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LAST MONTH’S CLINICAL CHALLENGE

 

A 50-year-old, otherwise healthy man was recently diagnosed with symptomatic Ig G kappa multiple myeloma. On initial evaluation, he had a serum M spike of 6.0 g/dl and beta2 microglobulin of 4.0 mg/L (Stage II by the International Staging System).  Interphase cytogenetics were not performed.  He has achieved a good response, with a serum M spike of 0.5 g/dl after 4 cycles of thalidomide plus dexamethsone.  Therapy was tolerated well with minimal side effects. He has an HLA-identical sibling.  What would you recommend next?


YOUR RESPONSES

 
  • Continued thalidomide and dexamethasone for several cycles beyond CR, then watchful waiting – 8% 

  • A single autologous transplant – 33%

  • A double (tandem) autologous transplant – 5%
  • An autologous transplant followed by a reduced intensity conditioning allogeneic transplant – 46%

  • An allogeneic transplant (myeloablative or reduced intensity conditioning) – 8%

       

 

Commentary Provided by John Koreth, MBBS, DPhil

Dana-Farber Cancer Institute

 

Until recently, treatment recommendations for patients with newly diagnosed chemoresponsive myeloma were straightforward: upfront single autologous transplantation, given randomized controlled trial (RCT) data indicating overall survival (OS) and progression-free survival (PFS) benefit.1  However, a recent meta-analysis of all randomized controlled trials (RCTs) assessing single autologous transplantation compared to non-transplant ‘standard dose therapy’ (SDT), indicates significant PFS benefit but no OS benefit with upfront autotransplantation.2

 

For those choosing SDT, the optimal regimen and treatment duration remain uncertain.  Novel agents (thalidomide, lenalidomide, bortezomib; with dexamethasone) are preferred.3-5  Maintenance novel agent therapy is often continued until disease progression or relapse.  Randomized data, albeit in the context of tandem autologous transplantation, documented PFS and possibly OS benefit with maintenance thalidomide.6, 7

 

Tandem autologous transplantation resulted in better OS and PFS than chemotherapy in one RCT, and additional studies are pending.8  Benefit was greatest for patients with a suboptimal response to the first transplant.  Given this patient’s excellent response to induction therapy, it is unlikely tandem autotransplants would be necessary.

 

Up-front allogeneic transplantation offers a curative option for myeloma, but a risk of graft versus host disease (GVHD) and increased treatment related mortality (TRM), particularly with myeloablative conditioning, although outcomes have improved.9  Reduced intensity conditioning (RIC) is associated with lower TRM, comparable GVHD, but higher relapse rates.10,11  Upfront allotransplantation may be considered in the context of a clinical trial.

 

Results of upfront autologous transplantation with sequential RIC allotransplantation have varied, partly for technical reasons.  A study of ‘high risk’ myeloma (elevated b2 microglobulin, chromosome 13 deletion) adding antithymocyte globulin to RIC allotransplantation documented low GVHD rates, but no survival benefit compared to tandem autotransplantation.12  Another RCT utilizing 2Gy irradiation conditioning described OS and PFS benefit with sequential RIC allotransplantation, with 36% PFS at 38 months.13  Additional RCTs are ongoing, but I would not recommend this approach outside of a clinical trial.

 

Currently, I would recommend upfront single autologous transplantation for this patient in an effort to extend PFS.  Continuing standard dose therapy is also reasonable, albeit with uncertainty regarding optimal regimen and duration.

 

1.   Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348(19):1875-83.

2.   Koreth J, Cutler CS, Djulbegovic B, et al. High-dose Therapy with Single Autologous Transplantation versus Chemotherapy for Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Biol Blood Marrow Transplant 2007;13(2):183-96.

3.   Richardson P, Anderson K. Thalidomide and dexamethasone: a new standard of care for initial therapy in multiple myeloma. J Clin Oncol 2006;24(3):334-6.

4.   Richardson PG, Schlossman R, Mitsiades C, Hideshima T, Munshi N, Anderson K. Emerging trends in the clinical use of bortezomib in multiple myeloma. Clin Lymphoma Myeloma 2005;6(2):84-8.

5.   Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106(13):4050-3.

6.   Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006;108(10):3289-94.

7.   Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354(10):1021-30.

8.   Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349(26):2495-502.

9.   Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983--93 and 1994--8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001;113(1):209-16.

10.  Koreth J, Schlossman R, Anderson K. Stem Cell Transplantation in Multiple Myeloma. In: Soiffer R, ed. Stem Cell Transplantation for Hematologic Malignancies. 2 ed. Totowa, New Jersey: Humana Press; 2007:in press.

11.  Crawley C, Iacobelli S, Bjorkstrand B, Apperley JF, Niederwieser D, Gahrton G. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007;109(8):3588-94.

12.  Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006;107(9):3474-80.

13.  Bruno B, Rotta M, Patriarca F, al. E. A comparison of allografting with autografting for newly diagnosed myeloma. New Engl J Med 2007;356:1110-20.