Molecular-oriented therapy approaches in patients with RRMM

Multiple myeloma (MM) is a malignant disease characterized by clonal proliferation of abnormal plasma cells.¹ Over the past two decades, the treatment landscape for MM has significantly advanced, including the development of next-generation sequencing techniques. As a result, actionable mutations such as BRAF can be identified and targeted for potentially tailored therapies.¹ For a greater overview of the current landscape of precision medicine in MM, check out our previous article highlighting current targeted treatments and future possible targets.

Andreozzi et al.¹ recently published results from the multiple myeloma early phase I (MM-EP1) study assessing the clinical benefits of personalized molecular-oriented (MO) versus non-molecular-oriented (no-MO) approaches in patients diagnosed with relapsed/refractory (R/R) MM. We summarize the key findings here.

Study design

This was a retrospective study analyzing data collected between 2013 and 2022 from 103 patients with R/R MM with at least one prior line of treatment. The study criteria for molecular characterization were as follows:

• Age ≥18 years
• Confirmed R/R MM
• Performance status 0–2
• Measurable disease in serum
• Consent for tumor molecular analysis and constitutional DNA analysis

Patients were considered as treated with a MO approach if they presented with t(11;14) and treated with BCL2 inhibitors, t(4;14) with FGFR3 rearrangement and treated with FGFR3 inhibitors, or a BRAF mutation and treated with BRAF inhibitors. Patients treated with therapies without an MO approach were included in the no-MO group. The efficacy endpoints included tumor response rate, overall survival, progression-free survival, and percentage reduction in monoclonal component.

Results

Baseline characteristics

The median age of patients was 67 years (range, 44–85 years) and the median number of previous lines of therapy was 4 (range, 1–8; Table 1).

Table 1. Patient characteristics*

Molecular characteristics

A total of 93 patients were included in the cytogenetic analysis. Figure 1 shows the most recurrent cytogenetics alterations.

Figure 1. Most recurrent cytogenetic alterations* 

*Adapted from Andreozzi, et al.¹

The median number of aberrant genes identified by next-generation sequencing analysis was 2 (range, 1–7) and the distribution of these gene mutations is shown in Figure 2.

Figure 2. Gene mutations identified by NGS* 

NGS, next-generation sequencing.
*Adapted from Andreozzi, et al.¹

The mutational interaction matrix identified a significant co-existence of NRAS and FAM46C mutations (p < 0.01) and a significant mutual exclusion of KRAS and NRAS mutations (p < 0.05). DIS3 and KRAS mutations were mostly associated with a chromosome 1 abnormality, while BRAF and NRAS mutations were associated with a normal karyotype.

Potentially actionable molecular targets were identified in 48% of patients (Figure 3). The median variation in measurable monoclonal component in serum was a reduction of 91% vs 30% (p = 0.33) in the MO and no-MO groups.

Figure 3. Potential actionable molecular targets* 

*Adapted from Andreozzi, et al.¹

Efficacy endpoints

The overall response rate was 65% vs 58% in the MO and no-MO groups, respectively (Figure 4). The median progression-free survival was 9 months vs 6 months (hazard ratio, 0.96; 95% confidence interval, 0.51–1.78; p = 0.88) and the median overall survival was 26 months vs 28 months (hazard ratio, 0.98; 95% confidence interval, 0.46–2.12; p = 0.98) in the MO and no-MO groups, respectively.

Figure 4. Response rates* 

MO; molecular oriented; MR, minimal response; no-MO, non-molecular oriented; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.
*Adapted from Andreozzi, et al.¹

Overall, 54 deaths occurred, eight in the MO group and 46 in the no-MO group. The causes of death included disease progression (n = 47), secondary malignancy (n = 3), COVID-19 (n = 2), influenza infection (n = 1), and coronary ischemic disease (n = 1).

Conclusion

This retrospective study highlights the potential relationships between genetic mutations and karyotype abnormalities. However, the benefits of MO treatment remain unclear as it did not translate into improved clinical outcomes compared with no-MO therapies. The study was limited by its retrospective nature, small sample size, patient selection bias, and the sequencing panel limit of 29 genes, thus, not allowing a complete characterization of the R/R MM samples. Therefore, future studies on the use of genomics and improving algorithms of molecular precision medicine for patients with MM are warranted.