Autologous stem cell transplantation in multiple myeloma: the big questions

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 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 regimens in 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/m²) conditioning followed by single versus tandem ASCT³
  • Newly diagnosed MM (NDMM), N = 358
  • Intention-to-treat (ITT) population (single vs tandem ASCT): 177 vs 181
  • 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 versus tandem ASCT in patients with NDMM⁴
  • Phase III trial using bortezomib-based induction therapy
  • Updated analysis showed improved 3-year PFS and OS in tandem ASCT group²
  • Three-year progression-free survival (PFS, single vs tandem): 60% vs 73%, 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 versus tandem ASCT in the era of novel agents⁵
  • Patients were randomized 1:1:1 to either: single HDM + ASCT + 4 cycles of bortezomib + lenalidomide + dexamethasone (VRD) consolidation (n = 254) vs tandem HDM + ASCT (n = 247) vs single HDM + ASCT (n = 257)
  • Median follow-up: 38 months
  • PFS: 57% (95% CI, 50-63%) vs 56% (95% CI, 49-63%) vs 52% (95% CI, 45-59%)
  • OS: 86% (95% CI, 80-90%) vs 82% (95% CI, 76-87%) vs 83% (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 vs tandem ASCT)⁶
  • ITT population (single vs tandem): 254 vs 352
  • Median PFS: 38 vs 50 months, P < 0.001
  • Five-year OS: 63% vs 75%, 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 disease², 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 subgroup¹ 

• 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 versus tandem 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 vs 1 vs 2 vs 3): 61 vs 56 vs 36 vs 26 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 vs double ASCT): 21 vs 42 months, HR: 0.41, P = 0.006
  • EMN02/HO95: single ASCT vs double ASCT in patients with high-risk cytogenetic abnormalities⁴
    • 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.² The evidence is summarized below:

• The IFM2009 phase III trial recruited patients <65 years with NDMM⁷
  • 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 vs HDM + ASCT + VRD): 36 vs 50 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% vs 81%)
  • 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 vs CRD): 43.3 vs 28.6 months (P < 0.0001)
  • Four-year OS (ASCT vs CRD): 86% vs 73% (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 versus novel 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.¹ Future 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) versus delayed ASCT (>12 months after diagnosis) have been conducted and are shown in the table below.¹ These 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 vs delayed ASCT

Conclusions: Early ASCT is the standard of care, improving outcomes regardless of whether it is performed in the frontline setting or as salvage therapy.² However, 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 ASCT¹
• BSBMT/UKMF Myeloma X study:¹¹
  • Patients who have relapsed after first ASCT
  • Salvage HDM + ASCT (n = 89) vs oral cyclophosphamide (n = 85)
  • TTP: 19 vs 11 months, P < 0.001
  • Median OS: 67 vs 52 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) versus chemotherapy (n = 144) in patients who relapsed after first ASCT and underwent a salvage ASCT¹²
  • In the salvage ASCT group, 73% (n = 35) received novel-agent based therapies
  • Median OS (salvage ASCT vs chemotherapy): 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 versus novel 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 future²
• The use of daratumumab may change the treatment landscape in MM²
• Future ASCT studies should be measured by MRD negativity²
  • 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 geographically²
• Novel agents such as immune-based and antibody-based therapies will likely be utilized earlier in treatment pathways to increase the clearance of resistant clones¹