Isatuximab Added to RVd Boosts Response in New Myeloma

Neil Osterweil

December 12, 2021

A new drug recently introduced for use in the treatment of refractory/relapsed multiple myeloma looks like it will also find a role in the treatment of patients with newly diagnosed transplant-eligible multiple myeloma.

The drug is isatuximab (Sarclisa, Sanofi), an anti-CD38 antibody that was approved last year for use in patients with advanced disease.

Now it has shown benefit in patients who have been newly diagnosed with the disease. When isatuximab was added onto a usual triplet therapy for myeloma, it increased the likelihood that patients would be negative for minimal residual disease (MRD) at the end of the induction phase of treatment, thereby increasing their chances for a successful autologous stem cell transplant (ASCT).

The new results come from the GMMG-HD7 trial, in which all patients were treated with the triplet combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd).

Some patients, after randomization, also received isatuximab, and in this group, the MRD-negativity rate was 50.1% at the end of induction therapy compared with 35.6% for patients treated with RVd alone.  

Patients who are MRD-negative at the time of ASCT have significantly better outcomes than patients who remain MRD-positive, as previously reported by Medscape Medical News.

"Isa-RVd is the first regimen to demonstrate significant MRD-negativity benefit at the end of induction versus RVd in a phase 3 trial," reported Hartmut Goldschmidt, MD, from University Hospital Heidelberg, Germany.

"The benefits of the addition of Isa to RVd versus RVd regarding MRD negativity after induction therapy was consistent in all subgroups," he added.

Goldschmidt spoke at a press briefing prior to his presentation of the data here at the 2021 American Society of Hematology (ASH) annual meeting.

"I think that these data are encouraging, but they are preliminary, and we need mature data to be absolutely certain about whether this presents a major advance in treatment," commented Ravi Vij, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis, Missouri. Vij was not involved in the study.

"We know that for transplant-eligible patients, for whom this trial was conducted, the field is moving toward giving four drugs for induction," he said in an interview with Medscape Medical News.

He noted that the combination of RVd with the other currently available anti-CD38 antibody, daratumumab (Darzalex), was approved for this indication in the United States in January 2021.

Vij said that isatuximab has been slow to catch on in the United States both because it was approved after clinicians had already become familiar with daratumumab and because it is given intravenously, compared with subcutaneous administration of the latest formulation of daratumumab.

"Whereas isatuximab can take an hour-and-a-half with each infusion, daratumumab takes 5 minutes for an injection and the patient is out of there, so it is convenient both for the patient and the treating institution," he said.

MRD vs CR?

Goldschmidt was asked during the briefing about whether MRD-negativity or complete response rates are better predictors of progression-free survival (PFS). He replied that with current standardized sequencing techniques and sensitivity down to 10-6, "it's a big benefit to analyze MRD negativity, and there is ongoing discussion between colleagues from the myeloma group with the Food and Drug Administration about how we can merge the data and predict PFS and overall survival."

Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada, who moderated the briefing, commented that "we're desperately looking for surrogate markers to speed up answers to clinical trials, and I think MRD in myeloma is quickly becoming a very important surrogate marker."

GMMG-7 Results

For their trial, Goldschmidt and colleagues enrolled 662 patients with newly diagnosed multiple myeloma who were candidates for high-dose therapy and ASCT, and after stratification by revised International Staging System (r-ISS) criteria, randomly assigned them six three-week cycles of induction therapy with Isa-RVd or RVd alone.

Following ASCT, patients were again randomized to maintenance with either isatuximab plus lenalidomide or lenalidomide alone.

As noted before, MRD rates at the end of induction were 50.1% with Isa-RVd versus 35.6% with RVd alone, translating to a hazard ratio favoring the four-drug combination of 1.83 (P < .001).

Treatment with Isa-RVd was the only significant predictor for the likelihood of MRD negativity in a multivariate analysis controlling for treatment group, r-ISS status, performance status, renal impairment, age, and sex.

Although the rate of complete responses at the end of induction was similar between the treatment groups, the rate of very good partial response or better was higher with the isatuximab-containing combination (77.3% vs 60.5%; P < .001).

The respective rates of disease progression at the end of induction in the Isa-RVd and RVd groups were 1.5% versus 4.0%.

The rates of adverse events were generally similar between the groups, except a higher proportion of patients had leukocytopenia or neutropenia in the Isa-RVd than the RVd group (26.4% vs 9.1%). There were four deaths in the Isa-RVd group and eight in the RVd group. Most of the deaths were attributable to disease progression or COVID-19, said Goldschmidt.

The study was funded by Sanofi. Goldschmidt has disclosed honoraria and research grants from Sanofi and others. Vij has disclosed honoraria or advisory board activities from various companies, including Sanofi. Sehn is a consultant for and has received honoraria from various companies, not including Sanofi.

ASH 2021. Abstract 463. Presented December 12, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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