What is the efficacy of second-line therapies for multiple myeloma (MM)?

Updated: May 11, 2021
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Thalidomide

Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm. [97]

Lenalidomide

An important prospective placebo-controlled trial of the addition of lenalidomide to dexamethasone in relapsed cases of MM demonstrated spectacular results. [98] The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 in the lenalidomide plus dexamethasone group vs 4.7% in the placebo group). Overall survival was significantly improved. [98]

Pomalidomide

A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory to both lenalidomide and bortezomib. [99] In February 2013, pomalidomide was approved by the FDA for use in patients with MM who have received at least two previous therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy. [100, 101]

This approval was supported by a phase II study comparing pomalidomide plus low-dose dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial response or better, compared with 7.4% in the pomalidomide-alone arm. [100] The median duration of response for the former was 7.4 months; the median had not been reached for the latter.

In another study, Miguel et al found that the combination of pomalidomide with low-dose dexamethasone yielded a longer median PFS in 455 patients with refractory or relapsed and refractory MM than high-dose dexamethasone alone. [102] In the open-label, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months), median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in the two groups. [102]

Selinexor

The first selective inhibitor of nuclear export (SINE), selinexor, was approved by the FDA in 2019. Selinexor acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells. Selinexor is indicated in combination with dexamethasone for adults with relapsed or refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The multicenter, single-arm, open-label STORM trial analyzed selinexor plus dexamethasone. STORM part 2 included 122 patients with relapsed/refractory MM who previously had 3 or more treatments including: an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody. Trial participants also had MM that was refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy that they had. FDA approval was based on results from the 83 patients from the STORM trial who were refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. This group had a 25.4% overall response rate, 1% stringent complete response rate, 5% very good partial response, and 19% partial response rate. [103, 104]  

Belantamab mafodotin-blmf 

In August 2020 the FDA granted accelerated approval to belantamab mafodotin-blmf (Blenrep) for adult patients with relapsed or refractory MM who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Approval was based on the open-label DREAMM-2 trial, in which the ORR was 31% (97.5% CI: 21%, 43%) in patients receiving the recommended dose of 2.5 mg/kg intravenously, once every 3 weeks until disease progression or unacceptable toxicity, with response duration ≥6 months in 73% of responders. Because of the risks of ocular toxicity (changes in the corneal epithelium), belantamab mafodotin-blmf is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. [105]


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