Use of Isatuximab as Early Therapy in Patients with Multiple Myeloma

Multiple myeloma (MM) immunotherapies are increasing in availability and efficacy. This is an exciting time for MM providers and patients affected with MM, an incurable blood cancer, as these treatments are extending survival and delaying MM progression. Isatuximab (Isa) is one example of a novel anti-CD38 monoclonal antibody therapy with remarkable efficacy. It was approved by the US Food and Drug Administration (FDA) in March 2020, for treatment of relapsed/refractory MM (RRMM). The ICARIA-MM and IKEMA-MM phase 3 trials have been pivotal in identifying Isa’s high efficacy and favorable tolerability profile as a notable therapy in the role of RRMM management. Recently, there have been additional updates illustrating the unique effects of Isa. This article focuses on these updates and how they may inform the role of Isa in the treatment of MM.

First is the recently updated survival outcome for the IKEMA-MM trial. The final published analysis shows an impressive 41.7-month (hazard ratio [HR], 0.59; 95% confidence interval [CI], 27.1-not reached; n = 179) median progression-free survival (mPFS) in the Isa combined with carfilzomib and dexamethasone (Isa-Kd) patient cohort compared with 20.8 months in patients treated with Kd alone (95% CI, 16.2-28.2; n = 123).¹ This lengthy duration of response in a population of patients with RRMM is rather remarkable, especially in the setting of lenalidomide refractoriness,² accentuating the superior beneficial outcome of the potent Isa triplet combination in the treatment of relapsed/refractory disease. Further updates in the IKEMA-MM trial include the persistent effects of sustained delay in MM disease progression, measured by the time to next therapy (TTNT) and progression-free survival 2 (PFS2), which were 44.9 and 47.2 months, respectively, for the Isa-Kd versus 25.0 and 35.6 months for the Kd cohort.² In comparison with similar phase 3 RRMM trials evaluating anti-CD38 monoclonal antibody–based triplet therapy versus doublet therapy, such as the CANDOR trial (mPFS of 28.6 months [95% CI, 22.7-not estimable] for Kd plus daratumumab vs 15.2 months for Kd [95% CI, 11.1-19.9; HR, 0.59; 95% CI, 0.45-0.78; P <.0001]),³ the IKEMA-MM mPFS outcome is notably more impressive. These results are the first to show such an extensive mPFS, surpassing 3 years, for patients with RRMM beyond first-line therapy. The results are even further illustrated by the delay of TTNT and PFS2. The clinical consequence is enhanced survival outcomes for patients with RRMM.

Building on this are the early inspiring results from the GMMG-HD7 trial of Isa in combination with bortezomib, lenalidomide, and dexamethasone (Isa-RVd) versus RVd in patients with newly diagnosed MM. The GMMG-HD7 trial showed that minimal residual disease (MRD) negativity rates after induction were 35.6% versus 50.1% (odds ratio [OR], 1.83; 95% CI, 1.34-2.51; P <.001) for RVd versus Isa-RVd. On multivariate analyses including treatment arm, revised International Staging System score, performance status, renal impairment, age, and sex, treatment with Isa-RVd (vs RVd) remained the only significant predictor for increased MRD negativity after induction (OR, 1.82; 95% CI, 1.33-2.49; P <.001). While the rates of complete response after induction did not yet differ between the RVd versus Isa-RVd arms (21.6% vs 24.2%, P = .46), the rate of very good partial response or better was significantly higher in the Isa-RVd arm (60.5% vs 77.3%, P <.001). The rates of progressive disease were 4.0% (RVd) versus 1.5% (Isa-RVd). This was compelling in that the depth of response was reached in such a short time frame. This met the study’s primary end point, but more importantly the primary end point was achieved in a mere unprecedented 18 weeks (4.5 months) of Isa-based induction therapy.

Secondly, an interesting signal noticed from subgroup analysis of the IKEMA-MM trial is the favorable PFS benefit seen in patients with chromosome 1q21 gain. This benefit was also seen in those patients with amplification in gain of chromosome 1q.^4,5 In the past few years, it has been shown that the gain 1q21 chromosomal abnormality occurs quite often in MM, both at diagnosis and even more frequently in RRMM.^5-7 This genetic somatic copy abnormality is associated with inferior clinical outcomes, such as shorter survival times and rapid myeloma disease progression.⁷ In RRMM, the gain 1q21 chromosomal mutation is often amplified, with increasing copies; this amplification conveys even poorer prognostic outcome.^6,7

In the current treatment era, there is momentum toward personalized and biomarker-targeted therapy. This is an area of ongoing clinical interest to improve MM patient survival through identification and selection of the best therapeutic agents to target specific biomarkers, such as chromosome 1q21 gain. In essence, personalizing MM therapy is meant to eradicate the most pathologic malignant clone in MM patients with this genetic abnormality. An early example is bortezomib, the first FDA-approved proteosome inhibitor, negating the poor prognostic effects of t(4;14) in patients with MM.^8,9 A more recent example of this biomarker-targeted approach being currently investigated in clinical trials is the use of venetoclax, an oral BCL-2 inhibitor, in treating MM patients with t(11;14) disease.¹⁰ Given the results of the IKEMA trial subgroup findings, Isa may be the PFS equalizer for MM patients with chromosomal gain of 1q21. Further prospective trials and investigation in this area are warranted.

Finally, the IKEMA-MM trial updates illustrated the benefit of using Isa in RRMM patients with severe renal insufficiency, such as those with an estimated glomerular filtration rate as low as 15.¹¹ Nearly two-thirds of patients with newly diagnosed MM present with renal insufficiency, and with further therapy over time we see increasing renal insufficiency in patients with RRMM.^12-14 This prespecified analysis showed that with Isa-based therapy, the patients with RRMM and renal insufficiency had more durable (32.0% vs 7.7%, Isa-Kd vs Kd) and complete responses (52.0% vs 30.8%, Isa-Kd vs Kd) than the non-Isa cohort.¹⁵ Further updates from the ICARIA-MM trial reinforce these findings, such as that inclusion of Isa with pomalidomide and dexamethasone (Pd) versus Pd alone shows longer mPFS (11.1 months [95% CI, 7.8-13.8] vs 5.9 months; HR, 0.60; 95% CI, 0.46-0.78; P <.0001).¹⁶ These effects of Isa in patients with MM and such severe renal insufficiency have not been demonstrated with other MM therapies.

In summary, the updated IKEMA-MM results alongside the ICARIA-MM and GMMG-HD7 trial results spotlight Isa’s unique activity and favorable therapeutic responses in comparison with the other FDA-approved anti-CD38 monoclonal antibody, daratumumab. Isa is the first anti-CD38 monoclonal antibody to show an extensive mPFS, beyond 3 years in post–lenalidomide-exposed RRMM patients. Isa is the only anti-CD38 monoclonal antibody that has shown favorable PFS benefit specifically in RRMM patients with chromosomal gain of 1q21, a high-risk prognostic marker for patients with MM.^1,17 Patients with MM with severe renal insufficiency may preferentially benefit with use of Isa early in therapeutic management.^11-14 These evolutionary results show that use of Isa as an early therapy in patients with MM translates to advantageous clinical outcomes, the most significant being the favorable extension of mPFS for patients with RRMM beyond what has been shown in prior phase 3 RRMM trials.

References

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