Carfilzomib, Lenalidomide, and Dexamethasone: A Curative Approach for Smoldering Multiple Myeloma

Study findings have shown a potential curative strategy for high-risk smoldering multiple myeloma (HRSMM) involving carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc), lenalidomide (Revlimid; Bristol Myers Squibb), and dexamethasone (KRd) followed by transplant, KRd consolidation, and lenalidomide plus dexamethasone (Rd) maintenance. The data showed that the combination therapy can improve undetectable measurable residual disease (uMRD) rates.

The findings from the phase 2 trial highlight a promising approach for HRSMM, suggesting the benefit of early intervention in place of observation. Image Credit: © Сергей Косилко - stock.adobe.com

SMM is a precursor disease to multiple myeloma (MM), a hematological malignancy originating from blood cells in the bone marrow. It is a precancerous condition characterized by low levels of myeloma cells. Patients with SMM have a 10% annual risk of progressing to MM, which is highest in the first 5 years following diagnosis. By the time SMM begins progressing to MM, mutated genes have been accumulating for 30 years. Traditionally, treatment for SMM is observation; however, emerging studies show that early treatment of patients with HRSMM can delay progression to MM.^1,2

In a nonrandomized, open-label, multicenter phase 2 trial (NCT02415413), 90 patients with HRSMM (>50% progression risk at 2 years) who were transplant candidates were included and received induction therapy with KRd for 6 cycles, followed by high-dose melphalan (200 mg/m2) autologous stem-cell transplantation (HDM-ASCT), 2 KRd consolidation cycles, and Rd maintenance for 2 years. Of the participants, 31% met at least 1 SixtyLightchain MRI (SLiM)-hypercalcemia, renal impairment, anemia, bone disease (CRAB) criterion. The study’s primary end point was uMRDrate by next-generation flow after ASCT, with a secondary end point of sustained uMRD 4 years after ASCT.^3,4

At a median follow-up of 70.1 months, 3 months after ASCT 62% of 90 patients had uMRD, which 31% sustained for 4 years. Of the patients, 5 progressed to MM with a 70-month progression rate of 94% (95% CI, 84 to 89), of which the presence of any SLiM CRAB criteria predicted progression to MM (4 of the 5 patients; hazard ratio, 0.12; 95% CI, 0.14 to 1.13; P = .03). The 70-month overall survival was 92% (95% CI, 82 to 89).⁴

The most frequent adverse events recorded were neutropenia and infections, which resulted in 1 treatment-related death. Additionally, 3 second primary malignancies were reported.⁴

The findings from the phase 2 trial highlight a promising approach for HRSMM, suggesting the benefit of early intervention in place of observation. The researchers reported that KRd and ASCT demonstrated favorable safety and results; however, the role of early treatment in SMM remains a topic of debate. Despite this, additional trials continue to investigate the potential of novel therapies in tackling SMM prior to MM progression, such as CENTAURUS (NCT02316106), evaluating daratumumab (Darzalex; Janssen Biotech) in patients with SMM; and ASCENT (NCT03289299) investigatingcarfilzomib, lenalidomide, daratumumab, and dexamethasone in patients with HRSMM.^5,6

REFERENCES

1. Smoldering multiple myeloma. Memorial Sloan Kettering Cancer Center. Accessed October 31, 2024. https://www.mskcc.org/cancer-care/types/multiple-myeloma/other-plasma-cell-diseases/smoldering-multiple-myeloma

2. Multiple myeloma precursor diseases: advancing diagnosis and treatment for mgus and smm. Pharmacy Times. September 25, 2024. Accessed October 31, 2024. https://www.pharmacytimes.com/view/multiple-myeloma-precursor-diseases-advancing-diagnosis-and-treatment-for-mgus-and-smm

3. Carfilzomib in treatment patients under 65 years with high risk smoldering multiple myeloma. ClinicalTrials.gov Identifier: NCT02415413. Updated September 10, 2022. Accessed October 31, 2024. https://www.clinicaltrials.gov/study/NCT02415413

4. Mateos M, Martínez-López J, Otero P, et al. Curative strategy for high-risk smoldering myeloma: carfilzomib, lenalidomide, and dexamethasone (krd) followed by transplant, krd consolidation, and rd maintenance. J Clin Oncol. July 22, 2024. doi:10.1200/JCO.23.02771

5. A study to evaluate 3 dose schedules of daratumumab in participants with smoldering multiple myeloma. ClinicalTrials.gov Identifier: NCT02316106. August 16, 2024. Accessed October 31, 2024. https://clinicaltrials.gov/study/NCT02316106

6. Aggressive smoldering curative approach evaluating novel therapies and transplant (ascent). ClinicalTrials.gov Identifier: NCT03289299. December 12, 2023. Accessed October 31, 2024. https://clinicaltrials.gov/study/NCT03289299