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Autologous stem cell transplantation in multiple myeloma: the big questions

May 15, 2019

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. 1The 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 Hubpresent 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 focusses on the big questions in ASCT:

  • 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 articles focussed on the optimal regimensin ASCT in MM, and allogeneic SCT.

Single versus tandem ASCT 1,2

Tandem ASCT (two ASCTs performed within a period of ≤6 months) has been shown to be superior to single ASCT in several trials. However, tandem ASCT has not been shown to be superior to single ASCT in the era of novel agents. 2

Trials comparing tandem and single ASCT include:

  • GMMG-HD2 trial: High dose melphalan (HDM, 200 mg/m 2) conditioning followed by single versustandem ASCT 3
    • Newly diagnosed MM (NDMM), N = 358
    • Intention-to-treat (ITT) population (single vstandem ASCT): 177 vs181
    • Median follow-up: 11 years
    • Single transplant was found to be non-inferior to tandem
    • In the ITT population, overall survival (OS) and event-free survival (EFS) did not differ ( P= 0.33 and P= 0.53 respectively)
    • Complete response (CR) rates were improved significantly after second ASCT in the tandem arm
    • Limitations: lack of subgroup analysis and high drop-out rates
  • EMN02/HO95 trial: single versustandem ASCT in patients with NDMM 4
    • Phase III trial using bortezomib-based induction therapy
    • Updated analysis showed improved 3-year PFS and OS in tandem ASCT group 2
    • Three-year progression-free survival (PFS, single vstandem): 60% vs73%, P= 0.030
    • PFS benefit of tandem transplant was seen in all subgroups
    • Conclusion: tandem ASCT with bortezomib induction was superior to single ASCT in relation to PFS and OS in NDMM
  • StaMINA: single versustandem ASCT in the era of novel agents 5
    • Patients were randomized 1:1:1 to either: single HDM + ASCT + 4 cycles of bortezomib + lenalidomide + dexamethasone (VRD) consolidation (n = 254) vstandem HDM + ASCT (n = 247) vssingle HDM + ASCT (n = 257)
    • Median follow-up: 38 months
    • PFS: 57% (95% CI, 50-63%) vs56% (95% CI, 49-63%) vs52% (95% CI, 45-59%)
    • OS: 86% (95% CI, 80-90%) vs82% (95% CI, 76-87%) vs83% (95% CI: 78-88%)
    • Conclusion: adding VRD consolidation, or conducting a tandem ASCT did not improve OS or PFS rates in patients with NDMM
  • European meta-analysis of four trials (single vstandem ASCT) 6
    • ITT population (single vstandem): 254 vs352
    • Median PFS: 38 vs50 months, P< 0.001
    • Five-year OS: 63% vs75%, P= 0.002
    • Benefit was most pronounced in the group who failed to achieve a CR after bortezomib-based induction therapy
    • Conclusion: tandem ASCT has a potential role in treating NDMM with poor prognosis

Conclusion:Tandem ASCT is feasible and likely beneficial in a small subgroup of patients with high-risk cytogenetics and RISS category 3 disease 2, and in those achieving less than a very good partial response (VGPR) to first transplant. However, the latter group may likely benefit from the newest consolidation methods, so this decision should be carefully considered. 1

Tandem SCT in the high-risk subgroup 1  

  • The presence of cytogenetic abnormalities; t(4;14), t(14;16), t(14;20), del17p, gain 1q or del1p are associated with a poor prognosis in MM and are considered high risk characteristics
  • ASCT in high-risk MM:
    • Four European phase III trials (pooled analysis) showed benefit of tandem ASCT in high-risk MM (single ASCT versustandem ASCT): 6
      • Patients were grouped 0–3 based on presence of three adverse variables: ISS stage 3, high risk cytogenetics and failure to achieve CR after induction therapy)
      • Group 0 had none, group 1 had 1, group 2 and 2 and group 3 had all 3 adverse variables
      • Median PFS (group 0 vs1 vs2 vs3): 61 vs56 vs36 vs26 months ( P< 0.001)
      • PFS benefit was most pronounced in patients with two adverse risk factors – high risk cytogenetics and failure to achieve CR after induction (single vsdouble ASCT): 21 vs42 months, HR: 0.41, P= 0.006
    • EMN02/HO95: single ASCT vsdouble ASCT in patients with high-risk cytogenetic abnormalities 4
      • Benefit of double ASCT in relation to PFS
      • HR = 0.57 and P= 0.024

Conclusion:it is unclear whether tandem ASCT is beneficial in high-risk MM, though the International Myeloma Working Group recommend tandem ASCT for patients with high-risk NDMM.

HDM/ASCT + triplet combinations containing novel agents 1,2

Historically, with VRD shown to be more effective than lenalidomide + dexamethasone (RD) alone, trials moved on to comparing VRD + ASCT to ASCT alone. The aim of this research was to determine whether adding the novel agent bortezomib, to an existing doublet in the context of ASCT, provided any further benefit. 2The evidence is summarized below:

  • The IFM2009 phase III trial recruited patients <65 years with NDMM 7
    • Patients (N = 700) received 3 cycles of VRD and were then randomized to 5 cycles of VRD or HDM + ASCT + 2 cycles of VRD followed by lenalidomide maintenance
    • PFS (VRD alone vsHDM + ASCT + VRD): 36 vs50 months, HR: 0.65, P< 0.001
    • Patients receiving transplant also had higher CR and minimal-residual disease (MRD) negativity rates
    • However, there was no difference in OS (82% vs81%)
    • Conclusion: VRD + ASCT provided longer PFS rates, but no difference in OS compared to VRD alone
  • The EMN-441 trial: 8
    • Patients with transplant eligible NDMM <65 years
    • Randomized (n = 256) to consolidation with HDM + ASCT (n = 127) or cyclophosphamide + dexamethasone + lenalidomide (CRD; n = 129)
    • Median PFS (ASCT vsCRD): 43.3 vs28.6 months ( P< 0.0001)
    • Four-year OS (ASCT vsCRD): 86% vs73% ( P= 0.004)
    • The authors concluded that consolidation with HDM + ASCT is the preferred treatment over chemotherapy, but may lead to more adverse events

Conclusion:trials of ASCT versusnovel agent-based treatments in patients with NDMM show an advantage of ASCT over non-transplant approaches. ASCT therefore remains standard of care despite increased availability of novel agents. 1Future studies comparing triplets + daratumumab + HDM + ASCT to triplet regimens + HDM + ASCT alone may change this dynamic. 2

Should ASCT be done early or late in the treatment pathway? 1,2

Retrospective analyses of early ASCT (<12 months after diagnosis) versusdelayed ASCT (>12 months after diagnosis) have been conducted and are shown in the table below. 1These studies did not show significant associations between time to progression (TTP) and when the ASCT was conducted, with comparable OS rates regardless of when transplant was undertaken.

Table 1:Summary of results from studies of early vsdelayed ASCT

 

N

Induction

Median time to progression (TTP)

OS

Kumar et al.(early, n = 173 vslate,n = 112) 9

290

IMiD based

20 vs16 months

P= not significant

4-year: 73% vs73%

P= 0.3

Dunavin et al.(early, n = 102 vslate, n = 65) 10

167

Novel agent based

28 vs23 months

P= 0.055

3-year: 90% vs82%

5-year: 63% vs63%

Conclusions: Early ASCT is the standard of care, improving outcomes regardless of whether it is performed in the frontline setting or as salvage therapy. 2However, delaying ASCT is feasible, though it is currently unclear which subgroup of patients would see the most benefit. Delayed ASCT may be considered based on patient preferences, lack of high-risk cytogenetics and a sufficient stem cell harvest. 1

Salvage ASCT 1,2

  • Another ASCT (second, or third) can be performed on patients who have signs of disease progression after a prior ASCT 1
  • BSBMT/UKMF Myeloma X study: 11
    • Patients who have relapsed after first ASCT
    • Salvage HDM + ASCT (n = 89) vsoral cyclophosphamide (n = 85)
    • TTP: 19 vs11 months, P< 0.001
    • Median OS: 67 vs52 months, P= 0.022
    • Conclusion: salvage ASCT increased OS following relapse to first ASCT but waiting until third or later relapse may not be as effective as in first relapse
    • Limitation: cyclophosphamide is not the current standard of care for relapse in the era of novel agents so this comparison may be viewed as less applicable
  • Korean Myeloma registry study: matched pair analysis of salvage ASCT (n = 48) versuschemotherapy (n = 144) in patients who relapsed after first ASCT and underwent a salvage ASCT 12
    • In the salvage ASCT group, 73% (n = 35) received novel-agent based therapies
    • Median OS (salvage ASCT vschemotherapy): 55.5 vs 25.4 months; P= 0.035
    • Salvage ASCT was superior to chemotherapy alone

Conclusion:Salvage ASCT is an option in fit patients for whom the time between ASCT and relapse is over 18 months and is recommended by both US and European guidelines, subject to a prior adequate stem cell collection. Trials looking at salvage ASCT versusnovel agents are ongoing, with it being a potentially difficult decision of who the optimal patient is for salvage ASCT, in light of the novel agents that are now available. 1,2

Conclusion and future perspectives

  • ASCT is recommended as part of the initial treatment plan, since this is when the disease is most sensitive
  • Chimeric antigen receptor (CAR) T therapy may move into earlier lines of treatment and possibly replace ASCT in the future 2
  • The use of daratumumab may change the treatment landscape in MM 2
  • Future ASCT studies should be measured by MRD negativity 2
    • MRD negativity (<10 -6) is indicative of PFS, OS and potential cure
    • Daratumumab will likely assist in achieving MRD negativity
  • Access to ASCT remains limited geographically 2
  • Novel agents such as immune-based and antibody-based therapies will likely be utilized earlier in treatment pathways to increase the clearance of resistant clones 1
  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. Mai E.K. et al.Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br. J. Haematol.2016 Mar 17. DOI: 10.1111/bjh.13994
  4. Cavo M. 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). Blood.2016 Dec 01. http://www.bloodjournal.org/content/128/22/991/tab-article-info
  5. 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
  6. Cavo M. et al.Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase European III studies [abstract]. Blood.2013 Dec 05. http://www.bloodjournal.org/content/122/21/767/tab-article-info
  7. Attal M. et al.Lenalidomide, Bortezomib, and Dexamethasone with transplantation for myeloma. N. Engl. J. Med. 2017 Apr 06. DOI: 10.1056/NEJMoa1611750
  8. Gay F. et al.Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial.  Lancet Oncol. 2015. DOI: 10.1016/S1470-2045(15)00389-7
  9. Kumar S.K. et al.Early versus delayed autologous transplantation after immunomodulatory agents–based induction therapy in patients with newly diagnosed multiple myeloma. Cancer.2012. DOI: 10.1002/cncr.26422
  10. Dunavin N.C. et al.Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma. Leuk Lymphoma. 2013 Sep 11. DOI: 10.3109/10428194.2012.751528
  11. Cook G. et al.The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol.2016. DOI: 10.1016/S2352-3026(16)30049-7
  12. Yhim H.Y. et al. Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT. Bone Marrow Transplant.2012 Sep 03. DOI: 10.1038/bmt.2012.164