Double or tandem HSCT, performed within a few months after the first procedure, has been shown to significantly increase PFS; in the EMN02/HO95 trial (ClinicalTrials.gov Identifier: NCT01208766), PFS was 63 months after 1 ASCT compared with 73 months after 2 ASCTs.1 As a general recommendation, tandem ASCT may be beneficial in high-risk patients with poor cytogenetics and Revised International Staging System (RISS) 3 category of disease.5

Of note, the Intergroupe Francais du Myelome (IFM) 2009 phase 3 study (ClinicalTrials.gov Identifier: NCT01191060) compared VRD treatment only with combination HDT/ASCT and VRD treatment in patients with newly diagnosed MM. Transplantation with VRD resulted in significant improvement in PFS (50 months vs 36 months), CR rate (59% vs 48%), and MRD negativity (79% vs 65%).6 These results were validated by the EMN02/HO95 trial, where upfront ASCT decreased risk of progression and death and improved 3-year PFS compared with VMP treatment.2

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Consolidation and Maintenance Therapy


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According to the authors, consolidation therapy after transplantation remains controversial. No PFS benefit was seen with VRD consolidation in patients with high-risk cytogenetics. In contrast, young, low-risk patients with newly diagnosed MM may benefit from VRD consolidation followed by lenalidomide maintenance.2

Even with a CR, progression and relapse are common after transplantation. Maintenance therapy aims to deepen response, prevent progression, and prolong OS.2 In large meta-analyses, lenalidomide maintenance treatment significantly increased PFS in all subgroups of patients (52.8 months vs 23.5 months; hazard ratio, 0.48; 95% CI 0.41-0.55) and was not neurotoxic.2 It also significantly improved OS, except in women over 60 years old with high-risk cytogenetics.7,8 Lenalidomide given in low doses until toxicities start to develop is considered the standard maintenance therapy in transplant-eligible patients.2

However, ASCT remains the standard of care in all eligible patients, according to Dr Mateos. “In patients with MRD-negative status after a triple-induction regimen — and possibly [treatment with] a monoclonal antibody — additional studies are required to establish superiority of maintenance treatment alone compared with ASCT and maintenance,” she said. “Only then may patients [go directly from induction to] maintenance treatment alone and [keep] ASCT reserved for the relapse setting.”

Other maintenance agents under investigation include bortezomib and the first oral PI, ixazomib. Though bortezomib yielded improvements in PFS, “[it] poses an obstacle due to its subcutaneous/intravenous administration,” the review authors noted. In contrast, in the TOURMALINE-MM3 study (ClinicalTrials.gov Identifier: NCT02181413), ixazomib induced a 39% improvement in PFS and a 28% reduction in disease progression or death after a median follow-up of 31 months.10

ASCT Remains the Standard

In fit young patients and select elderly patients with newly diagnosed MM, frontline ASCT is preferred over delayed ASCT and remains the established standard of care, though delayed ASCT could be considered to avoid potential side effects and toxicities due to HDT. In the relapse setting, salvage or rescue ASCT has significantly reduced time to disease progression (19 months vs 11 months) and OS (67 months vs 52 months) compared with reinduction chemotherapy.9 Salvage ASCT remains an option provided the interval between first ASCT and relapse is 18 months or more.2

For now, ASCT remains the preferred therapy in frontline and rescue settings. Additional studies evaluating novel therapies in comparison with ASCT will be required in order to redefine an optimal treatment approach.

References

  1. Harousseau J-L, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma [published online June 18, 2009]. N Engl J Med. doi:10.1056/NEJMct0805626
  2. Al Hamed R, Bazarbachi AH, Malard F, Harousseau J-L, Mohty M. Current status of autologous stem cell transplantation for multiple myeloma [published online April 8, 2019]. Blood Cancer J. doi:10.1038/s41408-019-0205-9
  3. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma [published online February 8, 2018]. N Engl J Med. doi:10.1056/NEJMoa1714678
  4. Darzalex (daratumumab) [package insert]. Horsham, PA: Janssen Biotech, Inc; 2018.
  5. Cavo M, Gay FM, Patriarca F, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/H095 study. Blood. 2017:130(Suppl 1), 401.
  6. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma [published online April 6, 2017]. N Engl J Med. doi:10.1056/NEJMoa1611750
  7. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis [published online July 25, 2017]. J Clin Oncol. doi:10.1200/JCO.2017.72.6679
  8. Jackson G, Davies FE, Pawlyn C, et al. Lenalidomide maintenance significantly improves outcomes compared to observation irrespective of cytogenetic risk: results of the Myeloma XI trial. Blood. 2017;130 (Suppl 1), 436.
  9. Cook G, Ashcroft AJ, Cairns DA, 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 randomized, open-label, phase 3 trial [published online July 1, 2016]. Lancet Haematol. doi:10.1016/S2352-3026(16)30049-7
  10. Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomized, placebo-controlled phase 3 trial [published online January 19, 2019]. Lancet. doi:10.1016/S20140-6736(18)33003-4
  11. Moreau P, Avet-Loiseau H, Harousseau J-L, Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies [published online April 11, 2011]. J Clin Oncol. doi:10.1200/JCO.2010.32.5878