original articles
Annals of Oncology
Annals of Oncology 25: 189–195, 2014 doi:10.1093/annonc/mdt509
Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents M. Merz1,2, K. Neben1, M. S. Raab1,3, S. Sauer1, G. Egerer1, M. Hundemer1, D. Hose1, C. Kunz4, C. Heiß1, A. D. Ho1, H. Goldschmidt1,5 & J. Hillengass1,2*
Received 21 June 2013; revised 25 September 2013; accepted 26 September 2013
Background: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients 65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. Patients and methods: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60–64, 65–69 and 70–75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. Results: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60–64 years: 27 months; 65–69 years: 23 months; 70–75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. Conclusion: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment. Key words: multiple myeloma, elderly, high-dose therapy, autologous stem cell transplantation, novel agents, maintenance therapy
introduction High-dose therapy (HDT) with melphalan 200 mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) in combination with novel agents (thalidomide, lenalidomide and bortezomib) is considered the standard of care for patients with newly diagnosed multiple myeloma (MM) younger than 65 years [1, 2]. MM is a disease of the elderly with a median age at diagnosis of 70 years [3]. Therefore, a large proportion of patients are considered ineligible for HDT because of increased treatment related *Correspondence to: Dr Jens Hillengass, Department of Medicine V, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel: +49-622156-39397; Fax: +49-6221-56-4171; E-mail: [email protected]
toxicity and mortality of MEL200 and the lack of results from randomized phase III trials with MEL-200 in elderly patients [4]. Previous studies have shown that HDT with intermediate dose (100 mg/m2) melphalan (MEL100) is feasible for elderly myeloma patients up to 75 years of age [5, 6]. The benefit of HDT in these patients compared with the current standard of novel agents with or without chemotherapy is uncertain as in most studies HDT was not supported by the use of novel agents during induction therapy and no maintenance therapy was administered. Furthermore, Palumbo et al. demonstrated that MEL100 is inferior to MEL200 regarding depth of remission and time to progression in younger patients with MM [7]. As a consequence, rates of complete remission (CR) in MEL100 trials were low and
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on March 9, 2015
1 Department of Medicine V, University Hospital of Heidelberg, Heidelberg; 2Department of Radiology; 3Experimental Therapies for Hematologic Malignancies; 4Division of Biostatistics, German Cancer Research Centre, Heidelberg; 5National Centre for Tumor Disease, Heidelberg, Germany
original articles only one prospective trial showed that MEL100 is superior to conventional chemotherapy with melphalan and prednisone (MP) [6]. Furthermore, the Intergroupe Francophone du Myélome (IFM) showed in a phase III trial that the addition of thalidomide to melphalan/prednisone (MPT) was superior to MEL100 in patients between 65 and 75 years [5]. However, there is still a lack of information about feasibility and outcome of HDT with MEL200 in combination with novel agents in elderly patients. In the current study, we, therefore, retrospectively evaluated the treatment-related toxicity and mortality of elderly MM patients treated with MEL200 followed by ASCT. Additionally, the impact of integrating novel agents into the HDT regimen on remission and outcome was investigated.
Annals of Oncology physicians in a weekly interdisciplinary transplantation conference. Patients were considered eligible for HDT when showing no signs of severe comorbidity requiring acute medical intervention. For application of HDT and surveillance during neutropenia, all patients were admitted to our transplant unit. HDT consisted of melphalan (total dose 200 mg/m2) divided and administered separately on days -3 and -2 before ASCT. In seven patients (4%), a single application of 100 mg/m2 melphalan was used due to renal function impairment (creatinine clearance 70 years can be reduced to 2% by dose reduction, recent retrospective studies showed that HDT with MEL200 is also feasible for selected elderly patients with
Volume 25 | No. 1 | January 2014
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0
EFS (%)
60–64 vs. 65–69 P = .198 65–69 vs. 70–75 P = .328 70–75 vs. 60–64 P = .980
original articles
Annals of Oncology
Table 2. Summary of results from uni- and multivariate Cox PH regression analyses of event-free and overall survival
Univariate HR
P-value
Overall survival Multivariate HR P-value
Univariate HR
P-value
1.0 1.0 0.8
0.918 0.521
1.0 1.2 1.4
0.391 0.219
1.0 1.3 0.7
0.532 0.626
1.0 1.6 0.9
0.204 0.888
1.0 1.5 1.7
– 0.127 0.044
1.0 1.7 2.0
0.022 0.002
1.0 1.5 3.7
0.948 0.001
1.0 2.4 4.2
0.052 0.001
1.0 4.0
0.000
1.0 2.6
0.001
1.0 5.5
0.001
1.0 3.5
0.005
1.0 1.6 1.5
0.288 0.392
1.0 1.6 1.3
0.115 0.387
1.0 1.1 1.7
0.791 0.644
1.0 2.5 3.2
0.210 0.136
1.0 0.5
0.050
1.0 0.5
0.003
1.0 1.1
0.917
1.0 0.5
0.149
1.0 2.5 2.4
0.002 0.058
1.0 2.1 2.1
0.001 0.043
1.0 4.3 7.0
0.570 0.610
1.0 3.7 4.6
0.016 0.045
1.0 0.4 0.5
0.006 0.005
1.0 0.7 0.6
0.119 0.013
1.0 0.8 0.5
0.750 0.213
1.0 1.3 0.6
0.599 0.186
HR, hazard ratio; Bold/italic values = significant values.
MM [15–18]. In our retrospective analysis, we also found no significant differences among three different age groups (60–64, 65–69 and 70–75 years) regarding engraftment after ASCT, need for supportive care and TRM. Remarkably, no patient between 70 and 75 years died because of early complications due to HDT. Furthermore, uni- and multivariate analyses demonstrated that age had no influence on EFS and OS after HDT and response rates and rates of CR were not different in the different age groups. The major downside of the currently available studies on HDT in elderly myeloma patients—either with MEL100 or MEL200—is the fact that most studies were carried out before the introduction of novel agents and the incorporation of maintenance therapy in the HDT concept. This might explain the relatively low nCR + CR rates reported in the prospective trials of MEL100 from Italy (25% [6]) and France (18% [5]) and the inferiority of MEL100 treatment without new drugs compared with MPT shown in the IFM study. Correspondingly, Palumbo et al. demonstrated in a prospective trial of 102 patients between 65 and 75 years that CR rates after HDT substantially improved when MEL100 was combined with a bortezomib-based induction therapy up to 38% [7]. This is in agreement with our results of nCR + CR rates after HDT of 43% in the group receiving
Volume 25 | No. 1 | January 2014
novel agents during induction therapy compared with 20% in patients treated without novel agents. The interpretation of this finding is limited by the fact that novel agents during induction therapy were not equally distributed in our cohort and only 37% of all patients were treated without novel agents. In the study by Palumbo et al., CR rates increased to 66% by adding a lenalidomide consolidation and maintenance therapy [7]. The role of maintenance therapy after ASCT in younger myeloma patients has been discussed extensively in the last years [19]. With our present study, we demonstrate that maintenance therapy with a novel agent or interferon also improves EFS of elderly patients eligible for HDT. However, due to the small number of patients treated with interferon (12%), we are not able to draw general conclusions and, given the common side-effects, especially in elderly patients and the positive effect only in this small group of patients, we do not recommend the routine use of interferon. In younger patients eligible for HDT, risk stratification based on the ISS and cytogenetic aberrations as detected by FISH is widely accepted [20]. A recent study by the IFM demonstrated the prognostic significance of t(4;14) and del17p in elderly patients treated with MP-based regimens. Interestingly, they showed a decreased prevalence of high-risk aberrations,
doi:10.1093/annonc/mdt509 |
Downloaded from http://annonc.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on March 9, 2015
Age 60–64 65–69 70–75 ISS I II III Cytogenetic Low-risk High-risk Remission before HDT nCR + CR PR - VGPR SD or PD Tandem ASCT No Yes Remission after HDT nCR + CR PR - VGPR SD or PD Maintenance therapy No Interferon-α Novel agent
Event-free survival Multivariate HR P-value
original articles
acknowledgements We thank Katrin Heimlich, Maria Dörner and Hildegard Bethäuser for technical assistance in the enrichment of CD138positive plasma cells and Michaela Brough, Stephanie Pschowski-Zuck and Desiree Kirn for performing interphase fluorescence in situ hybridization analysis.
funding This work was supported by a grant from the Dietmar Hopp Foundation (DHS05/2006), Heidelberg, Germany.
| Merz et al.
disclosure HG and KN received honoraria and research funding and acted as advisors for Celgene and Janssen-Cilag. All remaining authors declared no conflict of interest.
references 1. Palumbo A, Cavallo F. Have drug combinations supplanted stem cell transplantation in myeloma? Hematology Am Soc Hematol Educ Program 2012; 2012: 335–341. 2. Harousseau JL. Autologous transplantation for multiple myeloma. Ann Oncol 2008; 19 (Suppl 7): vii128–vii133. 3. Klepin HD, Hurd DD. Autologous transplantation in elderly patients with multiple myeloma: are we asking the right questions? Bone Marrow Transplant 2006; 38: 585–592. 4. Cavo M, Rajkumar SV, Palumbo A et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 2011; 117: 6063–6073. 5. Facon T, Mary JY, Hulin C et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial. Lancet 2007; 370: 1209–1218. 6. Palumbo A, Triolo S, Argentino C et al. Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood 1999; 94: 1248–1253. 7. Palumbo A, Gay F, Falco P et al. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol 2010; 28: 800–807. 8. Durie BG, Kyle RA, Belch A et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003; 4: 379–398. 9. Greipp PR, San Miguel J, Durie BG et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420. 10. Neben K, Lokhorst HM, Jauch A et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 2012; 119: 940–948. 11. Durie BG, Harousseau JL, Miguel JS et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473. 12. Sonneveld P, Schmidt-Wolf IG, van der Holt B et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed. J Clin Oncol 2012; 30: 2946–2955. 13. Neben K, Jauch A, Bertsch U et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica 2010; 95: 1150–1157. 14. Badros A, Barlogie B, Siegel E et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol 2001; 114: 600–607. 15. Sirohi B, Powles R, Treleaven J et al. The role of autologous transplantation in patients with multiple myeloma aged 65 years and over. Bone Marrow Transplant 2000; 25: 533–539. 16. Siegel DS, Desikan KR, Mehta J et al. Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 1999; 93: 51–54. 17. Jantunen E, Kuittinen T, Penttila K et al. High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>or=65 years) myeloma patients: comparison with younger patients treated on the same protocol. Bone Marrow Transplant 2006; 37: 917–922. 18. Qazilbash MH, Saliba RM, Hosing C et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplant 2007; 39: 279–283. 19. Ludwig H, Durie BG, McCarthy P et al. IMWG Consensus on maintenance therapy in multiple myeloma. Blood 2012; 119: 3003–3015.
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especially t(4;14), with increasing age [21]. This is partially in line with our data since no patient >70 years had t(4;14). However, high-risk cytogenetics were more prevalent in patients >70 years in our study. This might be explained by the fact that we also classified gain1q21 as high-risk aberration based on previously published results [10]. Our data reveal that risk assessment according to ISS and cytogenetic evaluation is also highly relevant for elderly patients eligible for HDT. We furthermore demonstrate that combining ISS and cytogenetic risk stratification identifies three subgroups of elderly patients with a different prognosis after HDT. This is in line with previous results from a large prospective trial including younger patients with newly diagnosed MM [10]. The combined information about cytogenetics and ISS was superior, especially to predict EFS compared with ISS staging only. The reason for this finding might be that the ISS was initially evaluated to predict OS and not EFS [9]. We therefore conclude that risk assessment according to ISS and cytogenetic analysis should be carried out routinely in elderly patients eligible for ASCT. Especially since previous studies indicated that the effect of maintenance after HDT is influenced by the detected cytogenetic aberrations [10]. Evaluating our data, it has to be taken into account that especially the oldest group of patients analyzed in the current study is highly selected by the treating physicians. This selection was rather based on previous experiences of our center than a structured assessment of comorbidities. A recent retrospective analysis of over 1400 patients from four randomized trials proposed to take into account not only the age but also comorbidities of the elderly patients [22]. Because of the retrospective character of our study, we were not able to systematically assess comorbidities. However, we support the proposed structured analysis especially in this more vulnerable cohort of patients in future trials. Another limitation of the current study is the small number of patients between 70 and 75 years. Especially in this population, prospective clinical trials are needed to compare sequential treatment of novel agents and HDT with established regimens like MPT and VMP. In summary, we demonstrate with the current analysis that HDT with MEL200 is safe in selected elderly patients with newly diagnosed MM. The application of novel agents as induction/maintenance therapy improves response as well as outcome and should be implemented into the HDT concept in elderly patients. ISS and cytogenetic aberrations should be used for risk stratification of elderly.
Annals of Oncology
original articles
Annals of Oncology 20. Blade J, Rosinol L, Cibeira MT. Prognostic factors for multiple myeloma in the era of novel agents. Ann Oncol 2008; 19 (Suppl 7): vii117–vii120. 21. Avet-Loiseau H, Hulin C, Campion L et al. Chromosomal abnormalities are major prognostic factors in elderly patients with. J Clin Oncol 2013; 31: 2806–2809.
22. Bringhen S, Mateos MV, Zweegman S et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica 2013; 98: 980–987.
Annals of Oncology 25: 195–200, 2014 doi:10.1093/annonc/mdt483
M. A. Dimopoulos*, S. Delimpasi, E. Katodritou, A. Vassou, M. C. Kyrtsonis, P. Repousis, Z. Kartasis, A. Parcharidou, M. Michael, E. Michalis, D. Gika, A. Symeonidis, A. Pouli, K. Konstantopoulos, E. Terpos & E. Kastritis Greek Myeloma Study Group, Athens, Greece
Received 7 July 2013; revised 19 September 2013; accepted 25 September 2013
Background: Renal impairment (RI) is a common presenting complication of multiple myeloma (MM); the availability of new treatments has improved the outcomes of patients with MM; however, their impact on the survival of patients who present with RI has not been extensively studied. Patients and methods: We analyzed the characteristics and outcomes of 1773 consecutive unselected patients who were treated for symptomatic myeloma since January 1990. Results: Although there was a significant increase in the proportion of patients of advanced age in the more recent periods, the frequency of RI as well as the proportion of patients who presented with severe RI (eGFR < 30 ml/min/1.73 m2) remained unchanged around 18%. Thus, after adjustment for age, there was a decrease in the risk of severe RI at presentation after 2000. Myeloma response rates (≥PR) to frontline therapy have substantially increased, and this was translated in a significant increase in the median survival. Specifically for patients with severe RI, the median OS has improved from 18 and 19.5 months in the 1990–1994 and 1995–1999 to 29 and 32 months for the periods 2000–2004 and after 2005 (P = 0.005). Severe RI was associated with a high risk of early death (12% versus 7% for patients with moderate RI versus 3% for patients with mild or no RI (P < 0.001), especially among older patients, and has remained unchanged over time. Conclusions: There has been a major improvement in the survival of patients with severe RI in the past decade, despite the increasing numbers of patients of advanced age. However, the risk of early death remains high in patients with severe RI, especially in the elderly. Key words: renal impairment, bortezomib, elderly, lenalidomide, thalidomide
introduction Renal impairment (RI) is a common presenting complication of multiple myeloma (MM): 20%–40% of newly diagnosed patients with MM present with at least moderate RI [1, 2]. Renal dysfunction is associated with an increased risk of treatment-related toxicity and early death [3], and the management of such
*Correspondence to: Prof Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, University of Athens School of Medicine, 80 Vas. Sofias Ave 115 28, Athens Greece. Tel: +30 210 3381541; Fax: +30 213 216 2511; E-mail: mdimop@med. uoa.gr
patients is challenging [4]. Vigorous supportive measures and the immediate institution of antimyeloma therapy are the mainstays of therapy for patients with MM and RI [5]. The availability of novel drugs has resulted in higher rates of responses and more effective salvage regimens and as a consequence, there has been an improvement in the survival of myeloma patients [6, 7]. Novel drug combinations are associated with higher rates of renal recovery [8–10]; however, the impact of these therapies on the survival of MM patients who present with RI in the era of novel therapies has not been extensively studied. In addition to the introduction of novel drugs in the clinic, there is also a change in the demographics of patients with
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents
Annals of Oncology
Annals of Oncology 25: 189–195, 2014 doi:10.1093/annonc/mdt509
Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents M. Merz1,2, K. Neben1, M. S. Raab1,3, S. Sauer1, G. Egerer1, M. Hundemer1, D. Hose1, C. Kunz4, C. Heiß1, A. D. Ho1, H. Goldschmidt1,5 & J. Hillengass1,2*
Received 21 June 2013; revised 25 September 2013; accepted 26 September 2013
Background: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients 65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. Patients and methods: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60–64, 65–69 and 70–75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. Results: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60–64 years: 27 months; 65–69 years: 23 months; 70–75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. Conclusion: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment. Key words: multiple myeloma, elderly, high-dose therapy, autologous stem cell transplantation, novel agents, maintenance therapy
introduction High-dose therapy (HDT) with melphalan 200 mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) in combination with novel agents (thalidomide, lenalidomide and bortezomib) is considered the standard of care for patients with newly diagnosed multiple myeloma (MM) younger than 65 years [1, 2]. MM is a disease of the elderly with a median age at diagnosis of 70 years [3]. Therefore, a large proportion of patients are considered ineligible for HDT because of increased treatment related *Correspondence to: Dr Jens Hillengass, Department of Medicine V, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Tel: +49-622156-39397; Fax: +49-6221-56-4171; E-mail: [email protected]
toxicity and mortality of MEL200 and the lack of results from randomized phase III trials with MEL-200 in elderly patients [4]. Previous studies have shown that HDT with intermediate dose (100 mg/m2) melphalan (MEL100) is feasible for elderly myeloma patients up to 75 years of age [5, 6]. The benefit of HDT in these patients compared with the current standard of novel agents with or without chemotherapy is uncertain as in most studies HDT was not supported by the use of novel agents during induction therapy and no maintenance therapy was administered. Furthermore, Palumbo et al. demonstrated that MEL100 is inferior to MEL200 regarding depth of remission and time to progression in younger patients with MM [7]. As a consequence, rates of complete remission (CR) in MEL100 trials were low and
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on March 9, 2015
1 Department of Medicine V, University Hospital of Heidelberg, Heidelberg; 2Department of Radiology; 3Experimental Therapies for Hematologic Malignancies; 4Division of Biostatistics, German Cancer Research Centre, Heidelberg; 5National Centre for Tumor Disease, Heidelberg, Germany
original articles only one prospective trial showed that MEL100 is superior to conventional chemotherapy with melphalan and prednisone (MP) [6]. Furthermore, the Intergroupe Francophone du Myélome (IFM) showed in a phase III trial that the addition of thalidomide to melphalan/prednisone (MPT) was superior to MEL100 in patients between 65 and 75 years [5]. However, there is still a lack of information about feasibility and outcome of HDT with MEL200 in combination with novel agents in elderly patients. In the current study, we, therefore, retrospectively evaluated the treatment-related toxicity and mortality of elderly MM patients treated with MEL200 followed by ASCT. Additionally, the impact of integrating novel agents into the HDT regimen on remission and outcome was investigated.
Annals of Oncology physicians in a weekly interdisciplinary transplantation conference. Patients were considered eligible for HDT when showing no signs of severe comorbidity requiring acute medical intervention. For application of HDT and surveillance during neutropenia, all patients were admitted to our transplant unit. HDT consisted of melphalan (total dose 200 mg/m2) divided and administered separately on days -3 and -2 before ASCT. In seven patients (4%), a single application of 100 mg/m2 melphalan was used due to renal function impairment (creatinine clearance 70 years can be reduced to 2% by dose reduction, recent retrospective studies showed that HDT with MEL200 is also feasible for selected elderly patients with
Volume 25 | No. 1 | January 2014
Downloaded from http://annonc.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on March 9, 2015
0
EFS (%)
60–64 vs. 65–69 P = .198 65–69 vs. 70–75 P = .328 70–75 vs. 60–64 P = .980
original articles
Annals of Oncology
Table 2. Summary of results from uni- and multivariate Cox PH regression analyses of event-free and overall survival
Univariate HR
P-value
Overall survival Multivariate HR P-value
Univariate HR
P-value
1.0 1.0 0.8
0.918 0.521
1.0 1.2 1.4
0.391 0.219
1.0 1.3 0.7
0.532 0.626
1.0 1.6 0.9
0.204 0.888
1.0 1.5 1.7
– 0.127 0.044
1.0 1.7 2.0
0.022 0.002
1.0 1.5 3.7
0.948 0.001
1.0 2.4 4.2
0.052 0.001
1.0 4.0
0.000
1.0 2.6
0.001
1.0 5.5
0.001
1.0 3.5
0.005
1.0 1.6 1.5
0.288 0.392
1.0 1.6 1.3
0.115 0.387
1.0 1.1 1.7
0.791 0.644
1.0 2.5 3.2
0.210 0.136
1.0 0.5
0.050
1.0 0.5
0.003
1.0 1.1
0.917
1.0 0.5
0.149
1.0 2.5 2.4
0.002 0.058
1.0 2.1 2.1
0.001 0.043
1.0 4.3 7.0
0.570 0.610
1.0 3.7 4.6
0.016 0.045
1.0 0.4 0.5
0.006 0.005
1.0 0.7 0.6
0.119 0.013
1.0 0.8 0.5
0.750 0.213
1.0 1.3 0.6
0.599 0.186
HR, hazard ratio; Bold/italic values = significant values.
MM [15–18]. In our retrospective analysis, we also found no significant differences among three different age groups (60–64, 65–69 and 70–75 years) regarding engraftment after ASCT, need for supportive care and TRM. Remarkably, no patient between 70 and 75 years died because of early complications due to HDT. Furthermore, uni- and multivariate analyses demonstrated that age had no influence on EFS and OS after HDT and response rates and rates of CR were not different in the different age groups. The major downside of the currently available studies on HDT in elderly myeloma patients—either with MEL100 or MEL200—is the fact that most studies were carried out before the introduction of novel agents and the incorporation of maintenance therapy in the HDT concept. This might explain the relatively low nCR + CR rates reported in the prospective trials of MEL100 from Italy (25% [6]) and France (18% [5]) and the inferiority of MEL100 treatment without new drugs compared with MPT shown in the IFM study. Correspondingly, Palumbo et al. demonstrated in a prospective trial of 102 patients between 65 and 75 years that CR rates after HDT substantially improved when MEL100 was combined with a bortezomib-based induction therapy up to 38% [7]. This is in agreement with our results of nCR + CR rates after HDT of 43% in the group receiving
Volume 25 | No. 1 | January 2014
novel agents during induction therapy compared with 20% in patients treated without novel agents. The interpretation of this finding is limited by the fact that novel agents during induction therapy were not equally distributed in our cohort and only 37% of all patients were treated without novel agents. In the study by Palumbo et al., CR rates increased to 66% by adding a lenalidomide consolidation and maintenance therapy [7]. The role of maintenance therapy after ASCT in younger myeloma patients has been discussed extensively in the last years [19]. With our present study, we demonstrate that maintenance therapy with a novel agent or interferon also improves EFS of elderly patients eligible for HDT. However, due to the small number of patients treated with interferon (12%), we are not able to draw general conclusions and, given the common side-effects, especially in elderly patients and the positive effect only in this small group of patients, we do not recommend the routine use of interferon. In younger patients eligible for HDT, risk stratification based on the ISS and cytogenetic aberrations as detected by FISH is widely accepted [20]. A recent study by the IFM demonstrated the prognostic significance of t(4;14) and del17p in elderly patients treated with MP-based regimens. Interestingly, they showed a decreased prevalence of high-risk aberrations,
doi:10.1093/annonc/mdt509 |
Downloaded from http://annonc.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on March 9, 2015
Age 60–64 65–69 70–75 ISS I II III Cytogenetic Low-risk High-risk Remission before HDT nCR + CR PR - VGPR SD or PD Tandem ASCT No Yes Remission after HDT nCR + CR PR - VGPR SD or PD Maintenance therapy No Interferon-α Novel agent
Event-free survival Multivariate HR P-value
original articles
acknowledgements We thank Katrin Heimlich, Maria Dörner and Hildegard Bethäuser for technical assistance in the enrichment of CD138positive plasma cells and Michaela Brough, Stephanie Pschowski-Zuck and Desiree Kirn for performing interphase fluorescence in situ hybridization analysis.
funding This work was supported by a grant from the Dietmar Hopp Foundation (DHS05/2006), Heidelberg, Germany.
| Merz et al.
disclosure HG and KN received honoraria and research funding and acted as advisors for Celgene and Janssen-Cilag. All remaining authors declared no conflict of interest.
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Volume 25 | No. 1 | January 2014
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especially t(4;14), with increasing age [21]. This is partially in line with our data since no patient >70 years had t(4;14). However, high-risk cytogenetics were more prevalent in patients >70 years in our study. This might be explained by the fact that we also classified gain1q21 as high-risk aberration based on previously published results [10]. Our data reveal that risk assessment according to ISS and cytogenetic evaluation is also highly relevant for elderly patients eligible for HDT. We furthermore demonstrate that combining ISS and cytogenetic risk stratification identifies three subgroups of elderly patients with a different prognosis after HDT. This is in line with previous results from a large prospective trial including younger patients with newly diagnosed MM [10]. The combined information about cytogenetics and ISS was superior, especially to predict EFS compared with ISS staging only. The reason for this finding might be that the ISS was initially evaluated to predict OS and not EFS [9]. We therefore conclude that risk assessment according to ISS and cytogenetic analysis should be carried out routinely in elderly patients eligible for ASCT. Especially since previous studies indicated that the effect of maintenance after HDT is influenced by the detected cytogenetic aberrations [10]. Evaluating our data, it has to be taken into account that especially the oldest group of patients analyzed in the current study is highly selected by the treating physicians. This selection was rather based on previous experiences of our center than a structured assessment of comorbidities. A recent retrospective analysis of over 1400 patients from four randomized trials proposed to take into account not only the age but also comorbidities of the elderly patients [22]. Because of the retrospective character of our study, we were not able to systematically assess comorbidities. However, we support the proposed structured analysis especially in this more vulnerable cohort of patients in future trials. Another limitation of the current study is the small number of patients between 70 and 75 years. Especially in this population, prospective clinical trials are needed to compare sequential treatment of novel agents and HDT with established regimens like MPT and VMP. In summary, we demonstrate with the current analysis that HDT with MEL200 is safe in selected elderly patients with newly diagnosed MM. The application of novel agents as induction/maintenance therapy improves response as well as outcome and should be implemented into the HDT concept in elderly patients. ISS and cytogenetic aberrations should be used for risk stratification of elderly.
Annals of Oncology
original articles
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22. Bringhen S, Mateos MV, Zweegman S et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica 2013; 98: 980–987.
Annals of Oncology 25: 195–200, 2014 doi:10.1093/annonc/mdt483
M. A. Dimopoulos*, S. Delimpasi, E. Katodritou, A. Vassou, M. C. Kyrtsonis, P. Repousis, Z. Kartasis, A. Parcharidou, M. Michael, E. Michalis, D. Gika, A. Symeonidis, A. Pouli, K. Konstantopoulos, E. Terpos & E. Kastritis Greek Myeloma Study Group, Athens, Greece
Received 7 July 2013; revised 19 September 2013; accepted 25 September 2013
Background: Renal impairment (RI) is a common presenting complication of multiple myeloma (MM); the availability of new treatments has improved the outcomes of patients with MM; however, their impact on the survival of patients who present with RI has not been extensively studied. Patients and methods: We analyzed the characteristics and outcomes of 1773 consecutive unselected patients who were treated for symptomatic myeloma since January 1990. Results: Although there was a significant increase in the proportion of patients of advanced age in the more recent periods, the frequency of RI as well as the proportion of patients who presented with severe RI (eGFR < 30 ml/min/1.73 m2) remained unchanged around 18%. Thus, after adjustment for age, there was a decrease in the risk of severe RI at presentation after 2000. Myeloma response rates (≥PR) to frontline therapy have substantially increased, and this was translated in a significant increase in the median survival. Specifically for patients with severe RI, the median OS has improved from 18 and 19.5 months in the 1990–1994 and 1995–1999 to 29 and 32 months for the periods 2000–2004 and after 2005 (P = 0.005). Severe RI was associated with a high risk of early death (12% versus 7% for patients with moderate RI versus 3% for patients with mild or no RI (P < 0.001), especially among older patients, and has remained unchanged over time. Conclusions: There has been a major improvement in the survival of patients with severe RI in the past decade, despite the increasing numbers of patients of advanced age. However, the risk of early death remains high in patients with severe RI, especially in the elderly. Key words: renal impairment, bortezomib, elderly, lenalidomide, thalidomide
introduction Renal impairment (RI) is a common presenting complication of multiple myeloma (MM): 20%–40% of newly diagnosed patients with MM present with at least moderate RI [1, 2]. Renal dysfunction is associated with an increased risk of treatment-related toxicity and early death [3], and the management of such
*Correspondence to: Prof Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, University of Athens School of Medicine, 80 Vas. Sofias Ave 115 28, Athens Greece. Tel: +30 210 3381541; Fax: +30 213 216 2511; E-mail: mdimop@med. uoa.gr
patients is challenging [4]. Vigorous supportive measures and the immediate institution of antimyeloma therapy are the mainstays of therapy for patients with MM and RI [5]. The availability of novel drugs has resulted in higher rates of responses and more effective salvage regimens and as a consequence, there has been an improvement in the survival of myeloma patients [6, 7]. Novel drug combinations are associated with higher rates of renal recovery [8–10]; however, the impact of these therapies on the survival of MM patients who present with RI in the era of novel therapies has not been extensively studied. In addition to the introduction of novel drugs in the clinic, there is also a change in the demographics of patients with
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Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents
