Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

Ricardo D. Parrondo, MD; Sikander Ailawadhi, MD; Taimur Sher, MD; Asher A. Chanan-Khan, MD; Vivek Roy, MD

Disclosures

J Oncol Pract. 2020;16(2):56-66. 

In This Article

Post-transplantation Maintenance

Post-transplantation maintenance therapy currently involves the use of 1 to 2 novel agents at a lower dose than that used for induction with the goal of maintaining the depth of response achieved by ASCT. Thalidomide was the first immunomodulatory agent tested as maintenance therapy. A meta-analysis analyzing five trials involving 2,456 patients found a significant OS benefit for thalidomide maintenance (HR, 0.75; 95% CI, 0.64 to 0.87; P < .001), although patients with high-risk cytogenetics experienced shorter OS (P = .009).[40] In three of the five studies, survival after relapse was found to be reduced after thalidomide exposure, which suggests the development of more resistant disease.

Maintenance therapy with lenalidomide is better tolerated than thalidomide. A meta-analysis of three trials showed a median PFS of 52.8 months for the lenalidomide maintenance group and 23.5 months for the placebo group (HR, 0.48; 95% CI, 0.41 to 0.55). At a median follow-up time of 79.5 months for all surviving patients, median OS had not been reached for the lenalidomide maintenance group, whereas it was 86.0months for the placebo group (HR, 0.75; 95% CI, 0.63 to 0.90; P = .001).[41] Unlike thalidomide, lenalidomide maintenance did not induce resistant disease upon relapse. Lenalidomide maintenance produced a PFS, but not an OS, benefit in patients with high-risk cytogenetics. Lenalidomide maintenance increased the rate of secondary primary malignancy compared with placebo.[41] The recent Myeloma XI trial also demonstrated a PFS benefit—across all cytogenetic risk groups—but not an OS benefit with maintenance lenalidomide.[42]

After follow-up of 91.4 months, the phase III HOVON-65/GMMG-HD4 trial showed a PFS advantage (35 v 28 months; P = .002) for bortezomib maintenance compared with thalidomide maintenance, especially in patients with renal failure and del17p.[43] A caveat of this study is that the induction regimen before transplantation did not contain both a proteasome inhibitor and immunomodulatory agent, which raises the question of whether novel triplet induction regimens that contain both a proteasome inhibitor and immunomodulatory agent make bortezomib maintenance obsolete. The recent TOURMALINE-MM3 trial—where 30% of patients received induction with both a proteasome inhibitor and immunomodulatory agent—which evaluated oral ixazomib maintenance after ASCT, revealed after a median follow-up of 31 months a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS, 26.5 v 21.3 months; HR, 0.72; 95% CI, 0.58 to 0.89; P=.0023). PFS benefit was also observed in patients with high-risk cytogenetics (HR, 0.625).[44] In a phase I and II trial of patients with high-risk cytogenetics, use of VRD maintenance after ASCT resulted in an impressive response rate with 96% achieving a very good partial response or better as well as a median PFS of 32 months and a 3-year OS of 93%.[45] Trials evaluating the use of novel agents in maintenance therapy are underway (Table 2).

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