PFS and Depth of Response Associated With Isatuximab Plus Carfilzomib and Dexamethasone in Patients With Multiple Myeloma

Winston Wong, PharmD, Editor-in-Chief of the Journal of Clinical Pathways, discusses results from the IKEMA trial, a randomized, open-label, multicenter phase 3 study comparing isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in patients with relapsed multiple myeloma.

Transcript

Welcome to this segment of Perspectives in Oncology.  My name is Winston Wong, Editor-in-Chief of the Journal of Clinical Pathways.

In June 2021, the first read-out of the IKEMA clinical trial was published.  The IKEMA trial was a randomized, open-label, multicenter phase 3 study comparing isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs carfilzomib and dexamethasone in patients with relapsed multiple myeloma.  An update of the IKEMA readout was recently published reporting the results of additional analysis completed on the study population

Over the past 10 years, the development of several novel treatments with different mechanisms of action has improved the survival of patients with multiple myeloma. As a result, an increasing proportion of patients with multiple myeloma are achieving improved and deeper responses. However, despite these therapeutic advances, multiple myeloma remains incurable, and new potent treatment regimens are required to address this unmet clinical need.

A “Deep Response” to treatment in a patient with multiple myeloma is associated with improved progression-free survival (PFS) and overall survival (OS). Minimal residual disease (MRD) is an important prognostic factor, and achievement of negative MRD status is associated with improved survival outcomes. Importantly, use of MRD assessment to measure response to multiple myeloma treatment and predict survival outcomes in clinical practice may lead to early utilization of the most effective targeted therapies.

As previously noted, patients with multiple myeloma are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and decreases end-organ damage.  The goal of therapy is to achieve and maintain a response, improve quality of life, and prolong overall survival.  Initial treatment is dependent upon the patient’s presentation and determination of having either standard-risk disease or high-risk disease, based upon testing for specific translocations and /or deletions, as well as the presence of other clinical features.  It bears noting that the definition of high-risk disease continued to evolve as we learn more about the natural course of the disease.

Many of the preferred treatment options have not been compared directly with each other in a randomized trial. As such, there is no standard of care, and different Key Opinion Leaders use different regimens. Data supporting their use come largely from single- arm trials or randomized trials comparing different regimens. Three-drug regimens are preferred over two-drug regimens whenever possible because they appear to provide an overall survival (OS) benefit. Four-drug regimens may offer additional benefit to patients with high-risk disease.  The development of novel therapeutic agents such as the proteasome inhibitors and the immunomodulatory drugs have improved the clinical outcome of patients with multiple myeloma in recent decades. In newly diagnosed patients, the response rate, progression-free survival, and overall survival have all increased dramatically.

Multiple myeloma remains a chronic and incurable disease in the majority of instances. Most patients will have an initial response to treatment, however, will ultimately relapse due to the emergence of drug-resistant clones, thereby becoming refractory to standard treatment regimens. Patients double-refractory to a proteasome inhibitors and immunomodulatory drugs have a particularly poor prognosis.  As a result, alternative mechanisms of action are urgently needed to overcome drug resistance and reduce disease relapse.

Monoclonal antibody–based therapies have substantially improved clinical outcomes for patients with multiple myeloma. In late 2015, the FDA approved two monoclonal antibodies to treat patients with relapsed and refractory multiple myeloma after demonstrating promising preclinical and clinical activities.

Daratumumab was approved under the accelerated approval process in Nov 2015 for the treatment of patients with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or are double refractory to a proteasome inhibitor and an immunomodulatory agent.  Full approval was granted in Nov 2016. Currently, Daratumumab is approved for 7 different indications for the treatment of newly diagnosed and relapsed or refractory multiple myeloma as monotherapy, three-drug regiments, and four drug regiments.  And as noted, Daratumumab is also indicated as monotherapy for double-refractory patients. 

Elotuzumab was also approved under the Breakthrough approval process in Nov 2015 for the treatment of multiple myeloma in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Full approval was granted in Nov 2018. Currently, Elotuzumab is indicated for 2 different triple regimens for relapsed or refractory multiple myeloma.

Isatuximab was approved under an orphan drug designation in March 2020 for use in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.  This approval was based upon the ICARIA trial, a multicenter, multinational, randomized, open-label, two-arm, phase 3 study in 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies including lenalidomide and a proteasome inhibitor. The primary endpoint was progression-free survival (PFS) where a 40% reduction in the risk of disease progression or death was observed. The median PFS for the patients who received the isatuximab, pomalidomide, and dexamethasone triplet was 11.53 months vs 6.47 months in patients receiving only the pomalidomide/dexamethasone doublet.

In March 2021, Isatuximab was again approved under an orphan designation for use in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.  This approval was based upon our focus for this perspectives segment, the IKEMA trial.

As I initially described, IKEMA trial was a multicenter, multinational, randomized, open-label, two-arm, phase 3 trial in patients with relapsed and/or refractory multiple myeloma who had received one to three prior lines of therapy. The trial evaluated the efficacy and safety of isatuximab in combination with carfilzomib and dexamethasone.   The trial randomized 302 patients in a 3:2 to receive the isatuximab based triplet, vs the carfilzomib/dexamethasone doublet.  The primary endpoint was progression-free survival, assessed by an independent response committee using International Myeloma Working Group criteria. At the time of the initial read-out in June 2021, following a median of 20.7 months of follow-up, the median progression-free survival had not been reached in the triplet group, whereas, in the doublet arm, the median PFS was 19.2 months, which was consistent with the protocol assumption and results from ENDEVOR trial.  The risk of disease progression or death was estimated to be 47% lower in the isatuximab group.  Key secondary end points were overall response rate (ORR), complete response (CR) rate, very good partial response or better (>VGPR) rate, minimal residual disease (MRD) negativity rate, and overall survival (OS).

An updated readout of the IKEMA trial was recently published, providing a full readout of the primary and secondary endpoints. The updated results report that the isatuximab triplet combination demonstrated a median progression free survival of 35.7 months, compared to the reported 19.2 months in patients treated with the doublet, representing the longest median PFS among studies investigating a proteasome inhibitor backbone in the second-line setting for the treatment of relapsed multiple myeloma (multiple myeloma).

At a median follow-up of 20.7 months, deeper responses were observed in the isatuximab triplet patients.  The >VGPR rate was 72.6% vs 56.1% and CR of 39.7% vs 27.6% in the triplet vs doublet groups respectively. MRD negativity occurred in 29.6% the triplet group vs 13.0% of the doublet group.  20.1% of the triplet group achieved both MRD–negative and CR status vs only 10.6% of the doublet group.  The conclusion reached was that depth and quality of response was superior in the isatuximab group when compared to the control group, including a high complete response with MRD negativity rate, which is a prognostic factor for better progression-free survival and overall survival.

So, what does this all mean.  There should be no disagreement that treatment options for relapsed multiple myeloma have improved significantly over the past decade resulting in increases in response rates, improved quality of life, and life expectancy.  However, given the nature of the disease with many patients experiencing relapses following multiple therapies, there is a continual need for new molecules and novel combinations of treatments to improve patient outcomes.

The IKEMA trial demonstrated significantly improved median PFS intervals, with a greater depth of response, with a higher percentage of patients achieving MRD – negative status and at least twice as many patients achieving both a complete response with MRD negativity. Furthermore, the ability to achieve an MRD-negative status is associated with longer PFS overall.  Due to a continued refinement of the diagnostic process to establish a complete response, it is actually being suggested that the actual complete response rate reported in the IKEMA trial is under estimated and using the new evaluation criteria to complete response rate could actually be an unprecedented 45.8% of patients previously treated with 1 to 3 prior lines of therapy.

This high incidence of patients with at least 1 prior line of treatment reaching MRD-negative/complete response supports the placement of isatuximab based regimens as a new standard of care for patients with relapsed multiple myeloma.

Thank you for taking the time to listen to this Perspectives segment.  Please check out www.journalofclinicalpathways.com for the latest updates on issues related to the development, implementation, and evaluation of clinical pathways.