S2209: Pursuing a Standard of Care for an Overlooked Group

Given that the median age at diagnosis for myeloma is close to 70, leaving this demographic understudied represents a significant unmet need. 

The SWOG S2209 trial is addressing that issue.

It’s designed to help define the most appropriate front-line treatment regimen for patients newly diagnosed with myeloma who are identified as frail or in a high-risk subset of intermediate-fit. 

These are patients typically excluded from industry-sponsored clinical trials and represent a real-world population most often treated at community practices rather than academic centers. 

A validated frailty score (from the International Myeloma Working Group) is available to help identify these patients, as they’re more likely to experience adverse events and have poorer outcomes with standard regimens.

Currently, for these patients, the standard induction therapy is either VRd-lite (VRd – bortezomib, lenalidomide, & dexamethasone – at reduced dosing) or DRd (daratumumab, lenalidomide, & dexamethasone). But no study has yet compared the efficacy, safety, and toxicity or quality-of-life (QoL) impact of these two regimens in this population.  

S2209 does just that. It’s been cleverly designed to combine what are effectively two studies into one three-arm trial, requiring fewer patients.

S2209 will let us answer two major questions – about the preferred induction regimen and the preferred maintenance regimen – in a single study with a shared control arm.

Given its two major questions, S2209 has dual primary objectives:

1. comparing progression-free survival (PFS) between arms 1 and 2 (different induction regimens, same maintenance regimen)
2. comparing overall survival (OS) between arms 1 and 3 (different induction regimens and different maintenance regimens)

As both of the induction regimens used in the trial have been shown to work in these patients, QoL and toxicity data will be particularly important in helping clinicians identify the preferred treatment approach for each patient. 

So, S2209 is collecting QoL data directly from patients using the EORTC Core Quality of Life Questionnaire (QLQ-30) and will use those data

• to compare global health status between arms at nine months after randomization (the end of induction) and
• to compare longitudinal changes in global health status between arms from baseline to nine months after randomization.

QoL instruments may not include all disease- and demographic-specific adverse events of interest, so the study is also comparing selected patient-reported symptoms (fatigue, pain, and neuropathy) among the three arms using PRO-CTCAE items. 

Other secondary objectives on S2209 will assess the risks of thromboembolism and risks related to anti-thrombotic prophylaxis, rates of minimal residual disease (MRD)-negativity after induction (and MRD conversion after one year of maintenance), median time to response across the three arms, and more.

A critical feature of S2209 is its “real-world” design. The eligibility criteria have been chosen to maximize enrollment under common clinical conditions and to minimize exclusions based on race, age, or organ dysfunction. The goal is that a patient newly diagnosed with myeloma who is elderly or frail should be able to enroll to this study. With this in mind, tissue-based correlative studies are optional and set up to be voluntary. 

All drugs used in the trial are standard of care, but they’re being given using an age- and performance status-adjusted dosage and schedule. One of the drugs, daratumumab, is provided by the trial. And as dexamethasone (used on all three arms) can be toxic for some of these patients, the trial allows for its discontinuation after initial benefit has been recorded.

S2209 is looking to enroll 510 patients, with a goal of randomizing 450 eligible participants.

Mercy Medical Center in Des Moines, Iowa, has the distinction of having enrolled the first S2209 patient, in October of 2023. Since then, 92 additional patients have been enrolled, at 48 sites, and the trial has been opened at roughly 500 sites nationwide.

The University of California – Davis Comprehensive Cancer Center is the trial’s top-accruing site, having enrolled seven patients. Breathing down UC Davis’s neck are Swedish Cancer Institute – Edmonds, Mayo Clinic – Florida, and VCU Massey Comprehensive Cancer Center.

You can learn more about this trial in the usual places, including on the SWOG S2209 page and the CTSU S2209 page. And when presenting the trial to patients, our S2209 patient-friendly trial summary can be a very useful aid (and is also available in Spanish).

S2209 is an important trial and should give us the data we need to make more effective treatment decisions for a significant chunk of the population of those with myeloma, a sizable subset of patients too often overlooked in clinical research.

As about 90 percent of sites with the trial open have yet to enroll a patient to it, the opportunities are enormous! If your site is among those, please take another look at this important study and make sure your staff are vigilant in scanning for potential participants (send them a link to this Front Line post!).

And if your site is among the elite group that have enrolled to S2209, thank you! Your efforts will improve our treatment options for a core group of patients with myeloma.

S2209: A Phase III Randomized Trial for Newly Diagnosed Multiple Myeloma (NDMM) Patients Considered Frail or in a Subset of “Intermediate Fit” Comparing Upfront Three-Drug Induction Regimens Followed by Double- or Single-Agent Maintenance 

S2209 study chairs:

• Sikander Ailawadhi, MD
• Jing Christine Ye, MD, MSc
• Brea Lipe, MD
• Krisstina Gowin, DO (patient-reported outcomes and QoL measures)
• Thomas Chauncey, MD, PhD (VA committee representative)
• David Claverley, MD

 S2209 study biostatisticians:

• Antje Hoering, PhD
• Adam Rosenthal, MS
• Joseph Unger, PhD (patient-reported outcomes and QoL measures)