1.  Time to progression among all response-evaluable patients treated with bortezomib in the APEX trial (n = 315) and according to quality of response to bortezomib.

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image

Figure 2.  Overall survival among all response-evaluable patients treated with bortezomib in the APEX trial (n = 315) and according to quality of response to bortezomib.

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Discussion

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

The results of this post-hoc cohort analysis of the phase 3 APEX trial indicate that CR could be a surrogate marker for clinical benefit with bortezomib therapy in patients with relapsed multiple myeloma, as evidenced by the significantly longer median TFI and TTAT seen in patients achieving CR compared with those achieving VGPR or lesser responses. These results also suggest a broader relationship between depth of response and clinical benefit with bortezomib; TFI and TTAT appeared prolonged in patients achieving VGPR/PR compared with the MR cohort, while patients achieving MR demonstrated greater clinical benefit compared with non-responding patients. Our findings support the validity of MR as a separate response category in patients with relapsed multiple myeloma, in contrast to its exclusion from the International Uniform Response Criteria (Durie et al, 2006). These data also suggest that patients achieving VGPR or PR with bortezomib experience similar levels of clinical benefit, possibly calling into question the relevance of the VGPR category (versus nCR) in this setting. It should be noted that the clinical benefit of a TFI is only possible with agents, such as bortezomib, that are administered for a finite treatment period, as opposed to those for which the paradigm is to treat until disease progression.

Similar trends to those seen for TFI and TTAT were apparent for TTP and OS, which appeared prolonged in patients achieving PR or better versus MR, versus, in turn, NR. However, median TTP was similar for the CR, VGPR and PR cohorts. The discordance between this finding and the data on TFI and TTAT may reflect the difference between the strict definition of relapse from CR (reappearance of M-protein on immunofixation), which is considered a progression event, and the definition of progression from PR (>25% M-protein increase which must also be ≥5·0 g/l) in the EBMT criteria (Bladéet al, 1998). As acknowledged by Bladéet al (1998), these definitions may lead to a paradoxically shorter remission duration in patients achieving CR than in patients not achieving CR; however, relapse from CR may follow a more indolent disease course compared with progression following VGPR or PR (Bladéet al, 1998), and consequently median TTP may be inconsistent with the true clinical benefit of therapy (Richardson et al, 2008). Therefore, although the median time to disease progression appeared similar between response cohorts, the median time to symptomatic clinical disease progression warranting therapy was nearly twice as long in patients achieving CR with bortezomib. This finding supports the revision of the definition of an event in TTP analyses in patients achieving CR, from the stringent definition of relapse from CR in the EBMT criteria (Bladéet al, 1998) to the definition of progression from CR in the International Uniform Response Criteria, which in part requires a minimum absolute increase in serum M-protein of 5·0 g/l (Durie et al, 2006). This may result in TTP more closely reflecting time to symptomatic clinical disease progression warranting therapy in patients achieving CR.

Median OS was not reached in the CR, VGPR and PR cohorts, preventing any conclusions regarding the differential prognostic impact on survival of these responses in the relapsed setting. The observed benefits in TTAT and TFI may translate into prolonged OS, but further follow-up would be required to determine any differences between response cohorts.

Our findings regarding a relationship between depth of response and clinical benefit are supported by other studies in patients with relapsed and/or refractory multiple myeloma. We have previously reported a cohort analysis similar to the analysis presented here involving patients with relapsed and refractory multiple myeloma treated with bortezomib ± dexamethasone in the phase 2 SUMMIT study (Niesvizky et al, 2006). Results showed that median TFI (9·8 vs. 3·1 months), TTAT (15·4 vs. 8·5 months) and TTP (16·4 vs. 9·2 months) were prolonged in patients achieving CR/nCR versus PR (Niesvizky et al, 2006). The median OS had not been reached in either cohort (Niesvizky et al, 2006). In addition, Hussein et al (2006) investigated the impact of quality of response on PFS and OS in a phase 2 study of thalidomide, liposomal doxorubicin, vincristine and dexamethasone in 53 newly diagnosed and 49 previously treated multiple myeloma patients. In a multivariate analysis, patients achieving CR/VGPR were shown to have significantly longer PFS and OS (as measured from best response) compared with patients achieving PR/stable disease in both the newly diagnosed and previously treated groups (Hussein et al, 2006). Similarly, Harousseau et al (2007) recently reported, in abstract form, a combined analysis of two phase 3 studies of lenalidomide plus dexamethasone versus dexamethasone alone that showed that achieving CR/nCR versus PR with lenalidomide plus dexamethasone was associated with significantly longer duration of response, TTP and OS.

None of these studies analysed clinical benefit within more narrowly defined response cohorts, as in the present study. Given the numbers of responding patients in each study, statistically meaningful conclusions may not have been possible. Similarly, there were insufficient patients within the VGPR cohort in the present study (n = 31) to enable meaningful comparisons of clinical benefit among those meeting the criteria for nCR (n = 21) and the remaining patients with VGPR (n = 10). Analyses to date have been retrospective in nature; a study designed to evaluate prospectively the relationship between quality of response and clinical benefit would enable more meaningful investigation of, and further elucidate, the relative benefits of achieving CR, nCR, VGPR, PR and MR (vs. NR) in patients with relapsed and/or refractory multiple myeloma. Furthermore, such a study could also evaluate the category of stringent CR (sCR), as defined in the International Uniform Response Criteria (Durie et al, 2006). The findings from such a study could have important implications for assessing treatment effects in this setting.

In the present analysis, the elevated proportion of patients with ISS Stage I disease in the CR cohort may have had an impact on outcome and apparent clinical benefit; furthermore, this finding suggests the possibility of an inherent distinct biological feature in the patients who achieve CR with bortezomib. Nevertheless, attaining more robust responses with novel agents now appears to be a feasible goal in patients with otherwise relapsed or refractory disease. The advent of methods for more reliably assessing surrogate markers of response, such as flow cytometry and other molecular techniques for monitoring minimal residual disease (Fenk et al, 2004; Sarasquete et al, 2005), will ultimately resolve this issue. Furthermore, the use of such techniques is already producing information prognostic for EFS (Thulien et al, 2007), PFS (Bakkus et al, 2004), relapse-free survival (Martinelli et al, 2000; Corradini et al, 2003) and TTP/OS (Fenk et al, 2007).

In conclusion, bortezomib has substantial activity in patients with relapsed multiple myeloma, and the results of this cohort analysis of the phase 3 APEX trial indicate that achieving CR with bortezomib therapy is associated with significantly greater clinical benefit, as measured by TFI and TTAT, compared with achieving lower degrees of response. Our results also suggest a broad association between response and clinical benefit, and support the validity of MR as a separate response category in this setting. Moreover, these data suggest further studies are warranted to determine the relative impact of individual categories of response in different settings (e.g. newly diagnosed multiple myeloma versus relapsed and refractory disease), as well as between treatment modalities and respective drug combinations.

Conflict of interest

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

R.N. is a consultant for and has received honoraria and research funding from Celgene and Millennium Pharmaceuticals. P.G.R. serves on advisory boards and has received honoraria from Millennium Pharmaceuticals, and has received honoraria from Celgene. P.S. is a consultant for and has received honoraria from Johnson & Johnson. E.A.S. is a consultant for Johnson & Johnson. T.F. is a consultant for Celgene and Pharmion. J.-L.H. is a consultant for Celgene, Johnson & Johnson and Pharmion. K.C.A. is a consultant for and has received honoraria and research funding from Celgene, Millennium Pharmaceuticals and Johnson & Johnson. J.B. is a consultant and has received honoraria from Celgene, Janssen-Cilag Spain, Johnson & Johnson and Pharmion, and has received research funding from Janssen-Cilag Spain. A.L.B. and D.-L.E. are employees of and own stock in Millennium Pharmaceuticals. D.I., L.R., M.C., M.W.S. and S.J.R. have no conflicts of interest to disclose.

Acknowledgements

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References

The authors would like to thank Steve Hill and Rosemary Washbrook for editorial assistance in the development of this manuscript. Steve Hill is a medical writer and Rosemary Washbrook is a medical editor with Gardiner-Caldwell London.

This research was supported by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development L.L.C.

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  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Conflict of interest
  7. Acknowledgements
  8. References
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