Patients eligible for transplant

Autologous stem cell transplant in multiple myeloma: optimal regimens

In April, two review articles were published in peer-reviewed journals, reflecting on the role of stem cell transplantation (SCT) in multiple myeloma (MM). The first review, published in Cancer and authored by Roberto Mina and our co-chair Sagar Lonial, questioned the role of SCT in MM.1 The second review, in Blood Cancer Journal, by Rama Al Hamed, Adbul Hamid Bazarbachi and colleagues, including our Steering Committee member, Mohamad Mohty, reflected on the current status of autologous-SCT (ASCT) in MM.2

Here, the MM Hub present a series of three articles on the current status of SCT in MM and discuss it’s role in treatment both now, and in the future. This article focuses on the ideal induction, stem-cell mobilization, conditioning, consolidation and maintenance regimens in ASCT.

The relationship between ASCT and chemotherapy1
  • Historically, the use of high-dose chemotherapy and ASCT has been the standard of care in treating patients with newly diagnosed MM (NDMM)
  • However new drugs have been developed which have improved overall survival (OS) rates, including:
    • Immunomodulatory drugs (IMiDs): thalidomide, lenalidomide and pomalidomide
    • Proteasome inhibitors (PIs): bortezomib, carfilzomib and ixazomib
    • Monoclonal antibodies: daratumumab and elotuzumab
  • In the era of these novel agents, the role of ASCT, timing and the optimal induction, consolidation and maintenance treatments has been questioned
 Age as a factor for ASCT1,2
  • ASCT is the standard of care for young patients with NDMM (<65 years old)
  • Clinical trials tend to exclude patients >65 years old1
  • The age of patients receiving transplants has increased in recent years, as evaluated using the European Society of Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Research registries3
  • A trial by the DSSM group, examining ASCT in older patients (aged 60–70), used tandem ASCT + melphalan (140 mg/m2) and found patients >65 years old did not have inferior outcomes4
  • The use of melphalan at 140 mg/m2 (n = 18) versus 200 mg/m2 (n = 32) prior to ASCT was compared in patients >65 years old. The use of high dose melphalan (200 mg/m2, HDM) conferred superior progression-free survival (PFS) and OS rates. 5
  • In the United States (US), patients are generally considered for transplant up to age 80, dependent upon other co-factors1

Conclusion: transplant eligibility should not be defined solely on age, but the decision should be made based on age, performance status, comorbidities and other factors such as organ function.1 The advent of novel agents such as IMiDs, PIs and monoclonal antibodies, so far, have not replaced ASCT, and have actually proven its benefit.2

What is the optimal induction regimen for ASCT?2
  • Induction regimens aim to decrease tumor burden and increase likelihood of engraftment with minimal effect on normal hematopoietic cells.
  • Induction regimens were traditionally alkylating agent based, often using dexamethasone
  • Combining several newer agents into triplet, and even quadruplet regimens is now providing significantly higher complete response (CR) rates.
  • Most commonly used pre-transplant induction regimens are bortezomib, thalidomide and dexamethasone (VTD) and bortezomib, lenalidomide and dexamethasone (VRD).
  • The addition of daratumumab, an anti-CD38 monoclonal antibody, to doublet and triplet regimens is being tested in patients with relapsed/refractory MM (RRMM) and as induction for transplant eligible patients.

For a fuller explanation of the evolution of induction regimens, click here to read the MM Hub’s previous summary, and here for the real-world clinical experience of induction regimens.

Conclusion: VTD and VRD will likely remain the standards of care, though the addition of daratumumab is likely to show improved results and may, in future, be used in induction regimens.

What is the best strategy for stem cell mobilization?2
  • Prior to ASCT, the hematopoietic stem cells (HSCs) must be mobilized from the bone marrow
  • Optimal target: 5 x 106 CD34+ cells/kg
  • Stem cell mobilization is most commonly either:
    • Steady-state mobilization using granulocyte colony-stimulating factors (G-CSF) such as filgrastim or lenograstim:
      • May lead to a suboptimal HSC harvest
    • Chemomobilization- high-dose cyclophosphamide followed by G-CSF:
      • Increases the time to harvest
      • May cause undesirable side effects
      • May decrease tumor burden
  • Patients with HSC mobilization failure may be given new mobilization agents such as plerixafor:
    • Not widely available
    • May be given pre-emptively to patients with a low circulating CD34 count
  • The use of lenalidomide in induction regimens has been connected to a lack of stem cell mobilization and this may be considered

Conclusion: Chemomobilization with high-dose cyclophosphamide plus G-CSF or steady-state mobilization, with the addition of pre-emptive plerixafor, if necessary, are currently the most frequently used regimens.

What is the ideal conditioning regimen?2

The most commonly used conditioning regimen is HDM (200 mg/m2). Trials have attempted many alternative strategies, with conflicting results.

  • Oral busulfan: GEM2000 study showed oral busulfan increased toxicity, including more veno-occlusive disease-related deaths. The authors suggested intravenous administration should be investigated6
  • Intravenous (IV) busulfan: comparing IV busulfan + melphalan (Bu-Mel, 140 mg/m2, n =51) to HDM (n = 102) did not show superiority with PFS rates of 33 months vs 24 months (P = 0.10)7
  • Melphalan (200 mg/m2, n = 65 vs 280 mg/m2, n = 66) + pretreatment with amifostine:8
    • ≥ near CR (nCR): 22% (14/65) vs 39% (26/66), P = 0.03
    • Melphalan at 280 mg/m2: higher overall response rate (ORR) and nCR but no improvement in OS and PFS
    • Melphalan 280 mg/m2 was well-tolerated with no grade 4 adverse events, but caused increased grade II–III mucositis (P = 0.004), gastrointestinal toxicity (P = 0.17) and more hospitalizations (P = 0.08)
  • Bortezomib + HDM vs HDM alone: IFM 2014-02 trial reported PFS rates of 76% vs 79%, P = 0.53, with 2-year OS of >93% in both arms. Therefore may be little advantage of adding bortezomib in relation to CR, PFS and OS rates.9
  • IV Bu-Mel (n = 104) vs HDM (n = 100) phase III trial10
    • At day +90, CR rates were: 26% vs 33%, P = 0.29
    • IV Bu-Mel increased PFS: 64.7 vs4 months (P = 0.013)
    • No difference in OS rates between arms
  • Bendamustine + melphalan: ongoing investigations11
    • Dose-intensified bendamustine (200 mg/m2) + HDM before a tandem ASCT in adverse-risk patients with MM who either did not achieve a CR to first ASCT, or who had high-risk cytogenetics (N = 12)
    • CR (ASCT1 vs ASCT2): 42% vs 75%
    • PFS: 67%
    • OS: 83%
    • Reversible acute renal injury: 25% (n = 3)

Conclusion: HDM remains the conditioning regimen of choice prior to ASCT

What is the optimal consolidation therapy?2
  • Short-term consolidation therapy is designed to improve response rates, without causing additional side effects.
  • Utilizing consolidation therapy effectively has prolonged PFS rates in patients achieving a good response to ASCT. Currently, there is conflicting evidence from clinical trials on the use of consolidation therapy.
    • In the EMN02/HO95 trial, patients (N = 892) were randomized to receive consolidation with VRD (n = 455), or no consolidation (n = 437). Both groups received lenalidomide maintenance. Median five-year PFS (VRD vs no consolidation) was 59 vs 45 months. The PFS benefit from VRD was seen in all subgroups, except those with high-risk cytogenetics.12
    • StaMINA phase III trial randomized patients 1:1:1 to either: HDM + ASCT + VRD consolidation vs tandem HDM + ASCT vs single ASCT. This study concluded that adding VRD consolidation or a second ASCT was not superior to ASCT + lenalidomide maintenance alone in NDMM.13

Conclusion: VRD consolidation + lenalidomide maintenance may be effective in young, fit patients with low-risk NDMM, but is still debated.

What is the optimal maintenance therapy?2

Since ASCT is not a curative measure, maintenance therapy is administered long-term, post-transplant, to prevent disease progression and prolong OS. Therefore, maintenance therapy needs to be well-tolerated. The currently used drugs and their suggested doses are listed below:

  • Thalidomide:
    • Studies report conflicting results
    • One meta-analysis has shown thalidomide can improve responses and PFS, and is associated with a late benefit in OS14
    • Suggested dosage is 100 mg/day with a treatment duration of 6–12 months2
    • Associated with undesirable toxicities2
  • Lenalidomide:
    • Proposed as the standard of care for maintenance in transplant-eligible patients
      • Meta-analysis of three randomized controlled trials (CALGB, IFM and GIMEMA) compared lenalidomide maintenance (n = 605) to placebo/observation (n = 603). Median PFS (lenalidomide vs placebo/observation): 52.8 vs5 months (HR: 0.48) shows lenalidomide significantly improves PFS and OS rates compared to placebo or observation alone15
    • Well-tolerated2 but associated with higher rates of secondary primary malignancies15
    • Currently approved administration continues in low doses until progression or adverse events due to AEs or secondary malignancies (30% of cases are ended early)2
    • Optimal duration of treatment is yet to be identified
  • Bortezomib:
    • The phase III HOVON-65/GMMG-HD4 trial: induction with vincristine, doxorubicin and dexamethasone (VAD) and maintenance with thalidomide (n = 414) versus induction with bortezomib, doxorubicin and dexamethasone (PAD) and maintenance with bortezomib (n = 413)16
      • PFS (PAD vs VAD): 28 vs 35 months
      • Five-year OS (PAD vs VAD): 61% vs 55%
      • Maintenance with bortezomib for 2-years was better tolerated than thalidomide
      • Bortezomib maintenance improved the nCR + CR rate from 31% to 49%
    • Subcutaneous or IV administration method is also a limitation in many cases
  • Ixazomib:
    • Ixazomib (an oral PI) is showing promise in the TOURMALINE–MM3 trial:17
    • Phase III, double-blind, placebo-controlled trial of patients with NDMM
    • Ixazomib (n = 395) vs placebo (n = 261)
    • Median follow-up: 31 months
    • Risk of reduction in progression or death with ixazomib: 28% (HR: 0.72, 95% CI, 0.582–0.890, P = 0.002)
    • Grade ≥3 AE: 42% vs 26%

Conclusion: lenalidomide is proposed as the standard of care in this transplant eligible setting, though trials involving newer agents, such as ixazomib, are ongoing and show promising results.

Future perspectives

Minimal residual disease (MRD) negativity is becoming an increasingly utilized and important measure, which is likely to become essential in patient stratification for maintenance and consolidation therapy moving forwards.2

The next article in this series will focus on the big questions of ASCT in myeloma:

  • Is single or tandem ASCT more beneficial?
  • Is tandem ASCT beneficial in the high-risk subgroup?
  • Which gives better responses; triplet combinations containing novel agents or ASCT?
  • Should ASCT be conducted early or late in the treatment pathway?
  • Is there a role for salvage ASCT?

The previous article on allogeneic SCT can be viewed here

References
  1. Mina R. and Lonial S. Is there still a role for stem cell transplantation in multiple myeloma? Cancer. 2019 Apr 15. DOI: 10.1002/cncr.32060
  2. Al Hamed R., Bazarbachi A.H. et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019 Apr 08. DOI: 10.1038/s41408-019-0205-9
  3. Auner H.W. et al. Trends in autologous hematopoietic cell transplantation  or multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2014 Nov 10. DOI: 10.1038/bmt.2014.255
  4. Straka C. et al. Autotransplant with and without induction  hemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial. Haematologica. 2016 Aug 04. DOI: 10.3324/haematol.2016.151860
  5. Garderet L. et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study.  Haematologica. 2016 Sep 09. DOI: 10.3324/haematol.2016.150334
  6. Lahuerta J.J. et al. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study. Haematologica. 2010 Jul 20. DOI: 10.3324/haematol.2010.028027
  7. Blanes M. et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach. Biol. Blood Marrow Transplant. 2013 Jan. DOI: 10.1016/j.bbmt.2012.08.009
  8. Bensinger W.I. et al. A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant. 2015 Sep 14. DOI: 10.1038/bmt.2015.211
  9. Roussel M. et al. Bortezomib and high-dose Melphalan vs. high-dose melphalan as conditioning regimen before autologous stem cell transplantation in de novo multiple myeloma patients: a phase 3 study of the Intergroupe Francophone Du Myelome (IFM 2014-02). Blood. 2017 Dec 07. http://www.bloodjournal.org/content/130/Suppl_1/398
  10. Qazilbash M.H. et al. A randomized phase III trial of Busulfan+Melphalan vs Melphalan alone for multiple myeloma. Blood. 2017. http://www.bloodjournal.org/content/130/Suppl_1/399
  11. Farag, S. et al. Dose-intensified bendamustine and melphalan (BenMel) conditioning before second autologous transplantation in myeloma patients. Hematol. Oncol. 2018 Aug 15. DOI: 10.1002/hon.2546
  12. Sonneveld P. et al. Consolidation Followed by Maintenance vs Maintenance Alone in Newly Diagnosed, Transplant Eligible Multiple Myeloma: A Randomized Phase 3 Study of Tte European Myeloma Network (Emn02/Ho95 Mm Trial). #214488. 2018 Jun 15. https://learningcenter.ehaweb.org/eha/2018/stockholm/214488/pieter.sonneveld.consolidation.followed.by.maintenance.vs.maintenance.alone.in.html
  13. Stadtmauer E.A. et al. Comparison of autologous hematopoietic cell transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem Autohct with Len maintenance (TAM) and Autohct with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702-StaMINA Trial). Blood. 2016. 128; LBA-1. http://www.bloodjournal.org/content/128/22/LBA-1
  14. Morgan G.J. et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 05. DOI: 10.1182/blood-2011-06-357038
  15. McCarthy P.L. et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J. Clin. Oncol. 2017 Jul 25. DOI: 10.1200/JCO.2017.72.6679
  16. Sonneveld P. et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J. Clin. Oncol. 2012 Jul 16. DOI: 10.1200/JCO.2011.39.6820
  17. Morgan G. et al. Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial. Biol. Blood Marrow Trans. 2019 March. DOI: 10.1016/j.bbmt.2018.12.087

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