Research aims to address clinical challenges of triple-class refractory multiple myeloma
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Novel therapies and treatment strategies could help to address the clinical challenges of triple-class refractory multiple myeloma, according to a speaker at Chemotherapy Foundation Symposium.
“Triple-class refractory multiple myeloma is kind of the all-equalizer because it tells us where the patient is in terms of sensitivity or refractoriness to prior therapies,” Noa Biran, MD, of the multiple myeloma division at Hackensack Meridian John Theurer Cancer Center, said during her presentation.
The subgroup includes patients who experience disease progression while on or within 60 days of treatment with proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.
“This represents an unmet need for patients with myeloma,” she said. “We need to develop therapies specifically targeting this population.”
FDA-approved treatments include traditional chemotherapy, B-cell maturation antigen (BCMA)-directed therapy — including the CAR T-cell therapy idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) — small-molecule inhibitors, monoclonal antibodies and histone deacetylase inhibitors. In addition, several agents are under investigation in clinical trials.
In the randomized phase 3 IKEMA trial, the addition of isatuximab (Sarclisa, Sanofi-Aventis), an anti-CD-38 monoclonal antibody, to the proteasome inhibitor carfilzomib (Kyprolis, Amgen) and dexamethasone improved PFS among 302 patients with relapsed multiple myeloma with a median of two prior lines of therapy (median PFS, not reached vs. 19.1 months; HR = 0.53). The isatuximab group had a higher rate of grade 3 adverse events, many of which were related to infections or prolonged cytopenias, Biran said. A subgroup analysis showed a PFS benefit among patients with high-risk and standard-risk cytogenetic abnormality, isolated 1q21 gain or 1q21 gain combined with cytogenetic abnormality, and 1q21 amplification.
Isatuximab also demonstrated a PFS benefit when added to pomalidomide (Pomalyst, Bristol Myers Squibb) and dexamethasone in the randomized phase 3 ICARIA trial, which included 307 patients with relapsed or refractory multiple myeloma. Median PFS was 11.1 months with the isatuximab combination vs. 5.8 months with pomalidomide and dexamethasone alone (HR = 0.599; P < .0001), with a higher rate of any grade 3 or higher treatment-related adverse events in the isatuximab group (90.8% vs. 75.2%) but fewer treatment-related discontinuations (11.8% v. 14.1%).
“The theme here is that triplets are better than doublets, and quadruplets always tend to be better than triplets ... and perhaps we need to compare treatments to triplets, not doublets, moving forward,” Biran said.
Other agents that have shown promise among patients with refractory multiple myeloma include:
- Selinexor (Xpovio, Karyopharm Therapeutics), an oral exportin 1 inhibitor, which — when added to bortezomib (Velcade, Takeda) and dexamethasone in a once-weekly regimen — improved overall response rate (76.4% vs. 62.3%) and median PFS (13.9 months vs. 9.5 months; HR = 0.7) among 402 patients in the randomized phase 3 BOSTON trial, which included 13 triple-class exposed and six triple-class refractory patients. In a study by Gasparetto and colleagues, a combination of selinexor, carfilzomib and dexamethasone showed overall response rates of 78% among the entire cohort of 33 patients and 67% among 12 triple-class refractory patients.
- Venetoclax (Venclexta; AbbVie, Genentech), a BCL-2 inhibitor, which — when added to bortezomib and dexamethasone in the randomized phase 3 BELLINI trial — significantly improved PFS but not OS, possibly due to increased risk for infections, Biran said.
- Belantamab mafodotin-blmf (Blenrep; GlaxoSmithKline), a BCMA-directed antibody that received FDA approval last year for treatment of patients with relapsed or refractory multiple myeloma. The agent conferred an ORR of 78% (95% CI, 52.4-93.6) in combination with bortezomib and dexamethasone among patients in the phase 2 DREAMM-2 study who had one or more prior lines of therapy. It also is being investigated in combination with other agents.
- Iberdomide (CC-220, Celgene), a CRBN E3 ligase modulator that inhibits the degradation of target proteins Ikaros and Aiolos, which are thought to mediate efficacy of immunomodulatory agents, Biran said. The CC-220-MM-001 study is examining the agent in combination with several backbone drugs for multiple myeloma. Results showed ORRs of 45.9% in combination with daratumumab/dexamethasone, 56% in combination with bortezomib/dexamethasone and 50% with carfilzomib/dexamethasone, with a favorable safety profile. At least 30% of patients in each of the cohorts had triple-class refractory disease, Biran said.
Further study of personalized medicine approaches continues in the MyDRUG (Myeloma-Developing Regimens Using Genomics) trial, she said.
Biran concluded by listing four goals for treatment of triple-refractory multiple myeloma: improve symptoms, obtain a deep remission, use your most effective therapies first rather than reserving them for later, and consider clinical trials at every relapse, even early relapse.
“Later on in the disease course, the disease may be progressing too rapidly or the patient may have end-organ disease and not qualify,” she said.
References:
Biran N. Tackling the clinical challenges of triple-class refractory multiple myeloma. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
Grosicki S, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)32292-3.
Kumar SK, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30525-8.
Lonial S, et al. Abstract 1087033. Presented at: International Myeloma Workshop 2021; Sept. 8-11, 2021, Vienna.
Moreau P, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00592-4.
Nooka A, et al. Abstract 8502. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Perrot A. Abstract S186. Presented at: European Hematology Association Annual Congress; June 10-13, 2021.
Spicka I, et al. J Clin Oncol. 2021;doi: 10.1200/JCO.2021.39.15_suppl.8042.
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Biran N. Tackling the clinical challenges of triple-class refractory multiple myeloma. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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