The latest results from the randomized, multi-center, open lable, Phase 3 IKEMA clinical trial evaluating isatuximab (Sarclisa®; Sanofi) in combination with carfilzomib (Kyprolis®; Amgen) and dexamethasone (Decadron®; Merck & Co) in the treatment of patients with relapsed multiple myeloma receiving a proteasome inhibitor therapy, demonstrated a median progression free survival (mPFS) of 35.7 months (Hazard Ratio [HR] 0.58; 95% Confidence Interval [CI]: 25.8 to 44.0; n=179), compared to 19.2 months in patients treated with dexamethasone alone (95% CI: 15.8 to 25.1; n=123), as evaluated by an Independent Review Committee.
The results of the study, presented at the 8th World Congress on Controversies in Multiple Myeloma (CoMy) held in Paris, France, May 12 – 15, 2022, represent the longest mPFS among studies investigating a proteasome inhibitor backbone in the second-line setting for the treatment of relapsed multiple myeloma. These data will also be presented at the European Society for Medical Oncology on May 19, 2022.
Common hematologic malignancy
Multiple myeloma, a cancer of the bone marrow plasma cells, is the second most common hematologic malignancy with more than 130,000 new diagnoses of multiple myeloma worldwide yearly.  Despite available treatments, multiple myeloma remains an incurable malignancy and is associated with significant patient burden. Since multiple myeloma does not have a cure, most patients will, in time, relapse.
In addition to chemotherapy, alkylators and corticosteroids, there are a number of different agents used to treat multiple myeloma. Among these active treatments are proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs or IMiDs (thalidomide, lenalidomide, and pomalidomide), histone deacetylase inhibitors or HDACs (panobinostat), and monoclonal antibodies (elotuzumab, daratumumab and isatuximab) targeting SLAMF7 and CD38. And while each of these anti-cancer agents works in a different way, in essence, their common goal is to control and destroy multiple myeloma cells. In addition currently approved agents, there are clinical trials under way to evaluate the benefits and risks of drugs that are in development.
Although Isatuximab, an antibody that targets a specific epitope on the CD38 receptor on multiple myeloma cells, is approved in a number of countries (including the U.S. and EU) in combination with pomalidomide (Pomalyst® Celgene Corporation, a Bristol-Myers Squibb Company) and dexamethasone for the treatment of patients with relapsed refractory multiple myeloma (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor, the drug continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the multiple myeloma treatment continuum.
Mechanism of action
Isatuximabis is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of multiple myeloma cells, making it a potential target for antibody-based therapeutics such as isatuximab.
As part of the Phase 3 IKEMA study, isatuximab was administered through an intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with carfilzomib twice weekly at the 20/56mg/m2 dose and dexamethasone at the standard dose for the duration of treatment. The results of the study confirmed a mPFS of more than three years in patients with relapsed multiple myeloma when isatuximab was added to the proteasome inhibitor backbone of therapy.
Increase in mPFS
“The increase in progression free survival was observed consistently across all subgroups, when adding isatuximab to carfilzomib and dexamethasone is remarkable in patients with relapsed multiple myeloma in a proteasome inhibitor combination,” said Philippe Moreau, M.D. Head of the Department of Hematology, University Hospital of Nantes, France.
“Relapse is common in multiple myeloma, creating the need for differentiated second-line treatments that provide patients a longer period of time without disease progression. This updated analysis reinforces the potential for isatuximab to become a new standard of care for patients with relapsed multiple myeloma,” Moreau added.
A PFS analysis following the U.S. Food and Drug Administration (FDA) recommendations on censoring rules, as applied in the approved U.S. prescribing information, showed an mPFS of 41.7 months for isatuximab added to dexamethasone (isatuximab combination therapy) compared to 20.8 months in patients treated with dexamethasone alone (HR 0.59; 95% CI: 27.1 to Not Calculable [NC]).
Time to next treatment for patients treated with isatuximab combination therapy was 44.9 months (HR 0.55; 95% CI: 31.6 to NC) versus those treated with dexamethasone alone at 25 months (95% CI: 17.9 to 31.3). Time to next treatment measured the interval from the date of randomization to the date of commencement of the next line of therapy, thereby allowing for measurement of the period of therapeutic benefit. 
“To observe progression free survival of more than three years in patients with relapsed multiple myeloma when isatuximab was added to a proteasome inhibitor backbone of therapy is unprecedented and reinforces our confidence in isatuximab as a potential best in class anti-CD38 antibody,” said Peter C. Adamson, MD, Global Head of Oncology Clinical Development and Pediatric Innovation at Sanofi.
Safety and tolerability
The safety and tolerability of isatuximab observed in this analysis were consistent with the safety profile of Sarclisa in other clinical trials, with no new safety signals observed. For the isatuximab combination therapy and dexamethasone groups, the most common adverse events were infusion related reaction (45.8%, 3.3%), diarrhea (39.5%, 32%), hypertension (37.9%, 35.2%), upper respiratory tract infection (37.3%, 27%), fatigue (31.6%, 20.5%), dyspnoea (30.5%, 22.1%), pneumonia (27.1%, 21.3%), back pain (25.4%, 21.3%), insomnia (25.4%, 24.6%), and bronchitis (24.3%, 12.3%).
“Treatment exposure in the isatuximab combination therapy arm was 30 weeks longer than in the control arm. Treatment emergent adverse events (TEAEs) of ≥ Grade 3 were reported in 83.6% of patients treated with isatuximab combination therapy and in 73% of those treated with Kd alone. Serious TEAEs were higher in the isatuximab combination therapy arm versus dexamethasone alone (70.1% versus 59.8%). No difference was observed after exposure adjustment,” Adamson concluded.
These results will be discussed with regulatory authorities at a future date.
Multinational Clinical Study Comparing Isatuximab, Carfilzomib And Dexamethasone To Carfilzomib And Dexamethasone In Relapse And/Or Refractory Multiple Myeloma Patients (IKEMA) – NCT03275285
Highlights of prescription information
Isatuximab (Sarclisa®; Sanofi) (prescribing information)
Carfilzomib (Kyprolis®; Amgen) (prescribing information)
Dexamethasone (Decadron®; Merck & Co) (prescribing information)
Pomalidomide (Pomalyst® Celgene Corporation/Bristol-Myers Squibb)(prescribing information)
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