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Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

In New Zealand, around 400 new cases of multiple myeloma (MM) are reported each year. This equates to an age standardised incidence rate of 5.19 cases per 100,000 population, which is similar to other western countries and is increasing with time. The incidence is higher in Māori and Pacific Islanders.1 The MM treatment landscape has rapidly evolved over the last two decades, with increasing number of novel agents and immunotherapies available. These agents are effective and usually well tolerated. They have led to a significant improvement in outcome in MM patients.1,2 PHARMAC, the pharmaceutical management agency in New Zealand, has recently made changes to funding for anti-myeloma therapy, which included unrestricted access to bortezomib and lenalidomide maintenance therapy. The New Zealand Myeloma Interest Group has taken this opportunity to review and update the national treatment pathway accordingly. These recommendations aim to unify upfront therapy for transplant-eligible MM patients in New Zealand and form the basis of ensuring equity and consistency of MM care in New Zealand. This goal is in line with national Cancer Action Plan, as published by the New Zealand Cancer Control Agency.3 However, these recommendations are for guidance only, and final patient treatment decisions should be made at clinicians’ discretion, taking into consideration all patient factors.

Method

The New Zealand Myeloma Interest Group is comprised of representative haematologists from District Health Boards around the country with a special interest and expertise in MM. We reviewed the currently available evidence, including randomised controlled trials, retrospective data and conference abstracts, and interpreted these in the context of treatment options available in New Zealand to form a recommendation that is best suited for our population.

Induction chemotherapy

The funded front-line option for induction chemotherapy remains bortezomib-based treatment for transplant-eligible patients. The preferred regimen is to combine bortezomib with an alkylating agent such as cyclophosphamide and dexamethasone. In younger patients or those with suboptimal response, defined as less than a very good partial response by International Myeloma Working Group (IMWG) criteria, changing to bortezomib–thalidomide–dexamethasone (VTD) regimen (Table 1) prior to autologous stem cell transplant (ASCT) can be considered. VTD has been shown to improve responses in the upfront setting compared to bortezomib–cyclophosphamide–dexamethasone combination; however, whether this translates to survival outcome is unknown.4 The decision will need to be balanced against the increased risk of neurological toxicity with the VTD regimen, as reported in the IFM2013-04 study,4 although this trial used twice-weekly bortezomib instead of the weekly regimen used in New Zealand. The optimal number of induction cycles has not been clearly defined by current evidence but, based on international practice, a minimum of four cycles is recommended.5,6

The group recognises that the more effective regimen of lenalidomide–bortezomib–dexamethasone is currently recommended in many countries as upfront induction chemotherapy, based on its improved response and outcome.7 However, this regimen is not currently available as induction, as lenalidomide is not funded for front-line induction treatment in New Zealand.

High-dose therapy and autologous stem cell transplant

High-dose therapy with autologous stem cell transplant remains an integral part of front-line therapy in newly diagnosed MM, even in the era of novel agents. ASCT has been shown to significantly improve the depth of response and progression-free survival (PFS) but not overall survival (OS).8,9 This may be partly due to the short follow-up in trials and the availability of effective salvage agents. Based on the improved PFS, it is recommended that eligible patients should be considered for front-line ASCT rather than delaying to relapse. This recommendation is further supported by the result of IFM2009 trial, which showed 21% patients were unable to receive ASCT at relapse due to disease refractoriness.8

Until recently, the role of tandem ASCT has been unclear, and published data have shown conflicting results. However, recently, two large randomised controlled trials, the EMN02 trial and updated result from STaMINA trial (on as-treated analysis), have shown improvements in PFS for patients treated with tandem ASCT over single ASCT in patients with high-risk cytogenetic abnormalities.9,10 However, in the EMN02 trial this difference did not reach statistical significance. The definitions of high-risk disease were different between these two trials and the number of patients with high-risk cytogenetic was small. The subgroup analysis showed the PFS improvement to be significant in those with 17p deletion (del17p) in the EMN02 study, while the benefit in other high-risk groups have yet to be published.9 There does not appear to be an OS difference between tandem or single ASCT.9,10 Based on these results, the group is recommending tandem transplant for patients with del17p by fluorescence in situ hybridisation (FISH). Tandem ASCT is currently not uniformly recommended for other high-risk patients based on clinical or genetic factors, due to a lack of strong evidence supporting this approach and potentially increased toxicities. However, this should be reviewed on an individual patient basis.

Most international guidelines are moving away from using chronological age to determine transplant eligibility. Instead, assessment should be based on biological age, performance status and coexisting comorbidities. Multiple retrospective studies have shown the feasibility of ASCT in elderly patients to achieve equivalent survival outcomes compared to younger patients.11,12 Although toxicity during ASCT appears to be increased in the older transplant patients, including length of hospital stay and infection, transplant related mortality is reported to be between 1% and 1.5%, which is comparable to the younger population.13,14 The definition of elderly differed between trials but generally used cut off between 65 to 70 years of age. It is worth noting that these evidences are mainly based on large retrospective analyses, and therefore an inherent bias cannot be excluded. Consideration should be given to reduce the conditioning melphalan dose to 140mg/m2 in older or frailer patients, but this should also be balanced against treatment efficacy, as the reduced dose may compromise outcomes in patients with suboptimal response prior to ASCT.11,15 Assessment using tools like the haematopoietic stem cell comorbidities index has been shown to correlate with survival outcome and may aid in patient selection and decisions on conditioning intensity.16

Post-transplant consolidation therapy

In New Zealand, bortezomib-based consolidation has been given to patients, as maintenance therapy was not available and bortezomib was funded for up to nine cycles in the front-line setting. Recently, lenalidomide maintenance has become available, prompting a review of the need for consolidation therapy.

When conventional chemotherapy was used as induction and maintenance therapy was not given, consolidation with proteasome inhibitor (PI)- or IMiD-based regimens have been shown to deepen responses and improve PFS outcomes, although no consistent OS benefit has been demonstrated.17–19 However, in the era of novel agent-based induction treatment and post-ASCT maintenance, the role of consolidation is less clear. In the STaMINA trial, there was no advantage of RVD consolidation compared to patients who received single ASCT followed immediately by lenalidomide maintenance.20 The EMN02 trial showed consolidation therapy improves PFS in the upfront setting, but the follow-up is too short at this stage to determine if this benefit is maintained in the ASCT cohort.9

As the benefit of consolidation therapy in the post-ASCT setting is unclear at this stage, its routine use is not supported by the group. However, it remains a valid option for patients who have a high-risk disease or suboptimal response. Traditionally, up to four cycles of consolidation were given post ASCT in New Zealand. In more recent international trials, if consolidation therapy is included, two cycles are typically used. Based on these factors, we propose that if consolidation is to be used, it can be given for two to four cycles. One proposed consolidation regimen is the modified RVD regimen (Table 1). Although this modified regimen has not been tested in prospective studies, it has the same bortezomib and lenalidomide dosing schedule as other commonly used anti-MM regimens in New Zealand. The dose of 10mg of lenalidomide was proposed, as this would still fall within the latest PHARMAC Special Authority funding criteria for lenalidomide maintenance. The group will aim to collect data on the use of this consolidation regimen and its impact on patient outcome.

Table 1: Recommended regimens and dosing.

Maintenance therapy

Lenalidomide maintenance has become the standard of care as part of front-line therapy, based on results of multiple trials showing that it deepens responses, which translates to a PFS benefit, although OS benefit is less consistently shown.21–25 The benefit is particularly seen in patients who have not achieved a complete response prior to maintenance; however, patients who are minimal residual disease (MRD) negative also benefited.24,26

Not all trials included baseline cytogenetic results, and therefore the evidence for patients with high-risk cytogenetic abnormalities has been less robust. In a meta-analysis and the Myeloma XI trial, there appears to be PFS benefit for those with high-risk cytogenetic compared to observation.24,25 Based on these results, lenalidomide maintenance should be recommended for all patients post ASCT unless there is a contraindication.

Lenalidomide maintenance therapy can be started up to six months post ASCT, as per the current funding criteria, although in the studies it was generally started around 100 days after the ASCT. Lenalidomide should be continued until disease progression or if patients experience intolerant side effects. Recent data suggest that a shortened length of maintenance compromises outcome.10 There is a small increase in secondary malignancies, but the benefit outweighs this risk.21,24,25

PI-based maintenance strategies have been investigated in clinical trials. In HOVON-65/GMMG-HD4, bortezomib-based maintenance improved outcome particularly for patients with high-risk cytogenetic.27 However, the standard arm used conventional chemotherapy for induction versus bortezomib-based induction, making it difficult to determine whether the improved outcome is solely due to bortezomib maintenance. There is no randomised controlled trial comparing a PI-based with an IMiD-based maintenance strategy. Retrospective single-centre data suggest they may be equally efficacious, especially in high-risk cytogenetic patients.28,29 Based on the currently available data, bortezomib maintenance therapy is not recommended routinely but can be considered for patients who cannot tolerate lenalidomide maintenance and have high-risk diseases. Ixazomib maintenance has been tested as post-transplant maintenance treatment in a prospective study. Although it has shown an improved progression-free survival compared with placebo, the degree of clinical benefit appears to be small.30 Currently, this is not funded in New Zealand.

Conclusion

The treatment landscape of MM changes rapidly as evidence evolves. The increasing number of novel agents available continues to improve outcomes, although the cost is making public funding difficult in many countries. The New Zealand Myeloma Interest Group has formed the above consensus recommendation (Figure 1) based on best available evidence and modified to suit the New Zealand setting.

Figure 1: Treatment pathway for transplant-eligible, newly diagnosed multiple myeloma patients.

*May consider VTD induction for younger patients (<65) or those with a suboptimal response to CyBorD. **Modified RVD maybe considered for patients who have a suboptimal response to ASCT (ie, less than VGPR) or have high-risk clinical features. ***Tandem/double ASCT maybe considered for patients with high-risk FISH cytogenics

Summary

Abstract

Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

Aim

Method

Results

Conclusion

Author Information

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland, New Zealand; Ken Romeril, Myeloma New Zealand, New Zealand. Bart Baker, Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand; Hugh Goodman, Department of Haematology, Waikato Hospital, Hamilton, New Zealand; Henry Chan, Department of Haematology, Waitemata District Health Board, Auckland, New Zealand.

Acknowledgements

Correspondence

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland.

Correspondence Email

chienn@adhb.govt.nz

Competing Interests

Dr Romeril reports grants from Celgene, outside the submitted work. Dr Chan reports grants, personal fees and non-financial support from Janssen, non-financial support from Celgene, personal fees from Abbvie, non-financial support from Amgen, outside the submitted work.

1. Milne, Richard; Boyd, Matt; Chan, Henry; Milne, Barry; Zhang D. The burden of multiple myeloma: A study of the human and economic costs of myeloma in New Zealand. Myeloma New Zealand; 2019.

2. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014 May 25;28(5):1122–8.

3. Ministry of health. New Zealand Cancer Action Plan 2019–2029 – Te Mahere mō te Mate Pukupuku o Aotearoa 2019–2029. Revised January 2020 Wellington: Ministry of Health. 2019.

4. Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569–74.

5. Mikhael J, Ismaila N, Cheung MC, Costello C, Dhodapkar M V., Kumar S, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019 May 10;37(14):1228–63.

6. Gay F, Engelhardt M, Terpos E, Wäsch R, Giaccone L, Auner HW, et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica. 2018 Feb;103(2):197–211.

7. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb;389(10068):519–27.

8. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017 Apr 6;376(14):1311–20.

9. Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456–68.

10. Hari P, Pasquini MC, Stadtmauer EA, Fraser R, Fei M, Devine SM, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol. 2020 May 20;38(15_suppl):8506–8506.

11. Munshi PN, Hari P, Vesole DH, Jurczyszyn A, Zaucha J, Davila O, et al. Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma. Blood. 2019 Nov 13;134 (Supplement_1):782–782.

12. Merz M, Neben K, Raab MS, Sauer S, Egerer G, Hundemer M, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014 Jan;25(1):189–95.

13. Sanchez L, Sylvester M, Parrondo R, Mariotti V, Eloy JA, Chang VT. In-Hospital Mortality and Post-Transplantation Complications in Elderly Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Population-Based Study. Biol Blood Marrow Transplant. 2017 Jul;23(7):1203–7.

14. Stettler J, Novak U, Baerlocher GM, Seipel K, Mansouri Taleghani B, Pabst T. Autologous stem cell transplantation in elderly patients with multiple myeloma: evaluation of its safety and efficacy. Leuk Lymphoma. 2017 May 4;58(5):1076–83.

15. Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, et al. Melphalan 140 mg/m 2 or 200 mg/m 2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018 Mar;103(3):514–21.

16. Saad A, Mahindra A, Zhang M-J, Zhong X, Costa LJ, Dispenzieri A, et al. Hematopoietic Cell Transplant Comorbidity Index Is Predictive of Survival after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Biol Blood Marrow Transplant. 2014 Mar;20(3):402-408.e1.

17. Mellqvist U-H, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647–54.

18. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, et al. Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077–84.

19. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. Consolidation Therapy With Low-Dose Thalidomide and Prednisolone Prolongs the Survival of Multiple Myeloma Patients Undergoing a Single Autologous Stem-Cell Transplantation Procedure. J Clin Oncol. 2009 Apr 10;27(11):1788–93.

20. Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37(7):589–97.

21. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012 May 10;366(19):1770–81.

22. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–91.

23. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Yehuda DB, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905.

24. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol. 2017;35(29):3279–89.

25. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57–73.

26. De Tute R, Cairns D, Rawstron A, Pawlyn C, Davies F, Jones J, et al. Sequential minimal residual disease (MRD) monitoring: Results from the UK Myeloma XI trial. Clin Lymphoma Myeloma Leuk. 2019 Oct;19(10):e45–6.

27. Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, Van Holt B Der, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8.

28. Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, et al. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(2):262–8.

29. Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, et al. Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. Leukemia. 2018 Mar 14;32(3):712–8.

30. Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253–64.

Contact diana@nzma.org.nz
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Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

In New Zealand, around 400 new cases of multiple myeloma (MM) are reported each year. This equates to an age standardised incidence rate of 5.19 cases per 100,000 population, which is similar to other western countries and is increasing with time. The incidence is higher in Māori and Pacific Islanders.1 The MM treatment landscape has rapidly evolved over the last two decades, with increasing number of novel agents and immunotherapies available. These agents are effective and usually well tolerated. They have led to a significant improvement in outcome in MM patients.1,2 PHARMAC, the pharmaceutical management agency in New Zealand, has recently made changes to funding for anti-myeloma therapy, which included unrestricted access to bortezomib and lenalidomide maintenance therapy. The New Zealand Myeloma Interest Group has taken this opportunity to review and update the national treatment pathway accordingly. These recommendations aim to unify upfront therapy for transplant-eligible MM patients in New Zealand and form the basis of ensuring equity and consistency of MM care in New Zealand. This goal is in line with national Cancer Action Plan, as published by the New Zealand Cancer Control Agency.3 However, these recommendations are for guidance only, and final patient treatment decisions should be made at clinicians’ discretion, taking into consideration all patient factors.

Method

The New Zealand Myeloma Interest Group is comprised of representative haematologists from District Health Boards around the country with a special interest and expertise in MM. We reviewed the currently available evidence, including randomised controlled trials, retrospective data and conference abstracts, and interpreted these in the context of treatment options available in New Zealand to form a recommendation that is best suited for our population.

Induction chemotherapy

The funded front-line option for induction chemotherapy remains bortezomib-based treatment for transplant-eligible patients. The preferred regimen is to combine bortezomib with an alkylating agent such as cyclophosphamide and dexamethasone. In younger patients or those with suboptimal response, defined as less than a very good partial response by International Myeloma Working Group (IMWG) criteria, changing to bortezomib–thalidomide–dexamethasone (VTD) regimen (Table 1) prior to autologous stem cell transplant (ASCT) can be considered. VTD has been shown to improve responses in the upfront setting compared to bortezomib–cyclophosphamide–dexamethasone combination; however, whether this translates to survival outcome is unknown.4 The decision will need to be balanced against the increased risk of neurological toxicity with the VTD regimen, as reported in the IFM2013-04 study,4 although this trial used twice-weekly bortezomib instead of the weekly regimen used in New Zealand. The optimal number of induction cycles has not been clearly defined by current evidence but, based on international practice, a minimum of four cycles is recommended.5,6

The group recognises that the more effective regimen of lenalidomide–bortezomib–dexamethasone is currently recommended in many countries as upfront induction chemotherapy, based on its improved response and outcome.7 However, this regimen is not currently available as induction, as lenalidomide is not funded for front-line induction treatment in New Zealand.

High-dose therapy and autologous stem cell transplant

High-dose therapy with autologous stem cell transplant remains an integral part of front-line therapy in newly diagnosed MM, even in the era of novel agents. ASCT has been shown to significantly improve the depth of response and progression-free survival (PFS) but not overall survival (OS).8,9 This may be partly due to the short follow-up in trials and the availability of effective salvage agents. Based on the improved PFS, it is recommended that eligible patients should be considered for front-line ASCT rather than delaying to relapse. This recommendation is further supported by the result of IFM2009 trial, which showed 21% patients were unable to receive ASCT at relapse due to disease refractoriness.8

Until recently, the role of tandem ASCT has been unclear, and published data have shown conflicting results. However, recently, two large randomised controlled trials, the EMN02 trial and updated result from STaMINA trial (on as-treated analysis), have shown improvements in PFS for patients treated with tandem ASCT over single ASCT in patients with high-risk cytogenetic abnormalities.9,10 However, in the EMN02 trial this difference did not reach statistical significance. The definitions of high-risk disease were different between these two trials and the number of patients with high-risk cytogenetic was small. The subgroup analysis showed the PFS improvement to be significant in those with 17p deletion (del17p) in the EMN02 study, while the benefit in other high-risk groups have yet to be published.9 There does not appear to be an OS difference between tandem or single ASCT.9,10 Based on these results, the group is recommending tandem transplant for patients with del17p by fluorescence in situ hybridisation (FISH). Tandem ASCT is currently not uniformly recommended for other high-risk patients based on clinical or genetic factors, due to a lack of strong evidence supporting this approach and potentially increased toxicities. However, this should be reviewed on an individual patient basis.

Most international guidelines are moving away from using chronological age to determine transplant eligibility. Instead, assessment should be based on biological age, performance status and coexisting comorbidities. Multiple retrospective studies have shown the feasibility of ASCT in elderly patients to achieve equivalent survival outcomes compared to younger patients.11,12 Although toxicity during ASCT appears to be increased in the older transplant patients, including length of hospital stay and infection, transplant related mortality is reported to be between 1% and 1.5%, which is comparable to the younger population.13,14 The definition of elderly differed between trials but generally used cut off between 65 to 70 years of age. It is worth noting that these evidences are mainly based on large retrospective analyses, and therefore an inherent bias cannot be excluded. Consideration should be given to reduce the conditioning melphalan dose to 140mg/m2 in older or frailer patients, but this should also be balanced against treatment efficacy, as the reduced dose may compromise outcomes in patients with suboptimal response prior to ASCT.11,15 Assessment using tools like the haematopoietic stem cell comorbidities index has been shown to correlate with survival outcome and may aid in patient selection and decisions on conditioning intensity.16

Post-transplant consolidation therapy

In New Zealand, bortezomib-based consolidation has been given to patients, as maintenance therapy was not available and bortezomib was funded for up to nine cycles in the front-line setting. Recently, lenalidomide maintenance has become available, prompting a review of the need for consolidation therapy.

When conventional chemotherapy was used as induction and maintenance therapy was not given, consolidation with proteasome inhibitor (PI)- or IMiD-based regimens have been shown to deepen responses and improve PFS outcomes, although no consistent OS benefit has been demonstrated.17–19 However, in the era of novel agent-based induction treatment and post-ASCT maintenance, the role of consolidation is less clear. In the STaMINA trial, there was no advantage of RVD consolidation compared to patients who received single ASCT followed immediately by lenalidomide maintenance.20 The EMN02 trial showed consolidation therapy improves PFS in the upfront setting, but the follow-up is too short at this stage to determine if this benefit is maintained in the ASCT cohort.9

As the benefit of consolidation therapy in the post-ASCT setting is unclear at this stage, its routine use is not supported by the group. However, it remains a valid option for patients who have a high-risk disease or suboptimal response. Traditionally, up to four cycles of consolidation were given post ASCT in New Zealand. In more recent international trials, if consolidation therapy is included, two cycles are typically used. Based on these factors, we propose that if consolidation is to be used, it can be given for two to four cycles. One proposed consolidation regimen is the modified RVD regimen (Table 1). Although this modified regimen has not been tested in prospective studies, it has the same bortezomib and lenalidomide dosing schedule as other commonly used anti-MM regimens in New Zealand. The dose of 10mg of lenalidomide was proposed, as this would still fall within the latest PHARMAC Special Authority funding criteria for lenalidomide maintenance. The group will aim to collect data on the use of this consolidation regimen and its impact on patient outcome.

Table 1: Recommended regimens and dosing.

Maintenance therapy

Lenalidomide maintenance has become the standard of care as part of front-line therapy, based on results of multiple trials showing that it deepens responses, which translates to a PFS benefit, although OS benefit is less consistently shown.21–25 The benefit is particularly seen in patients who have not achieved a complete response prior to maintenance; however, patients who are minimal residual disease (MRD) negative also benefited.24,26

Not all trials included baseline cytogenetic results, and therefore the evidence for patients with high-risk cytogenetic abnormalities has been less robust. In a meta-analysis and the Myeloma XI trial, there appears to be PFS benefit for those with high-risk cytogenetic compared to observation.24,25 Based on these results, lenalidomide maintenance should be recommended for all patients post ASCT unless there is a contraindication.

Lenalidomide maintenance therapy can be started up to six months post ASCT, as per the current funding criteria, although in the studies it was generally started around 100 days after the ASCT. Lenalidomide should be continued until disease progression or if patients experience intolerant side effects. Recent data suggest that a shortened length of maintenance compromises outcome.10 There is a small increase in secondary malignancies, but the benefit outweighs this risk.21,24,25

PI-based maintenance strategies have been investigated in clinical trials. In HOVON-65/GMMG-HD4, bortezomib-based maintenance improved outcome particularly for patients with high-risk cytogenetic.27 However, the standard arm used conventional chemotherapy for induction versus bortezomib-based induction, making it difficult to determine whether the improved outcome is solely due to bortezomib maintenance. There is no randomised controlled trial comparing a PI-based with an IMiD-based maintenance strategy. Retrospective single-centre data suggest they may be equally efficacious, especially in high-risk cytogenetic patients.28,29 Based on the currently available data, bortezomib maintenance therapy is not recommended routinely but can be considered for patients who cannot tolerate lenalidomide maintenance and have high-risk diseases. Ixazomib maintenance has been tested as post-transplant maintenance treatment in a prospective study. Although it has shown an improved progression-free survival compared with placebo, the degree of clinical benefit appears to be small.30 Currently, this is not funded in New Zealand.

Conclusion

The treatment landscape of MM changes rapidly as evidence evolves. The increasing number of novel agents available continues to improve outcomes, although the cost is making public funding difficult in many countries. The New Zealand Myeloma Interest Group has formed the above consensus recommendation (Figure 1) based on best available evidence and modified to suit the New Zealand setting.

Figure 1: Treatment pathway for transplant-eligible, newly diagnosed multiple myeloma patients.

*May consider VTD induction for younger patients (<65) or those with a suboptimal response to CyBorD. **Modified RVD maybe considered for patients who have a suboptimal response to ASCT (ie, less than VGPR) or have high-risk clinical features. ***Tandem/double ASCT maybe considered for patients with high-risk FISH cytogenics

Summary

Abstract

Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

Aim

Method

Results

Conclusion

Author Information

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland, New Zealand; Ken Romeril, Myeloma New Zealand, New Zealand. Bart Baker, Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand; Hugh Goodman, Department of Haematology, Waikato Hospital, Hamilton, New Zealand; Henry Chan, Department of Haematology, Waitemata District Health Board, Auckland, New Zealand.

Acknowledgements

Correspondence

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland.

Correspondence Email

chienn@adhb.govt.nz

Competing Interests

Dr Romeril reports grants from Celgene, outside the submitted work. Dr Chan reports grants, personal fees and non-financial support from Janssen, non-financial support from Celgene, personal fees from Abbvie, non-financial support from Amgen, outside the submitted work.

1. Milne, Richard; Boyd, Matt; Chan, Henry; Milne, Barry; Zhang D. The burden of multiple myeloma: A study of the human and economic costs of myeloma in New Zealand. Myeloma New Zealand; 2019.

2. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014 May 25;28(5):1122–8.

3. Ministry of health. New Zealand Cancer Action Plan 2019–2029 – Te Mahere mō te Mate Pukupuku o Aotearoa 2019–2029. Revised January 2020 Wellington: Ministry of Health. 2019.

4. Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569–74.

5. Mikhael J, Ismaila N, Cheung MC, Costello C, Dhodapkar M V., Kumar S, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019 May 10;37(14):1228–63.

6. Gay F, Engelhardt M, Terpos E, Wäsch R, Giaccone L, Auner HW, et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica. 2018 Feb;103(2):197–211.

7. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb;389(10068):519–27.

8. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017 Apr 6;376(14):1311–20.

9. Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456–68.

10. Hari P, Pasquini MC, Stadtmauer EA, Fraser R, Fei M, Devine SM, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol. 2020 May 20;38(15_suppl):8506–8506.

11. Munshi PN, Hari P, Vesole DH, Jurczyszyn A, Zaucha J, Davila O, et al. Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma. Blood. 2019 Nov 13;134 (Supplement_1):782–782.

12. Merz M, Neben K, Raab MS, Sauer S, Egerer G, Hundemer M, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014 Jan;25(1):189–95.

13. Sanchez L, Sylvester M, Parrondo R, Mariotti V, Eloy JA, Chang VT. In-Hospital Mortality and Post-Transplantation Complications in Elderly Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Population-Based Study. Biol Blood Marrow Transplant. 2017 Jul;23(7):1203–7.

14. Stettler J, Novak U, Baerlocher GM, Seipel K, Mansouri Taleghani B, Pabst T. Autologous stem cell transplantation in elderly patients with multiple myeloma: evaluation of its safety and efficacy. Leuk Lymphoma. 2017 May 4;58(5):1076–83.

15. Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, et al. Melphalan 140 mg/m 2 or 200 mg/m 2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018 Mar;103(3):514–21.

16. Saad A, Mahindra A, Zhang M-J, Zhong X, Costa LJ, Dispenzieri A, et al. Hematopoietic Cell Transplant Comorbidity Index Is Predictive of Survival after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Biol Blood Marrow Transplant. 2014 Mar;20(3):402-408.e1.

17. Mellqvist U-H, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647–54.

18. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, et al. Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077–84.

19. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. Consolidation Therapy With Low-Dose Thalidomide and Prednisolone Prolongs the Survival of Multiple Myeloma Patients Undergoing a Single Autologous Stem-Cell Transplantation Procedure. J Clin Oncol. 2009 Apr 10;27(11):1788–93.

20. Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37(7):589–97.

21. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012 May 10;366(19):1770–81.

22. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–91.

23. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Yehuda DB, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905.

24. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol. 2017;35(29):3279–89.

25. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57–73.

26. De Tute R, Cairns D, Rawstron A, Pawlyn C, Davies F, Jones J, et al. Sequential minimal residual disease (MRD) monitoring: Results from the UK Myeloma XI trial. Clin Lymphoma Myeloma Leuk. 2019 Oct;19(10):e45–6.

27. Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, Van Holt B Der, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8.

28. Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, et al. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(2):262–8.

29. Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, et al. Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. Leukemia. 2018 Mar 14;32(3):712–8.

30. Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253–64.

Contact diana@nzma.org.nz
for the PDF of this article

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Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

In New Zealand, around 400 new cases of multiple myeloma (MM) are reported each year. This equates to an age standardised incidence rate of 5.19 cases per 100,000 population, which is similar to other western countries and is increasing with time. The incidence is higher in Māori and Pacific Islanders.1 The MM treatment landscape has rapidly evolved over the last two decades, with increasing number of novel agents and immunotherapies available. These agents are effective and usually well tolerated. They have led to a significant improvement in outcome in MM patients.1,2 PHARMAC, the pharmaceutical management agency in New Zealand, has recently made changes to funding for anti-myeloma therapy, which included unrestricted access to bortezomib and lenalidomide maintenance therapy. The New Zealand Myeloma Interest Group has taken this opportunity to review and update the national treatment pathway accordingly. These recommendations aim to unify upfront therapy for transplant-eligible MM patients in New Zealand and form the basis of ensuring equity and consistency of MM care in New Zealand. This goal is in line with national Cancer Action Plan, as published by the New Zealand Cancer Control Agency.3 However, these recommendations are for guidance only, and final patient treatment decisions should be made at clinicians’ discretion, taking into consideration all patient factors.

Method

The New Zealand Myeloma Interest Group is comprised of representative haematologists from District Health Boards around the country with a special interest and expertise in MM. We reviewed the currently available evidence, including randomised controlled trials, retrospective data and conference abstracts, and interpreted these in the context of treatment options available in New Zealand to form a recommendation that is best suited for our population.

Induction chemotherapy

The funded front-line option for induction chemotherapy remains bortezomib-based treatment for transplant-eligible patients. The preferred regimen is to combine bortezomib with an alkylating agent such as cyclophosphamide and dexamethasone. In younger patients or those with suboptimal response, defined as less than a very good partial response by International Myeloma Working Group (IMWG) criteria, changing to bortezomib–thalidomide–dexamethasone (VTD) regimen (Table 1) prior to autologous stem cell transplant (ASCT) can be considered. VTD has been shown to improve responses in the upfront setting compared to bortezomib–cyclophosphamide–dexamethasone combination; however, whether this translates to survival outcome is unknown.4 The decision will need to be balanced against the increased risk of neurological toxicity with the VTD regimen, as reported in the IFM2013-04 study,4 although this trial used twice-weekly bortezomib instead of the weekly regimen used in New Zealand. The optimal number of induction cycles has not been clearly defined by current evidence but, based on international practice, a minimum of four cycles is recommended.5,6

The group recognises that the more effective regimen of lenalidomide–bortezomib–dexamethasone is currently recommended in many countries as upfront induction chemotherapy, based on its improved response and outcome.7 However, this regimen is not currently available as induction, as lenalidomide is not funded for front-line induction treatment in New Zealand.

High-dose therapy and autologous stem cell transplant

High-dose therapy with autologous stem cell transplant remains an integral part of front-line therapy in newly diagnosed MM, even in the era of novel agents. ASCT has been shown to significantly improve the depth of response and progression-free survival (PFS) but not overall survival (OS).8,9 This may be partly due to the short follow-up in trials and the availability of effective salvage agents. Based on the improved PFS, it is recommended that eligible patients should be considered for front-line ASCT rather than delaying to relapse. This recommendation is further supported by the result of IFM2009 trial, which showed 21% patients were unable to receive ASCT at relapse due to disease refractoriness.8

Until recently, the role of tandem ASCT has been unclear, and published data have shown conflicting results. However, recently, two large randomised controlled trials, the EMN02 trial and updated result from STaMINA trial (on as-treated analysis), have shown improvements in PFS for patients treated with tandem ASCT over single ASCT in patients with high-risk cytogenetic abnormalities.9,10 However, in the EMN02 trial this difference did not reach statistical significance. The definitions of high-risk disease were different between these two trials and the number of patients with high-risk cytogenetic was small. The subgroup analysis showed the PFS improvement to be significant in those with 17p deletion (del17p) in the EMN02 study, while the benefit in other high-risk groups have yet to be published.9 There does not appear to be an OS difference between tandem or single ASCT.9,10 Based on these results, the group is recommending tandem transplant for patients with del17p by fluorescence in situ hybridisation (FISH). Tandem ASCT is currently not uniformly recommended for other high-risk patients based on clinical or genetic factors, due to a lack of strong evidence supporting this approach and potentially increased toxicities. However, this should be reviewed on an individual patient basis.

Most international guidelines are moving away from using chronological age to determine transplant eligibility. Instead, assessment should be based on biological age, performance status and coexisting comorbidities. Multiple retrospective studies have shown the feasibility of ASCT in elderly patients to achieve equivalent survival outcomes compared to younger patients.11,12 Although toxicity during ASCT appears to be increased in the older transplant patients, including length of hospital stay and infection, transplant related mortality is reported to be between 1% and 1.5%, which is comparable to the younger population.13,14 The definition of elderly differed between trials but generally used cut off between 65 to 70 years of age. It is worth noting that these evidences are mainly based on large retrospective analyses, and therefore an inherent bias cannot be excluded. Consideration should be given to reduce the conditioning melphalan dose to 140mg/m2 in older or frailer patients, but this should also be balanced against treatment efficacy, as the reduced dose may compromise outcomes in patients with suboptimal response prior to ASCT.11,15 Assessment using tools like the haematopoietic stem cell comorbidities index has been shown to correlate with survival outcome and may aid in patient selection and decisions on conditioning intensity.16

Post-transplant consolidation therapy

In New Zealand, bortezomib-based consolidation has been given to patients, as maintenance therapy was not available and bortezomib was funded for up to nine cycles in the front-line setting. Recently, lenalidomide maintenance has become available, prompting a review of the need for consolidation therapy.

When conventional chemotherapy was used as induction and maintenance therapy was not given, consolidation with proteasome inhibitor (PI)- or IMiD-based regimens have been shown to deepen responses and improve PFS outcomes, although no consistent OS benefit has been demonstrated.17–19 However, in the era of novel agent-based induction treatment and post-ASCT maintenance, the role of consolidation is less clear. In the STaMINA trial, there was no advantage of RVD consolidation compared to patients who received single ASCT followed immediately by lenalidomide maintenance.20 The EMN02 trial showed consolidation therapy improves PFS in the upfront setting, but the follow-up is too short at this stage to determine if this benefit is maintained in the ASCT cohort.9

As the benefit of consolidation therapy in the post-ASCT setting is unclear at this stage, its routine use is not supported by the group. However, it remains a valid option for patients who have a high-risk disease or suboptimal response. Traditionally, up to four cycles of consolidation were given post ASCT in New Zealand. In more recent international trials, if consolidation therapy is included, two cycles are typically used. Based on these factors, we propose that if consolidation is to be used, it can be given for two to four cycles. One proposed consolidation regimen is the modified RVD regimen (Table 1). Although this modified regimen has not been tested in prospective studies, it has the same bortezomib and lenalidomide dosing schedule as other commonly used anti-MM regimens in New Zealand. The dose of 10mg of lenalidomide was proposed, as this would still fall within the latest PHARMAC Special Authority funding criteria for lenalidomide maintenance. The group will aim to collect data on the use of this consolidation regimen and its impact on patient outcome.

Table 1: Recommended regimens and dosing.

Maintenance therapy

Lenalidomide maintenance has become the standard of care as part of front-line therapy, based on results of multiple trials showing that it deepens responses, which translates to a PFS benefit, although OS benefit is less consistently shown.21–25 The benefit is particularly seen in patients who have not achieved a complete response prior to maintenance; however, patients who are minimal residual disease (MRD) negative also benefited.24,26

Not all trials included baseline cytogenetic results, and therefore the evidence for patients with high-risk cytogenetic abnormalities has been less robust. In a meta-analysis and the Myeloma XI trial, there appears to be PFS benefit for those with high-risk cytogenetic compared to observation.24,25 Based on these results, lenalidomide maintenance should be recommended for all patients post ASCT unless there is a contraindication.

Lenalidomide maintenance therapy can be started up to six months post ASCT, as per the current funding criteria, although in the studies it was generally started around 100 days after the ASCT. Lenalidomide should be continued until disease progression or if patients experience intolerant side effects. Recent data suggest that a shortened length of maintenance compromises outcome.10 There is a small increase in secondary malignancies, but the benefit outweighs this risk.21,24,25

PI-based maintenance strategies have been investigated in clinical trials. In HOVON-65/GMMG-HD4, bortezomib-based maintenance improved outcome particularly for patients with high-risk cytogenetic.27 However, the standard arm used conventional chemotherapy for induction versus bortezomib-based induction, making it difficult to determine whether the improved outcome is solely due to bortezomib maintenance. There is no randomised controlled trial comparing a PI-based with an IMiD-based maintenance strategy. Retrospective single-centre data suggest they may be equally efficacious, especially in high-risk cytogenetic patients.28,29 Based on the currently available data, bortezomib maintenance therapy is not recommended routinely but can be considered for patients who cannot tolerate lenalidomide maintenance and have high-risk diseases. Ixazomib maintenance has been tested as post-transplant maintenance treatment in a prospective study. Although it has shown an improved progression-free survival compared with placebo, the degree of clinical benefit appears to be small.30 Currently, this is not funded in New Zealand.

Conclusion

The treatment landscape of MM changes rapidly as evidence evolves. The increasing number of novel agents available continues to improve outcomes, although the cost is making public funding difficult in many countries. The New Zealand Myeloma Interest Group has formed the above consensus recommendation (Figure 1) based on best available evidence and modified to suit the New Zealand setting.

Figure 1: Treatment pathway for transplant-eligible, newly diagnosed multiple myeloma patients.

*May consider VTD induction for younger patients (<65) or those with a suboptimal response to CyBorD. **Modified RVD maybe considered for patients who have a suboptimal response to ASCT (ie, less than VGPR) or have high-risk clinical features. ***Tandem/double ASCT maybe considered for patients with high-risk FISH cytogenics

Summary

Abstract

Multiple myeloma is the second most common blood cancer in New Zealand with higher incidence in Māori and Pacific Island populations. It remains an incurable disease but the rapidly changing treatment landscape has led to improved outcome. In response to recent changes in funding of anti-myeloma therapy in New Zealand, the New Zealand Myeloma Interest Group has reviewed the latest literature and updated the treatment pathway of transplant-eligible patients with newly diagnosed multiple myeloma.

Aim

Method

Results

Conclusion

Author Information

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland, New Zealand; Ken Romeril, Myeloma New Zealand, New Zealand. Bart Baker, Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand; Hugh Goodman, Department of Haematology, Waikato Hospital, Hamilton, New Zealand; Henry Chan, Department of Haematology, Waitemata District Health Board, Auckland, New Zealand.

Acknowledgements

Correspondence

Nicole Chien, Department of Haematology, Auckland City Hospital, Auckland.

Correspondence Email

chienn@adhb.govt.nz

Competing Interests

Dr Romeril reports grants from Celgene, outside the submitted work. Dr Chan reports grants, personal fees and non-financial support from Janssen, non-financial support from Celgene, personal fees from Abbvie, non-financial support from Amgen, outside the submitted work.

1. Milne, Richard; Boyd, Matt; Chan, Henry; Milne, Barry; Zhang D. The burden of multiple myeloma: A study of the human and economic costs of myeloma in New Zealand. Myeloma New Zealand; 2019.

2. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014 May 25;28(5):1122–8.

3. Ministry of health. New Zealand Cancer Action Plan 2019–2029 – Te Mahere mō te Mate Pukupuku o Aotearoa 2019–2029. Revised January 2020 Wellington: Ministry of Health. 2019.

4. Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569–74.

5. Mikhael J, Ismaila N, Cheung MC, Costello C, Dhodapkar M V., Kumar S, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019 May 10;37(14):1228–63.

6. Gay F, Engelhardt M, Terpos E, Wäsch R, Giaccone L, Auner HW, et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica. 2018 Feb;103(2):197–211.

7. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb;389(10068):519–27.

8. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017 Apr 6;376(14):1311–20.

9. Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib–melphalan–prednisone, with or without bortezomib–lenalidomide–dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456–68.

10. Hari P, Pasquini MC, Stadtmauer EA, Fraser R, Fei M, Devine SM, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol. 2020 May 20;38(15_suppl):8506–8506.

11. Munshi PN, Hari P, Vesole DH, Jurczyszyn A, Zaucha J, Davila O, et al. Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma. Blood. 2019 Nov 13;134 (Supplement_1):782–782.

12. Merz M, Neben K, Raab MS, Sauer S, Egerer G, Hundemer M, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014 Jan;25(1):189–95.

13. Sanchez L, Sylvester M, Parrondo R, Mariotti V, Eloy JA, Chang VT. In-Hospital Mortality and Post-Transplantation Complications in Elderly Multiple Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Population-Based Study. Biol Blood Marrow Transplant. 2017 Jul;23(7):1203–7.

14. Stettler J, Novak U, Baerlocher GM, Seipel K, Mansouri Taleghani B, Pabst T. Autologous stem cell transplantation in elderly patients with multiple myeloma: evaluation of its safety and efficacy. Leuk Lymphoma. 2017 May 4;58(5):1076–83.

15. Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, et al. Melphalan 140 mg/m 2 or 200 mg/m 2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018 Mar;103(3):514–21.

16. Saad A, Mahindra A, Zhang M-J, Zhong X, Costa LJ, Dispenzieri A, et al. Hematopoietic Cell Transplant Comorbidity Index Is Predictive of Survival after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Biol Blood Marrow Transplant. 2014 Mar;20(3):402-408.e1.

17. Mellqvist U-H, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647–54.

18. Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, et al. Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077–84.

19. Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, et al. Consolidation Therapy With Low-Dose Thalidomide and Prednisolone Prolongs the Survival of Multiple Myeloma Patients Undergoing a Single Autologous Stem-Cell Transplantation Procedure. J Clin Oncol. 2009 Apr 10;27(11):1788–93.

20. Stadtmauer EA, Pasquini MC, Blackwell B, Hari P, Bashey A, Devine S, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: Results of the BMT CTN 0702 trial. J Clin Oncol. 2019;37(7):589–97.

21. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012 May 10;366(19):1770–81.

22. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782–91.

23. Palumbo A, Cavallo F, Gay F, Di Raimondo F, Yehuda DB, Petrucci MT, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905.

24. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. J Clin Oncol. 2017;35(29):3279–89.

25. Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20(1):57–73.

26. De Tute R, Cairns D, Rawstron A, Pawlyn C, Davies F, Jones J, et al. Sequential minimal residual disease (MRD) monitoring: Results from the UK Myeloma XI trial. Clin Lymphoma Myeloma Leuk. 2019 Oct;19(10):e45–6.

27. Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, Van Holt B Der, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8.

28. Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, et al. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(2):262–8.

29. Chakraborty R, Muchtar E, Kumar SK, Buadi FK, Dingli D, Dispenzieri A, et al. Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. Leukemia. 2018 Mar 14;32(3):712–8.

30. Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019;393(10168):253–64.

Contact diana@nzma.org.nz
for the PDF of this article

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