- Email: [email protected]
Treatment for elderly patients with multiple myeloma
Treatment for elderly patients with multiple myeloma
regimens as part of frontline therapy in myeloma is unclear. I declare that I have no conflict of interest.
Jayesh Mehta
The IFM 99-06 study (Oct 6, p 1209) showed that the combination of melphalan, prednisone, and thalidomide (MPT) was better than melphalan-prednisone (MP) and two cycles of intermediate-dose melphalan with stem-cell transplantation (MEL100) in myeloma, with higher response rates and survival. Although it confirms the beneficial effects of thalidomide-containing regimens in myeloma, the study raises concerns. The most obvious flaw in the study is lack of universal access to thalidomide for patients relapsing in the non-thalidomide groups. The extraordinary activity of thalidomide in advanced myeloma2 and its beneficial effect on the survival of relapsing patients3 suggest that not giving it to half the patients relapsing in the nonthalidomide groups might have been the sole factor responsible for the survival differences seen. Outcomes of transplantation studies are skewed as a result of high treatmentrelated mortality when inexperienced centres treat patients.4 Although small centres were supposed to refer patients to larger institutions for transplantation in this study, did this always happen? Significant imbalances in favour of the MPT group (compared with MEL100) to which no attention was drawn are as follows: lower albumin (p=0·012), higher C-reactive protein (p=0·099), and higher calcium (p=0·023). These and other factors on which no data have been provided, such as haemoglobin concentrations, leucocyte counts, marrow plasmacytosis, and platelet counts, could have contributed to the outcome differences recorded. Thalidomide has altered the treatment of myeloma substantially. However, until the questions raised above are answered satisfactorily, whether this study has proven the superiority of thalidomide-containing 1
www.thelancet.com Vol 371 March 22, 2008
[email protected] Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA 1
2
3
4
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: 1209–18. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71. Barlogie B, Tricot GJ, van Rhee F, et al. Longterm outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135: 158–64. Mehta J. Amyloidosis: graviores morbos, asperis remedii. Blood 2007; 110: 3409–91.
In Thierry Facon and colleagues’ trial of treatments for elderly patients with multiple myeloma,1 there was no significant difference in survival after progression between patients given melphalan and prednisone plus thalidomide (MPT) and those given melphalan and prednisone (MP), although the genetic causes of the disease were different between 83 patients who relapsed after MPT and 154 patients who relapsed after MP. Additionally, alkylating-agent-based regimens and bortezomib were more frequently used as rescue treatment in patients who relapsed after MPT than in those who relapsed after MP. These biases might be associated with overestimation of the effect of thalidomide on overall survival in patients given MPT. We declare that we have no conflict of interest.
*Masaharu Tsubokura, Masahiro Kami
I feel that the multiple myeloma patients enrolled in the IFM 99-06 trial1 were not representative of the overall elderly myeloma population. The trial was aimed at patients aged 65–75 years, but Thierry Facon and colleagues actually excluded from trial enrolment patients with very common myeloma symptoms or comorbidities whose prevalence increases in the agegroup studied. For example, the investigators excluded patients with light-chain amyloidosis, which affects 12–30% of myeloma patients.2 Similarly, they excluded patients with peripheral neuropathy: symptomatic peripheral neuropathy affects 13% of patients,3 and a subclinical neuropathy can be detected in 40–60% of patients on the basis of electrodiagnostic or histopathological studies.4 Cardiac dysfunction was not defined, but is likely to be prevalent after age 65 years. Further, I believe there is no reason to exclude these cohorts from trials since they could benefit from any of the treatments in the trial: even reduced-intensity autologous stemcell transplantation, the most toxic treatment in the trial, has been shown to be feasible in myeloma patients on haemodialysis.5 So I feel that Facon and colleagues did not emphasise the fact that the response to melphalan, prednisone, and thalidomide remains unknown for a large group of elderly myeloma patients with comorbidities.
1
Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reducedintensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial. Lancet 2007; 370: 1209–18.
See Department of Error page 986
I declare that I have no conflict of interest.
Daniele Focosi [email protected] University of Pisa, Ospedale S Chiara, 56126 Pisa, Italy 1
[email protected] Kameda General Hospital, 929 Higashi-cho, Kamogawa, Chiba 296-8602, Japan (MT); and Division of Exploratory Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan (MK)
Science Photo Library
Correspondence
2
3
4
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: 1209–18. Bahlis NJ, Lazarus HM. Multiple myelomaassociated AL amyloidosis: is a distinctive therapeutic approach warranted? Bone Marrow Transplant 2006; 38: 7–15. Walsh JC. The neuropathy of multiple myeloma: an electrophysiological and histological study. Arch Neurol 1971; 25: 404–14. Hesselvik M. Neuropathological studies on myelomatosis. Acta Neurol Scand 1969; 45: 95–108.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
983
regimens as part of frontline therapy in myeloma is unclear. I declare that I have no conflict of interest.
Jayesh Mehta
The IFM 99-06 study (Oct 6, p 1209) showed that the combination of melphalan, prednisone, and thalidomide (MPT) was better than melphalan-prednisone (MP) and two cycles of intermediate-dose melphalan with stem-cell transplantation (MEL100) in myeloma, with higher response rates and survival. Although it confirms the beneficial effects of thalidomide-containing regimens in myeloma, the study raises concerns. The most obvious flaw in the study is lack of universal access to thalidomide for patients relapsing in the non-thalidomide groups. The extraordinary activity of thalidomide in advanced myeloma2 and its beneficial effect on the survival of relapsing patients3 suggest that not giving it to half the patients relapsing in the nonthalidomide groups might have been the sole factor responsible for the survival differences seen. Outcomes of transplantation studies are skewed as a result of high treatmentrelated mortality when inexperienced centres treat patients.4 Although small centres were supposed to refer patients to larger institutions for transplantation in this study, did this always happen? Significant imbalances in favour of the MPT group (compared with MEL100) to which no attention was drawn are as follows: lower albumin (p=0·012), higher C-reactive protein (p=0·099), and higher calcium (p=0·023). These and other factors on which no data have been provided, such as haemoglobin concentrations, leucocyte counts, marrow plasmacytosis, and platelet counts, could have contributed to the outcome differences recorded. Thalidomide has altered the treatment of myeloma substantially. However, until the questions raised above are answered satisfactorily, whether this study has proven the superiority of thalidomide-containing 1
www.thelancet.com Vol 371 March 22, 2008
[email protected] Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA 1
2
3
4
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: 1209–18. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71. Barlogie B, Tricot GJ, van Rhee F, et al. Longterm outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006; 135: 158–64. Mehta J. Amyloidosis: graviores morbos, asperis remedii. Blood 2007; 110: 3409–91.
In Thierry Facon and colleagues’ trial of treatments for elderly patients with multiple myeloma,1 there was no significant difference in survival after progression between patients given melphalan and prednisone plus thalidomide (MPT) and those given melphalan and prednisone (MP), although the genetic causes of the disease were different between 83 patients who relapsed after MPT and 154 patients who relapsed after MP. Additionally, alkylating-agent-based regimens and bortezomib were more frequently used as rescue treatment in patients who relapsed after MPT than in those who relapsed after MP. These biases might be associated with overestimation of the effect of thalidomide on overall survival in patients given MPT. We declare that we have no conflict of interest.
*Masaharu Tsubokura, Masahiro Kami
I feel that the multiple myeloma patients enrolled in the IFM 99-06 trial1 were not representative of the overall elderly myeloma population. The trial was aimed at patients aged 65–75 years, but Thierry Facon and colleagues actually excluded from trial enrolment patients with very common myeloma symptoms or comorbidities whose prevalence increases in the agegroup studied. For example, the investigators excluded patients with light-chain amyloidosis, which affects 12–30% of myeloma patients.2 Similarly, they excluded patients with peripheral neuropathy: symptomatic peripheral neuropathy affects 13% of patients,3 and a subclinical neuropathy can be detected in 40–60% of patients on the basis of electrodiagnostic or histopathological studies.4 Cardiac dysfunction was not defined, but is likely to be prevalent after age 65 years. Further, I believe there is no reason to exclude these cohorts from trials since they could benefit from any of the treatments in the trial: even reduced-intensity autologous stemcell transplantation, the most toxic treatment in the trial, has been shown to be feasible in myeloma patients on haemodialysis.5 So I feel that Facon and colleagues did not emphasise the fact that the response to melphalan, prednisone, and thalidomide remains unknown for a large group of elderly myeloma patients with comorbidities.
1
Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reducedintensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial. Lancet 2007; 370: 1209–18.
See Department of Error page 986
I declare that I have no conflict of interest.
Daniele Focosi [email protected] University of Pisa, Ospedale S Chiara, 56126 Pisa, Italy 1
[email protected] Kameda General Hospital, 929 Higashi-cho, Kamogawa, Chiba 296-8602, Japan (MT); and Division of Exploratory Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan (MK)
Science Photo Library
Correspondence
2
3
4
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: 1209–18. Bahlis NJ, Lazarus HM. Multiple myelomaassociated AL amyloidosis: is a distinctive therapeutic approach warranted? Bone Marrow Transplant 2006; 38: 7–15. Walsh JC. The neuropathy of multiple myeloma: an electrophysiological and histological study. Arch Neurol 1971; 25: 404–14. Hesselvik M. Neuropathological studies on myelomatosis. Acta Neurol Scand 1969; 45: 95–108.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
983