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Case for More Autologous Transplants in Myeloma in Resource-Constrained Settings

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2022; 43(03): 311-313

DOI: DOI: 10.1055/s-0042-1743504

Author : Singh, Suvir; Sharma, Rintu

Abstract

Multiple myeloma is characterized by a near universal risk of relapse. Autologous stem cell transplantation provides a significant progression free survival benefit but is under utilized worldwide. We provide a small snapshot of why ASCT assumes greater importance in resource-constrained settings.

Keywords

hematology - medical oncology - myeloma - transplant

Publication History

Article published online:
28 June 2022

© 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

Abstract

Multiple myeloma is characterized by a near universal risk of relapse. Autologous stem cell transplantation provides a significant progression free survival benefit but is under utilized worldwide. We provide a small snapshot of why ASCT assumes greater importance in resource-constrained settings.

Keywords

hematology - medical oncology - myeloma - transplant

Multiple myeloma is a malignant plasma cell disorder that has witnessed a steady improvement in survival over the past two decades. The overall survival (OS) in the past 20 years has nearly doubled due to the progress in supportive care, drug therapy, and the increasing use of autologous stem cell transplantation (ASCT).[1] [2] Although ASCT alone has directly not led to an increase in OS, for all eligible patients, the choice of first-line of treatment includes induction therapy, followed by high-dose melphalan and ASCT.[3]

However, the role of ASCT as first-line therapy has been questioned with advances in drug therapy for myeloma. Novel agents are associated with unprecedented response rates, including very good partial response (VGPR) or better responses in over 70% of patients on bortezomib/lenalidomide-based triplets.[4] Newer agents, including carfilzomib and daratumumab, have enabled minimal residual disease negativity as a viable target in a significant majority of patients, questioning the need for upfront transplantation.[5] [6] [7] [8]

We provide a snapshot of data affirming the utility of ASCT in the current era and highlight how the importance of ASCT is further amplified in resource-constrained settings.

A few randomized trials have compared ASCT with chemotherapy alone for eligible patients. The randomized IFM2009 trial published in 2017 compared lenalidomide–bortezomib–dexamethasone (RVD) alone versus RVD with autoSCT and found significantly better progression-free survival (PFS) and measurable residual disease (MRD) negativity in the autoSCT arm.[9] The phase 3 HO95 study also found an improvement in the 3-year PFS with autoSCT compared with chemotherapy alone.[10] Randomized control trials (RCTs) comparing newer novel agents (daratumumab, carfilzomib, pomalidomide) with ASCT are expected in the near future. Randomized data comparing ASCT with chemotherapy alone has been evaluated by two meta-analyses, both of which included similar studies. The first study from China included four RCTs of ASCT versus novel agents and found a significant improvement in the PFS (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.44 to 0.73) with no significant change in OS.[11] A meta-analysis published in JAMA in 2019 found similar results and concluded that even in the absence of an OS benefit, autoSCT in the first remission should be preferred due to high rates of deeper responses including MRD negativity, low treatment-related mortality (TRM), and PFS benefit.[12] As of now, no treatment option has shown enough benefits to replace ASCT as the standard of care, which must be used for all eligible newly diagnosed patients.[13]

Nevertheless, the utilization of ASCT for myeloma worldwide has been less than ideal but is slowly increasing with time. Data from the USA over 1995 to 2010 indicate the utilization rates of less than 15%, being higher for younger patients.[14] Current data, derived from the SEER database, indicate a slight increase in the utilization rate to ∼30% (8,371 transplants out of 30,000 newly diagnosed patients in 2018). The Worldwide Network for Blood & Marrow Transplantation (WBMT) registry also recorded a 107% increase in worldwide transplant activity for myeloma during this period.[15] Increasing the use of first-line ASCT, even in settings with easy access to newer drugs, indicates ongoing clinical benefits in the eligible patients. Additionally, improving safety and reducing TRM with ASCT for myeloma over the past two decades has allowed easier adoption of this treatment modality. The TRM in most centers in India is less than 5% and typically averages 2 to 3%.[16]

In the absence of direct studies evaluating the utilization of ASCT for myeloma in India, it is easy to realize that very few eligible patients proceed to transplant. However, in resource-constrained settings, proceeding to transplant rather than continuing on newer drugs has several tangible benefits.

Economic concerns and access to newer drugs play a significant role in treatment decisions in low- and middle-income countries (LMICs). Compared with continued administration of newer novel agents, ASCT is more cost-effective in the long run. ASCT has been found to incur a cost of approximately Rs. 334,433 per QALY gained in India, and data from India have demonstrated that it can be made more cost-effective with early initiation of treatment.[18] Bortezomib and lenalidomide are now available as generics and available at a cost of approximately USD 90 and USD 30 for a month of therapy, respectively.

However, the cost of newer agents such as carfilzomib and daratumumab is still formidable. For instance, autoSCT in a public-sector hospital in India has been documented to cost approximately INR 395,527 (USD 6,085), compared with approximately USD 33,000 for 16 doses of daratumumab and USD 9,333 for 6 months of carfilzomib alone (communication with the drug company). The introduction of biosimilars or generic formulations may make newer agents more cost-effective in the future but would need a detailed cost-effectiveness analysis to guide the same.

Therefore, the best option for most patients is an early ASCT, with an aim to stall a relapse for as long as possible. Eliminating a very effective treatment option such as an ASCT is not a viable option for a resource-constrained setting such as India.

Another novel approach includes the use of outpatient transplantation, which now demonstrates results similar to conventional transplants with a careful patient and site selection.[19] Various models of outpatient transplant, including total outpatient, mixed inpatient–outpatient, or delayed admission can be adopted in an attempt to markedly reduce costs by reducing the duration of hospital admission.

ASCT utilization is expected to be lower than Western data in India due to a multitude of reasons including concurrent medical illness, lack of expertise or infrastructure for ASCT at various centers, and financial factors, which can lead to withholding this useful and cost-effective treatment for many patients. Inferring from daily practice, several patients do not undergo this effective treatment due to the fear of complications or after being advised against by family members and primary physicians.

Therefore, it is essential to compile collaborative data illustrating the rates of the utilization of ASCT for myeloma and delineation of underlying reasons for the same so that this efficacious and cost-effective therapy is provided to as many eligible patients as possible.

Conflict of Interest

None declared.

  • References

  1. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol 2007; 25 (15) 1993-1999
  2. Usui Y, Ito H, Koyanagi Y. et al. Changing trend in mortality rate of multiple myeloma after introduction of novel agents: a population-based study. Int J Cancer 2020; 147 (11) 3102-3109
  3. Dimopoulos MA, Moreau P, Terpos E. et al; EHA Guidelines Committee. Electronic address: guidelines@ehaweb.org, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up† . Ann Oncol 2021; 32 (03) 309-322
  4. Moreau P, Touzeau C. Optimizing outcomes for patients with newly diagnosed multiple myeloma eligible for transplantation. Leuk Suppl 2013; 2 (Suppl. 01) S15-S20
  5. Mateos M-V, Cavo M, Blade J. et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet 2020; 395 (10218): 132-141
  6. Kumar S, Jacobus SJ, Cohen AD. et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol 2020; 38 (18) 3
  7. Facon T, Kumar S, Plesner T. et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 2019; 380 (22) 2104-2115
  8. Gay F, Cerrato C, Petrucci MT. et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. J Clin Oncol 2019; 37 (15) 8002-8002
  9. Attal M, Lauwers-Cances V, Hulin C. et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 2017; 376 (14) 1311-1320
  10. Cavo M, Petrucci MT, Di Raimondo F. et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). American Society of Hematology; Washington, DC: 2016
  11. Su B, Zhu X, Jiang Y. et al. A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents. Leuk Lymphoma 2019; 60 (06) 1381-1388
  12. Dhakal B, Szabo A, Chhabra S. et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis. JAMA Oncol 2018; 4 (03) 343-350
  13. Gonsalves WI, Buadi FK, Ailawadhi S. et al. Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. Bone Marrow Transplant 2019; 54 (03) 353-367
  14. Costa LJ, Zhang M-J, Zhong X. et al. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. Biol Blood Marrow Transplant 2013; 19 (11) 1615-1624
  15. Cowan AJ, Baldomero H, Atsuta Y. et al. The global state of hematopoietic stem cell transplantation for multiple myeloma: an analysis of the worldwide network of blood and marrow transplantation (WBMT) database and the Global Burden of Disease Study. Biol Blood Marrow Transplant 2020; 26 (12) 2372-2377
  16. Kulkarni U, Devasia AJ, Korula A. et al. Clinical outcomes in multiple myeloma post-autologous transplantation-a single centre experience. Indian J Hematol Blood Transfus 2019; 35 (02) 215-222
  17. Cowan AJ, Allen C, Barac A. et al. Global burden of multiple myeloma: a systematic analysis for the Global Burden of Disease Study 2016. JAMA Oncol 2018; 4 (09) 1221-1227
  18. Prinja S, Kaur G, Malhotra P. et al. Cost-effectiveness of autologous stem cell treatment as compared to conventional chemotherapy for treatment of multiple myeloma in India. Indian J Hematol Blood Transfus 2017; 33 (01) 31-40
  19. Martino M, Paviglianiti A, Memoli M, Martinelli G, Cerchione C. Multiple myeloma outpatient transplant program in the era of novel agents: state-of-the-art. Front Oncol 2020; 10: 592487

Address for correspondence

Suvir Singh, MD, DM
Department of Clinical Hematology and Bone Marrow Transplantation, Dayanand Medical College and Hospital
Ludhiana, Punjab 141001
India   


Publication History

Article published online:
28 June 2022

© 2022. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

  • References

  1. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol 2007; 25 (15) 1993-1999
  2. Usui Y, Ito H, Koyanagi Y. et al. Changing trend in mortality rate of multiple myeloma after introduction of novel agents: a population-based study. Int J Cancer 2020; 147 (11) 3102-3109
  3. Dimopoulos MA, Moreau P, Terpos E. et al; EHA Guidelines Committee. Electronic address: guidelines@ehaweb.org, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up† . Ann Oncol 2021; 32 (03) 309-322
  4. Moreau P, Touzeau C. Optimizing outcomes for patients with newly diagnosed multiple myeloma eligible for transplantation. Leuk Suppl 2013; 2 (Suppl. 01) S15-S20
  5. Mateos M-V, Cavo M, Blade J. et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet 2020; 395 (10218): 132-141
  6. Kumar S, Jacobus SJ, Cohen AD. et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol 2020; 38 (18) 3
  7. Facon T, Kumar S, Plesner T. et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 2019; 380 (22) 2104-2115
  8. Gay F, Cerrato C, Petrucci MT. et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. J Clin Oncol 2019; 37 (15) 8002-8002
  9. Attal M, Lauwers-Cances V, Hulin C. et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 2017; 376 (14) 1311-1320
  10. Cavo M, Petrucci MT, Di Raimondo F. et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). American Society of Hematology; Washington, DC: 2016
  11. Su B, Zhu X, Jiang Y. et al. A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents. Leuk Lymphoma 2019; 60 (06) 1381-1388
  12. Dhakal B, Szabo A, Chhabra S. et al. Autologous transplantation for newly diagnosed multiple myeloma in the era of novel agent induction: a systematic review and meta-analysis. JAMA Oncol 2018; 4 (03) 343-350
  13. Gonsalves WI, Buadi FK, Ailawadhi S. et al. Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. Bone Marrow Transplant 2019; 54 (03) 353-367
  14. Costa LJ, Zhang M-J, Zhong X. et al. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. Biol Blood Marrow Transplant 2013; 19 (11) 1615-1624
  15. Cowan AJ, Baldomero H, Atsuta Y. et al. The global state of hematopoietic stem cell transplantation for multiple myeloma: an analysis of the worldwide network of blood and marrow transplantation (WBMT) database and the Global Burden of Disease Study. Biol Blood Marrow Transplant 2020; 26 (12) 2372-2377
  16. Kulkarni U, Devasia AJ, Korula A. et al. Clinical outcomes in multiple myeloma post-autologous transplantation-a single centre experience. Indian J Hematol Blood Transfus 2019; 35 (02) 215-222
  17. Cowan AJ, Allen C, Barac A. et al. Global burden of multiple myeloma: a systematic analysis for the Global Burden of Disease Study 2016. JAMA Oncol 2018; 4 (09) 1221-1227
  18. Prinja S, Kaur G, Malhotra P. et al. Cost-effectiveness of autologous stem cell treatment as compared to conventional chemotherapy for treatment of multiple myeloma in India. Indian J Hematol Blood Transfus 2017; 33 (01) 31-40
  19. Martino M, Paviglianiti A, Memoli M, Martinelli G, Cerchione C. Multiple myeloma outpatient transplant program in the era of novel agents: state-of-the-art. Front Oncol 2020; 10: 592487

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