Sarclisa Gets FDA Approval for Newly Diagnosed Multiple Myeloma — When to Use a Four-Drug Regimen

Written by Kaique Filardi

The use of a three-drug regimen, bortezomib-lenalidomide-dexamethasone (VRd), has proven to be the standard treatment in patients with newly diagnosed multiple myeloma. This advancement has led to increased overall survival (OS) and progression-free survival (PFS), significantly impacting the patient’s life. 

The SWOG trial established the bortezomib-lenalidomide-dexamethasone (VRd) as the regimen of choice, regardless of a patient’s indication/eligibility for transplantation, and it is commonly used in clinical practice. However, recent studies have now shown a new perspective on the treatment of multiple myeloma, pointing towards even better oncologic outcomes with a four-drug regimen. 

The choice of a four-drug regimen incorporates an anti-CD38 monoclonal antibody, isatuximab (brand name: Sarclisa), and has demonstrated a benefit over a three-drug regimen in this setting. However, it can increase cost and toxicity. A choice between three- and four-drug regimens is largely driven by disease characteristics along with patient values and preferences. 

Initial Evaluation

The primary step when selecting the best treatment for a newly diagnosed patient with multiple myeloma must be risk stratification. Patients with multiple myeloma can be categorized as having standard risk or high-risk stratification. This risk stratification not only predicts prognosis but also supports the choice of first-line therapy. 

High-Risk patients:

• 17p13 deletion
• t(4;14)
• t(14;16)
• t(14;20)
• Gain or amplification 1q
• LDH ≥2 times the institutional upper limit of normal
• Features of primary plasma cell leukemia
• High-risk gene expression profiling signature

Despite having this tool as an objective guide, it is crucial to consider the stratification along with the patient’s age,  presence of comorbidities, patient’s values, and potential side effects of the drugs. 

Dr. Joshua Richter, director of Multiple Myeloma at the Blavatnik Family-Chelsea Medical Center at Mount Sinai, tells SurvivorNet Connect that he always recommends looking at multiple factors before making treatment decisions.

“It’s important to take a multi-pronged approach when planning for induction therapy,” he explains. “Will transplant be an option either upfront or in the future? Are there major comorbidities that will interfere with therapeutic choice?  What is the patients performance status?”

Special consideration should be given to people with the following conditions:

1. Acute Kidney Failure:  In patients with acute kidney failure due to cast nephropathy, regimens that act rapidly and can be used safely without significant dose adjustment are preferred. Lenalidomide is typically avoided.
2. Frailty: This generally refers to older patients with comorbidities and the use of medicines; often, these patients present some degree of loss of independence, which can directly impact the treatment continuation. Before starting the treatment, a comprehensive geriatric assessment should be done to evaluate the frailty.

Patients may also be receiving treatment in a setting with limited resources. New agents are not always available in many countries or small cities.  In these settings, the choice of initial therapy should consider alternative regimens.

Transplant Eligibility: What’s Next?

It is important to note that autologous hematopoietic cell transplantation (HCT) is a standard of care for eligible patients with newly diagnosed multiple myeloma. Therefore, all patients with multiple myeloma should be assessed at the time of diagnosis to determine whether they are eligible for HCT, and the initial chemotherapy should avoid potential drugs that may damage stem cells. 

Conversely, for the patients who are considered ineligible for HCT, the ongoing discussion among experts regards the maintenance of chemotherapy or not.  Those who favor its maintenance advocate that chemotherapy has a high value in delaying progression and the potential for an OS benefit — and places a lower value on the risks associated with continued therapy.

What’s New: Four-Drug Regimen with Isatuximab

Isatuximab (Sarclisa) is an IgG1 monoclonal antibody that targets a specific epitope on human CD38, leading to myeloma cell death through multiple mechanisms. Phase III trials have demonstrated the efficacy of adding isatuximab to standard regimens. The combination therapies isatuximab-pomalidomide-dexamethasone (ICARIA trial) and isatuximab-carfilzomib-dexamethasone (IKEMA trial) have received approval for the treatment of relapsed or refractory multiple myeloma in several regions worldwide.

Previously used as an option for first-line therapy in newly diagnosed multiple myeloma patients eligible for HCT, the addition of isatuximab has now been validated by the phase III trial IMROZ in the setting of patients not eligible for HCT. 

In this trial, 446 patients with newly diagnosed multiple myeloma not eligible for HCT were randomly assigned to receive treatment with isatuximab plus VRd or VRd alone. After induction, patients in each arm received maintenance with isatuximab plus Rd or Rd alone, respectively. 

In a median follow-up of 60 months, IsaVRd improved PFS (5-year PFS 63 versus 45 percent; HR 0.60, 95% CI 0.41-0.88). IsaVRd also showed numerical improvements in OS that did not reach statistical significance. However, the ability to assess OS is limited by the crossover allowed in the trial (5-year OS 72 versus 66 percent; HR 0.78, 99% CI 0.41-1.48). The two treatment cohorts had similar rates of serious adverse effects (AEs) during treatment and AEs leading to discontinuation.

According to the main paper published in the New England Journal of Medicine, the incidence of adverse events leading to definitive discontinuation was 22.8% with isatuximab-VRd and 26.0% with VRd. Serious adverse events were reported in 70.7% of the patients who received isatuximab-VRd and in 67.4% of those who received VRd.

Important consideration should be given to the older population, according to Dr. Richter. He affirms that “up until now, the best data for transplant-ineligible patients was the MAIA trial (DRd), which gave a mPFS of ~ 60 months. IMROZ now provides mPFS of ~ 90 months. This means, for older patients, that they may never experience a relapse in their lifetime.”

Another isatuximab-based four-drug regimen is the IsaKrd (isatuximab + carfilzomib, lenalidomide, and dexamethasone). However, this option is still experimental and has not been used in clinical practice. The impact on PFS and OS is unclear as follow-up is short.

Daratumumab-Based vs. Isatuximab-Based Regimen

DVRd has been compared with bortezomib, lenalidomide, and dexamethasone (in two randomized trials). The addition of daratumumab to VRd deepens responses and improves PFS, albeit with a modest increased toxicity and cost. The impact on overall survival (OS) is unclear as follow-up is short.

There is no head-to-head clinical trial comparing the four-drug regimens, and the choice should be based on a several clinical factors as exposed above.

“Both are great approaches, and there is no head-to-head data. Daratumumab has the advantage of being subcutaneous, but Isatuximab will soon have an on-body device available. If I have given a daratumumab-based therapy and then the patient has had a non-CD-38 based therapy for a while (i.e., more than 4- 6 months), then CD-38 can repopulate on the myeloma cells and I often use isatuximab at that time,” Dr. Richter explains.