NYU Langone’s Dr. Marc Braunstein On Decision-Making In The New Era of Multiple Myeloma Treatment

By Jayson Haedrich

With the newly expanded frontline approval of a daratumumab-based quadruplet for transplant-ineligible patients, questions are being raised about who qualifies for intensified therapy, how clinicians should assess fitness, and how sequencing decisions are (or need to) evolve.

“In multiple myeloma, we have various options that allow us to tailor treatment selection to individual patients,” Dr. Marc Braunstein, a medical oncologist and bone marrow transplant specialist at NYU Langone Health, tells SurvivorNet Connect. 

In January 2026, the Food and Drug Administration (FDA) expanded approval of a four-drug regimen combining daratumumab, lenalidomide, bortezomib, and dexamethasone for newly diagnosed patients who are ineligible for stem cell transplant. “This four-drug regimen has already been used frequently for the past several years in patients who are fit for stem cell transplant,” Braunstein notes. “But now we essentially have the same regimen as an option for both transplant-eligible and transplant-ineligible patients.”

Availability To Appropriate Use

For Dr. Braunstein, qualification for a quadruplet regimen is never based on a single factor. “You have to evaluate the patient in front of you — how sick they are from their myeloma, how fit they are at baseline, and whether some of their frailty might actually be due to the disease itself,” he explains.

In some cases, apparent frailty reflects uncontrolled disease and may improve with effective therapy. “Some of that frailty can be overcome by pushing a little bit more with more intensive treatment,” Braunstein says.

While guidance suggests the quadruplet may be best suited for patients who are under 80 and not frail, Braunstein emphasizes that age alone is not determinative. Instead, clinicians must assess organ function, comorbidities, and the likelihood that a patient can tolerate added therapy without compromising quality of life.

“The data clearly suggest that adding a monoclonal antibody to a backbone regimen is superior,” he says. “But whether that backbone is two drugs or three drugs on top of the antibody really depends on how you perceive your patient’s ability to tolerate that regimen.”

Treatment Decision-Making Points

“The discussion starts with understanding the diagnosis and what makes a patient’s myeloma distinct,” Braunstein says. “What stage is it? Is it standard-risk or higher-risk? And it’s equally important to understand the patient’s goals.”

Some patients are focused on minimizing side effects and treatment burden, while others want to pursue the deepest possible response upfront. “A fit patient who wants to derive the maximum benefit from initial therapy may be an ideal candidate,” Dr. Braunstein says, “whereas a more frail patient may be better served with a less intensive approach.”

Fitness itself is assessed through a combination of objective tools and clinical judgment. Validated frailty indices can help quantify risk, but Dr. Braunstein stresses the importance of evaluating how patients function day to day, including their independence and caregiver support. “By combining those objective calculators with our medical evaluation, we can get a sense of how well someone will tolerate a more intensive versus a less intensive regimen,” he says.

Expanding Options Without Closing Doors

While some worry that intensified frontline therapy could limit options later, Dr. Braunstein sees that concern as increasingly outdated. “We always want to give our best therapies upfront because we hope it will be a very long time before patients actually need another line of therapy,” he says.

CEPHEUS, co-authored by Dr. Braunstein, underscored the possibility of that approach, with median progression-free survival not reached at nearly five years in the quadruplet arm. For Dr. Braunstein, durability matters. “If we can prolong patients’ survival from our first- and second-line treatments, they’re very likely to be candidates for new therapies that are going to develop in the next few years,” he says.

“When we think about sequencing now, we’re talking about therapies that weren’t even available in the first line,” Braunstein adds, pointing to bispecific antibodies and CAR T-cell therapies that have shown impressive efficacy in later lines and are now being studied earlier.

Braunstein points to the MAJESTEC-3 study, which evaluated the bispecific antibody teclistamab in combination with daratumumab in patients treated in the second through fourth line. The bispecific-containing regimen demonstrated superior progression-free survival, underscoring that effective options remain available after intensified frontline therapy.

“These randomized studies will ultimately help us determine whether we should be selecting a monoclonal antibody or a bispecific antibody,” Braunstein says. “But the key point is that both are very effective.”

As a result, he does not view quadruplet therapy as exhausting future choices. “These regimens allow for many years of progression-free survival, and newer agents will continue to be approved in the second-line space,” he says. “We want to give our most effective and best-tolerated options as early as possible.”

Balancing Efficacy, Safety & Quality Of Life

While deeper responses and longer remissions are central to frontline decision-making, tolerability and quality of life remain essential — particularly when treatment extends over many months.

Daratumumab, the monoclonal antibody used in CEPHEUS, is now most commonly administered subcutaneously, a formulation associated with far fewer infusion-related reactions than the original intravenous version.  The regimen is delivered entirely in the outpatient setting, with dosing more frequent early on and becoming less intensive over time. Patients are monitored through routine blood work tracking myeloma markers, with bone marrow biopsies used periodically to assess depth of response.

The most notable added toxicity with a four-drug regimen is an increased risk of infection due to effects on normal white blood cell production. “We have to be very vigilant about infections,” Dr. Braunstein says. “But these are things that oncologists in the myeloma field are very comfortable managing.”

Overall, he emphasized that the medications used in quadruplet regimens are well understood and broadly safe. “The scale tips much more toward benefit than risk,” he says.

Navigating A Fast-Moving Field

Moving daratumumab into the frontline for transplant ineligible patients as part of a quadruplet does not close off future choices — it may expand them. By achieving deeper responses earlier and higher MRD negative rates (MRD was  the primary endpoint of the CEPHEUS trial that brought approval), more patients may remain well enough, for long enough, to take advantage of the growing number of therapies now available in second line and beyond. The question is no longer about saving options, but about using the right ones at the right time.

“If we can prolong patients’ survival from our first- and second-line treatment, they’re very likely to be candidates for new therapies that are going to develop in the next few years,” Braunstein says.