Novel Small Molecule Drugs for the Treatment of Triple-Class Refractory Myeloma


Robert Z. Orlowski, MD, PhD, director of the Myeloma Section at the University of Texas MD Anderson Cancer Center, reviewed novel agents in the treatment of triple-class refractory myeloma during a session at the 2021 annual meeting of the Society of Hematologic Oncology (SOHO). According to Orlowski, the 2021 National Comprehensive Cancer Network Guidelines for the treatment of relapsed and refractory multiple myeloma specify more than 30 treatment options.

Melphalan flufenamide (melflufen; Pepaxto), the first novel small molecule treatment for triple-class refractory myeloma reviewed by Orlowski, is a highly lipophilic peptide drug conjugate. According to Orlowski, it is essentially a pro-drug of melphalan.

“Once this drug gets inside cells, aminopeptidases convert it to the active drug,” Orlowski said in the presentation. “Because these aminopeptidases are expressed at higher levels inside cancer cells, there is a better therapeutic index than there is with melphalan alone.”

The approval of melflufen is based on the HORIZON study, in which 76% of the study population had triple-class refractory disease and a median of 5 prior lines of therapy. The overall response rate (ORR) seen in the triple-class refractory portion of the study population was 26%, compared to an ORR of 29% in the general study population. Progression-free survival (PFS) was approximately 4 months for both the overall study population and the triple-class refractory population, whereas median overall survival (OS) was close to 1 year. The clinical benefit rate (CBR), which includes minimal responses, was approximately in the range of 40% to 50% of patients responding, according to Orlowski.

“Many of these responses were quite durable, with patients able to stay on for 6 to 12 months, and, in some cases, for an even longer period,” Orlowski said during the presentation.

The second agent Orlowski reviewed, Selinexor (Xpovio), blocks the transport of proteins between the nucleus and the cytoplasm of treated cells. In particular, it may work through the retention of tumor repressor proteins in the nucleus as opposed to them being exported into the cytoplasm, according to Orlowski.

“We know data from a few years ago about the efficacy of selinexor and dexamethasone,” Orlowski said in the presentation. “The quad- and penta-refractory patients had good overall responses.”

The median PFS for patients receiving the combination of selinexor and dexamethasone was 2.3 months, whereas the median OS was 9.3 months, which Orlowski said was somewhat impressive. The ORR for this drug combination was 21%, whereas the CBR was approximately 33%. Orlowski said that the toxicities associated with this treatment, which include thrombocytopenia, anemia, and hyponatremia at grade 3 or 4, are usually fairly easy to manage with some experience.


Robert Z. Orlowski. Treatment of Triple Class Refractory Myeloma: Novel Agents. Presented at: Society of Hematologic Oncology 2021 Annual Meeting; September 9, 2021. Accessed September 29, 2021.

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