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Originally published as JCO Early Release 10.1200/JCO.2005.04.0824 on January 23 2006 © 2006 American Society of Clinical Oncology. Descriptive and Prognostic Value of Patient-Reported Outcomes: The Bortezomib Experience in Relapsed and Refractory Multiple MyelomaFrom the Johnson & Johnson Pharmaceutical Services and Pharmaceutical Research and Development, Beerse, Belgium; Millennium Pharmaceuticals Inc, Boston, MA; and Mapi Values, Lyon, France Address reprint requests to Dominique Dubois, MD, Johnson & Johnson Pharmaceutical Services, c/o Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium; e-mail: ddubois{at}psmbe.jnj.com
PURPOSE: Bortezomib, a boronic acid dipeptide, has been recently introduced as a new approach to treating multiple myeloma (MM). The goal of this work was to evaluate the added value of patient-reported outcomes (PRO) in the interpretation of bortezomib clinical trial outcomes. PATIENTS AND METHODS: Two hundred two patients with relapsed, refractory MM were treated with bortezomib as part of the SUMMIT (Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy) study. Patients were administered the following four PRO measures at several time points: the European Organisation for Research and Treatment of Cancer (EORTC) core Quality of Life Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24), the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale, and the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG) Neurotoxicity (Ntx) scale. Minimal important difference (MID) thresholds were used to define patients as improved, stable, or worsened. A survival analysis was conducted to assess the predictive power of PRO data. RESULTS: For the total population, there was a positive change between baseline and best end point. Consistent with the clinical responses, change in PRO scores showed statistically significant differences between response groups with PRO improvement in patients with complete response (CR) or partial response (PR), mostly stable scores in patients with minor response or no change, and deterioration in most scores for patients with progressive disease. Change in scores for neuropathy-related symptoms was reasonably stable. In contrast, fatigue scores significantly improved for patients with CR or PR. When various MID thresholds were applied, the proportion of improved patients exceeded 35% for several domains within all change group definitions. Moreover, survival analysis results demonstrated the additional prognostic information PRO data can provide to supplement clinical data. CONCLUSION: This study demonstrated the complementary value for PRO assessments in further interpreting clinical response, the impact of adverse effects, and patient prognosis in clinical trials.
Bortezomib (Velcade; Millennium Pharmaceuticals Inc, Boston, MA) is the first in a new class of anticancer agents known as proteasome inhibitors. It is currently approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy and by the European Committee for Medicinal Products for Human Use as monotherapy for the treatment of progressive MM in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation. The safety and efficacy of bortezomib in patients with pretreated MM was initially established in the SUMMIT (Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy) study.1 The tumor complete response (CR)/partial response (PR) rate to bortezomib was 27%, with a median response duration of 12 months. The most clinically significant adverse event was a cumulative, dose-related peripheral sensory neuropathy, which was managed by treatment interruption and dose modification.2 Other reported adverse events include fatigue, neutropenia, thrombocytopenia, and GI effects such as nausea, vomiting, diarrhea, constipation, and anorexia.1,3 Recently, the antimyeloma activity of bortezomib was confirmed in the APEX (Assessment of Proteasome Inhibition for Extending Remissions) study, a randomized, phase III study comparing bortezomib with high-dose dexamethasone treatment in 669 patients with MM after one to three prior lines of therapy.3 This trial was halted at the time of the interim analysis because of a statistically significant improvement in time to disease progression in favor of bortezomib. A survival benefit was detected among patients randomly assigned to receive bortezomib compared with patients receiving dexamethasone, with both 1-year and overall survival being superior with bortezomib treatment compared with dexamethasone treatment.3 Bortezomib was also associated with better health-related quality of life (QOL), as measured with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity scale (FACT/GOG-Ntx), although scores in both treatment groups declined over time.4 Clinical trials in cancer have been successful in incorporating QOL assessments to complement the more traditional measures of tumor response, survival, freedom from relapse, and physician opinion concerning patient status.5 Previous work in newly diagnosed MM patients treated with high-dose chemotherapy or with melphalan and prednisone has demonstrated successful use of QOL assessments.6-8 The aim of this work was to evaluate the added value of patient-reported outcome (PRO) assessments in the interpretation of clinical trial outcomes in an advanced patient population of relapsed, refractory MM patients treated with bortezomib, a novel anticancer agent.
Study Design The SUMMIT study was an open-label, multicenter, pivotal phase II trial designed to evaluate the efficacy and safety of bortezomib 1.3 mg/m2 in up to eight treatment cycles in patients with refractory MM after at least two previous treatments. During each treatment cycle, bortezomib was administered twice per week for 2 weeks (days 1, 4, 8, and 11), with each treatment cycle being 21 days. Maximum duration of treatment was eight cycles. During the first two treatment cycles, all patients were to receive bortezomib. Thereafter, dexamethasone could be added in patients with progressive disease or with stable disease after four cycles. For detailed information on the study design, please refer to Richardson et al.1
Instruments The EORTC QLQ-C30 questionnaire is a reliable and valid measure of QOL in cancer patients,9-11 incorporating five functional scales, three symptom scales, a global health scale, and a QOL scale. Scale scores range from 0 to 100, with higher scores representing a better health state for the functional scores and lower scores representing a better health state for the symptom scores. The EORTC QLQ-MY24 is used in conjunction with the C30 scale. It consists of a brief questionnaire of 24 items grouped into the following four scales: disease symptoms, treatment adverse effects, social support, and future perspective. Scale scores range from 0 to 100, with 100 indicating a higher level of symptoms and, thus, poorer health. The FACIT-Fatigue scale12 is a 13-item, symptom-specific subscale of the FACIT scales.13 Lower values of the FACIT-Fatigue score denote higher fatigue (score range, 0 to 52). The FACT/GOG-Ntx scale14 is an 11-item, treatment-specific subscale of the FACIT for patients with neurotoxicity from systematic chemotherapy. Lower values of the FACT/GOG-Ntx score denote higher neurotoxicity (score range, 0 to 44).
Description of the Response to Treatment
Minimal Important Difference No MID threshold was found in the literature for the EORTC QLQ-MY24 and FACT/GOG-Ntx scales. In the absence of referenced MID, a threshold of 5 points was used for the EORTC QLQ-MY24, which corresponded to the value found in the literature for the other scales of the EORTC questionnaire,17 and a threshold of 3 points was used for the FACT/GOG-Ntx scale, which corresponded to the MID value obtained for the FACIT-Fatigue scale.18
Other criteria used to classify patients as improved, stable, or worsened were as follows: changes corresponding to an effect size (ES)
Clinical Variables
Statistical Methodology
A total of 202 patients were enrolled onto the study. The majority of patients were male (60%) and white (81%). The mean age was 60 years, with a range of 34 to 84 years. Of the 193 patients with measurable disease, there were 178 patients who had previously been treated with three or more of the major classes of agents for myeloma, and the median number of previous therapies was six (range, two to 15 therapies). The median duration of treatment with bortezomib was 3.8 months. Sixty-seven patients (35%) had a CR, PR, or MR to bortezomib alone, and 19 patients had a CR or near-CR. The return rates for each of the PRO questionnaires were greater than 95% at baseline and approximately 75% at end of treatment. A total of 144 patients who had both clinical response and PRO information available were included in the longitudinal PRO analysis, with their change in scores being assessed between baseline and the best postbaseline, predexamethasone, pre–progressive disease, post–best response to treatment (best end point). A description of the best-confirmed tumor response to treatment with bortezomib alone can be seen in Figure 1. Nine patients were excluded from response evaluation. For the total patient population with available clinical response information (n = 151) and available PRO data (n = 144), there was a positive change between baseline and the best end point during the study. The future perspective, disease symptoms, emotional, global QOL, cognitive, social, sleep disturbance, fatigue, pain, and constipation scores all showed improvements (ranging from 1- to 9-point improvements). Physical, role, diarrhea, and FACIT-Fatigue scores remained stable; whereas appetite loss, nausea and vomiting, treatment adverse effects, and FACT/GOG-Ntx scores indicated a worsening (1 to 5 points).
The change in PRO scores over time was assessed by comparing the change in scores according to clinical response (CR or PR, MR or NC, and PD) between baseline and the best end point. Statistically significant differences for the change in PRO scores were obtained between response groups for most domain scores. For the EORTC QLQ-C30 scores, improvements were seen for all scores in patients with PR or CR, and deterioration was seen in most scores for patients with PD (with the exception of the cognitive and sleep disturbance scores, which improved; Figs 2 and 3). Changes for the MR and NC group were mostly stable.
For the EORTC QLQ-MY24 scores (Fig 4), an improvement was seen in all groups for the disease symptoms and future perspective scores, with significant differences obtained between the three groups for the disease symptoms score. The change in treatment adverse effects indicated a slight worsening in all groups.
The change in the FACIT-Fatigue score indicated improvement in the CR and PR group, stability in the MR and NC group, and deterioration in the PD group. The difference in scores between the three groups approached but did not reach the 5% threshold for significance. The change in score for CR and PR patients was statistically different from zero (Fig 5). Fatigue at the end of cycle 7 was a function of fatigue at baseline but not of the total cumulative dose of bortezomib or of the best response to treatment.
The change in the FACT/GOG-Ntx score remained fairly stable and indicated no major difference between response groups. The change within each group and overall did not reach significance (Fig 6).
MID thresholds were used to define patients as having improved, stable, or worsened PRO scores. This analysis was performed on the change between baseline PRO scores and the best end point PRO score. When the various improvement thresholds were used, the proportion of improved patients was greater than 35% for several of the domains for all change group definitions used (Table 1).
An additional analysis was performed to correlate baseline clinical and PRO information to overall survival data from the patient population. All PRO and clinical variables were tested as predictors for survival using multivariate Cox proportional hazards regression. In a univariate analysis of the clinical baseline parameters, higher levels of Karnofsky performance status, albumin, platelet count, and hemoglobin were associated with a lower likelihood of death. In contrast, higher levels of total serum protein, percent plasma cells in bone marrow, beta2-microglobulin, and C-reactive protein and abnormal cytogenetics, ISS stage, and prior use of thalidomide were related to a higher likelihood of death. In a univariate analysis of the PRO baseline parameters, higher levels in appetite loss, constipation, disease symptoms, dyspnea, EORTC QLQ-C30 fatigue, pain, sleep disturbance, and treatment adverse effects scores were related to a higher likelihood of death, whereas higher levels in cognitive, emotional, FACIT-Fatigue (higher scores meaning lower level of fatigue), global QOL, physical, role, and social scores were related to a lower likelihood of death. In the multivariate analysis of the clinical parameters, Karnofsky performance status, albumin, platelet count, and NCI-CTC neuropathy grade remained significant; and in the multivariate analysis of the PRO parameters, the FACIT-Fatigue score remained significant. When using both clinical and PRO data together, serum albumin (hazard ratio = 0.480), platelet count (hazard ratio = 0.992), NCI-CTC neuropathy grade (hazard ratio = 0.602), and FACIT-Fatigue score (hazard ratio = 0.952) remained significant (Table 2).
Previous reports have shown the importance of PRO in the setting of initial therapy for MM and a positive correlation with survival in newly diagnosed MM patients.6-8 The aim of this study was to conduct secondary analyses of PRO data collected in a large phase II clinical trial assessing the efficacy and safety of bortezomib. More specifically, the objectives were to describe and interpret the response to treatment in relation to PRO scores and to explore the prognostic value of QOL assessment. The following four PRO questionnaires were used and analyzed: EORTC QLQ-C30, EORTC QLQ-MY24, FACIT-Fatigue scale, and FACT/GOG-Ntx scale. These questionnaires were appropriate because they provide coverage of the main adverse events noted with bortezomib treatment1 and allow comprehensive coverage of the impact on QOL. The patient acceptability of the questionnaires, as evaluated by their return rates (%), was good at baseline and acceptable at the end of treatment. Overall, the baseline scores indicated that relapsed and refractory MM patients had severely impaired QOL, which is comparable with other advanced cancer diseases such as head and neck, colorectal, small-cell lung, and breast cancers.21 By comparing the change in PRO scores according to response to treatment, it was observed that patients who had a favorable response to treatment, whether a CR or PR, also saw an improvement in their PRO scores and, thus, their QOL. Therefore, objective tumor responses to bortezomib monotherapy translate to subjective benefits and improvement in QOL. This is an important finding because chemotherapy agents and regimens sometimes have an adverse effect profile that might put into question the value of the tumor responses induced in a noncurative setting. Overall, the most common adverse effects reported for bortezomib were GI symptoms, fatigue, thrombocytopenia, and sensory neuropathy.1 The toxicity of the treatment and the effect it can have need to be justified by the gains that may be achieved.22 Therefore, the effect on an individual's QOL, although complex, must be understood, and failure to do this could result in treatment regimens actually contributing towards deterioration in QOL rather than improving it.23 To further investigate the question of the impact of potential toxicity on QOL, we specifically looked at the impact of two frequently reported adverse events, fatigue and neuropathy. Both adverse events represent important clinical challenges for the treating physician in managing patient care, particularly when judging whether prolonged therapy constitutes a real clinical benefit to the patient. Studies are increasingly demonstrating correlations between fatigue and overall QOL, with greater fatigue leading to poorer outcomes.24 This was corroborated in an exploratory analysis of the present study data, which demonstrated a significant correlation between QOL and fatigue.25 Fatigue scores did not significantly deteriorate with bortezomib treatment, and in fact, there was a significant improvement of fatigue in those patients with a CR or PR. Neuropathy-related symptom scores remained reasonably stable in all responder groups, suggesting that the subjective impact of neurotoxicity associated with bortezomib treatment can be controlled with appropriate dose modifications and treatment actions. In this and other clinical studies with bortezomib, the FACT/GOG-Ntx questionnaire was not only used as a PRO instrument but also as a safety screening tool for the treating physician to detect early patient-reported changes in neurologic functioning. Such information allows for early detection of emerging neuropathy and appropriate treatment actions. Together, these results suggest that PRO data provide useful information to better manage patient treatment. In the multivariate Cox proportional hazards regression analysis predicting time to death using baseline clinical parameters, Karnofsky performance status, albumin, platelet count, and NCI-CTC neuropathy grade had significant prognostic value in predicting survival, with a higher level in these parameters being related to a lower likelihood of death. Albumin is a known important prognostic factor in MM and, together with beta2-microglobulin, constitutes the cornerstone of the new ISS.20 Interestingly, beta2-microglobulin and ISS, although being identified as having prognostic importance in the univariate analysis, were not retained by the stepwise procedures in the multivariate analysis. Karnofsky performance status, another well-known prognostic factor in oncology, was retained in the multivariate analysis of the clinical parameters but was replaced by the FACIT-Fatigue score when clinical and PRO parameters were combined. This suggests that, although both parameters contain related information, the FACIT-Fatigue score constitutes a more sensitive tool with higher prognostic value. The baseline platelet count is probably related to disease-related bone marrow function impairment and may also be related to tolerance of full-dose bortezomib. Therefore, it is not surprising to see a correlation with overall survival. Why the baseline NCI-CTC neuropathy grade has significant prognostic value for survival (ie, why a higher neuropathy grade was related to a lower likelihood of death) is less clear. One can speculate about a relationship with the amount or duration of prior neurotoxic chemotherapy exposure or a disease-related phenomenon. This study is the first to describe PRO data assessed in a relapsed, refractory MM population treated with the novel agent bortezomib. These patients are a particularly challenging group to treat because they are heavily pretreated and late in disease course. Although both clinical and PRO data offer important information, the PRO data, by directly reflecting patients' perceptions, can provide integrated outcome information related to disease severity, treatment efficacy, and adverse effects. Being consistent with and complementary to traditional clinical assessments, PRO data, therefore, have been demonstrated to be meaningful and sensitive measures.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the patients, clinical investigators, and academic institutions involved in the SUMMIT trial.
Supported by Johnson and Johnson, Beerse, Belgium. Presented in part at the 46th Annual American Society of Hematology Meeting, San Diego, CA, December 4-7, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Richardson PG, Barlogie B, Berenson J, et al: A phase II study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 2. Richardson PG, Briemberg H, Jagannath S, et al: Peripheral neuropathy following bortezomib (VELCADE, formerly PS-341) therapy in patients with advanced multiple myeloma: Characterization and reversibility. Blood 102, 2003 (abstr 512) 3. Richardson PG, Sonneveld P, Schuster M, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005 4. Lee SJ, Richardson PG, Sonneveld P, et al: Health-related quality of life (HRQL) associated with bortezomib compared with high-dose dexamethasone in relapsed multiple myeloma (MM): Results from APEX study. J Clin Oncol 23:568s, 2005 (suppl; abstr 6535) 5. King CR, Haberman M, Berry DL, et al: Quality of life and the cancer experience: The state of the knowledge. Oncol Nurs Forum 24:27-41, 1997[Medline] 6. Wisloff F, Eika S, Hippe E, et al: Measurement of health-related quality of life in multiple myeloma: Nordic Myeloma Study Group. Br J Haematol 92:604-613, 1996[CrossRef][Medline] 7. Gulbrandsen N, Wisloff F, Brinch L, et al: Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support. Med Oncol 18:65-77, 2001[CrossRef][Medline] 8. Gulbrandsen N, Hjermstad MJ, Wisløff F: Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences. Eur J Haematol 72:172-180, 2004[CrossRef][Medline] 9. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 10. Osoba D, Zee B, Pater J, et al: Psychometric properties and responsiveness of the EORTC Quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. Qual Life Res 3:353-364, 1994[CrossRef][Medline] 11. King MT: The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res 5:555-567, 1996[CrossRef][Medline] 12. Yellen SB, Cella DF, Webster K, et al: Measuring fatigue and other anaemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 13:63-74, 1997[CrossRef][Medline] 13. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy (FACT) scale: Development and validation of the general measure. J Clin Oncol 11:570-579, 1993 14. Calhoun EA, Fishman DA, Roland PY, et al: Validity and selective sensitivity of the FACT/GOG-Ntx. Proc Am Soc Clin Oncol 19:446a, 2000 (suppl; abstr 1751) 15. Blade J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma subcommittee of the European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 16. Jaeschke R, Singer J, Guyatt GH: Measurement of health status: Ascertaining the minimal clinically important difference. Control Clin Trials 10:407-415, 1989[CrossRef][Medline] 17. Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16:139-144, 1998 18. Cella DF, Eton DT, Lai JS, et al: Combining anchor and distribution-based methods to derive minimal clinically important differences on the functional assessment of cancer therapy (FACT) anaemia and fatigue scales. J Pain Symptom Manage 24:547-561, 2002[CrossRef][Medline] 19. Cohen J: Statistical Power Analysis for the Behavioural Sciences (ed 8). New York, NY, Academic Press, 1977 20. Greipp PR, San Miguel J, Durie BGM, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412-3420, 2005 21. Fayers P, Weeden S, Curran D: EORTC QLQ-C30 Reference Values. Brussels, Belgium, European Organisation for Research and Treatment of Cancer Quality of Life Study Group, 1998 22. Gunnars B, Nygren P, Glimelius B: Assessment of quality of life during chemotherapy. Acta Oncol 40:175-184, 2001[Medline] 23. Waldron D, O'Boyle CA, Kearney M, et al: Quality-of-life measurement in advanced cancer: Assessing the individual. J Clin Oncol 17:3603-3611, 1999 24. Flechtner H, Bottomley A: Fatigue assessment in cancer clinical trials. Expert Rev Pharmacoecon Outcomes Res 2:67-76, 2002[CrossRef] 25. Dubois D, Dhawan R, van de Velde H, et al: Use of patient-reported outcomes (PRO's) to assess prognosis, toxicity, and response: The bortezomib experience in relapsed and refractory multiple myeloma (MM). Blood 104, 2004 (abstr 3468) Submitted September 1, 2005; accepted December 9, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.2 (lowest meaningful ES
