Anti-CD38 Monoclonal Antibody for Multiple Myeloma: A Review of Clinical Trials

Multiple myeloma (MM) is the most common type of plasma cell tumor. In 2019,¹ there were 27,825 newly reported cases and 12,455 deaths attributable to MM in the United States. The American Cancer Society² estimates approximately 34,470 new cases and 12,640 deaths in 2022.

Because MM occurs in bone marrow, patients may experience bone pain or weakness, as well as blood cell shortages potentially resulting in anemia, leukopenia, and thrombocytopenia. MM can also cause hypercalcemia, which can lead to kidney problems, abdominal pain, and other symptoms impacting patients’ quality of life.³

The 5-year relative survival for patients with MM was 53.9% as of 2016, up from 34.6% in 1998. This increase is attributed to the approval of an array of new drugs over the last several years.⁴

Isatuximab-irfc is a CD38-directed cytolytic antibody approved by the US Food and Drug Administration in March 2020. Its first approved indication was in combination with pomalidomide and dexamethasone for the treatment of adult patients who received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor.⁵ In March 2021, isatuximab was approved for use with carfilzomib and dexamethasone in adult patients with relapsed or refractory (R/R) MM who have received 1 to 3 prior therapies.⁶

Isatuximab’s first and second indications were supported by the ICARIA-MM and IKEMA trials, respectively. Additional trials and analyses have been conducted, and at least 2 more prospective studies are underway.

The SKylaRk trial,⁷ a phase 2 study designed to measure efficacy of isatuximab in combination with carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients with newly diagnosed, transplant-eligible MM was inspired by the GMGG-CONCEPT study, in which Isa-KRd produced fast, deep responses in patients with high-risk, newly diagnosed MM.

SKylaRk includes 50 patients with all-risk disease who were enrolled between August 2020 and February 2022. Participants received 4 cycles of induction therapy with Isa-KRd, after which stem cells were collected and transplant was conducted upfront or deferred. Patients who had upfront stem cell transplant received 2 additional cycles of Isa-KRd followed by maintenance therapy, while those who deferred received 4 additional cycles and then maintenance therapy.

Patients with high-risk cytogenetics received isatuximab, carfilzomib, and lenalidomide as maintenance therapy, while those with standard-risk cytogenetics received only lenalidomide.

Across 47 patients who qualified for analysis, researchers observed a 100% overall response rate, with 89% of patients achieving a very good partial response or better and 40% achieving a complete response to therapy. Data also showed 12-month progression-free survival and overall survival were 97.9% (95% CI 86.1% to 99.7%).

The most common grade 3 and 4 side effects were neutropenia (24%), elevated alanine aminotransferase (10%), acute kidney injury (6%), and thrombocytopenia (6%). One patient died due to unrelated causes, and 2 patients were removed after acute kidney injury.

The ongoing ITHACA study⁸ was designed after the phase 3 PETHEMA/GEM trial showed lenalidomide and dexamethasone may delay disease progression in patients with high-risk smoldering MM. In ITHACA, investigators are evaluating whether adding isatuximab to this regimen (Isa-Rd) will further improve patient outcomes.

ITHACA enrolled 23 patients, median 63 years of age, who were diagnosed with smoldering MM within the past 5 years, had high-risk disease, and did not receive prior anti-myeloma treatments. Patients underwent a median 20 cycles (range, 4 to 24) over a median 19.7 months (range, 3.7 to 22.1).

The most common treatment-emergent adverse events, which were predominantly grade 1 or 2, included insomnia (44%), constipation (30%), peripheral edema (30%), and headache (26%).

Eleven (47.8%) patients experienced adverse events of grade 3 or higher, including COVID-19 pneumonia (n=3) and insomnia (n=3), as well as pneumonia, hyperglycemia, agitation, lethargy, gastroesophageal reflux disease, retinal detachment, papular rash, and muscle spasms (n=1 each).

Grade 3 or 4 neutropenia was reported in 7 (30%) patients, and 1 (4%) patient developed grade 3 thrombocytopenia, but no patients discontinued treatment due to either adverse event.

In addition to updated safety data, investigators also reported patients’ responses to Isa-Rd had deepened over time, with an overall response rate of 100% at a median 19.4 months (range, 18.5 to 19.5). Some 13% of patients achieved a stringent complete response, while 30.4% achieved a complete response and another 30.4% achieved a very good partial response.

To understand how the addition of a proteasome inhibitor impacts outcomes, researchers in France are conducting a phase 3 trial called IFM2020-05/Benefit⁹ among older adults with newly diagnosed, transplant ineligible MM. Patients have been randomized to receive isatuximab, lenalidomide, and dexamethasone with or without bortezomib. The primary endpoint is minimum residual disease negativity, and researchers will also evaluate survival rates, response rates, durations of response, and safety.

A phase 2 trial called IsKPd/IFM2018-03¹⁰ is also underway, designed for researchers to assess minimum residual disease after adding carfilzomib to combination isatuximab, pomalidomide, and dexamethasone. Patients in this study have R/R MM, are at least 18 years of age, and have been treated with 1 or 2 prior lines of therapy.

Data readout is expected in 2023 for both trials.