Clinical Challenges: Tx Choices in Newly Diagnosed Multiple Myeloma

For patients with newly diagnosed multiple myeloma there are not a lot of hard data that tell clinicians that group “A” should get treatment “X” and group “B” should get treatment “Y.”

In fact, there is a lot of debate about which regimen to use first in these patients, according to Alfred L. Garfall, MD, of the Hospital of the University of Pennsylvania in Philadelphia.

The results of two studies presented at the 2021 American Society of Hematology meeting will surely only add to the ongoing debate about what regimen is the best for this patient population.

Results of the GMMG-HD7 trial showed that the addition of CD38-directed monoclonal antibody isatuximab (Sarclisa) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) improved outcomes for patients with transplant-eligible newly diagnosed multiple myeloma. Specifically, 50.1% of patients achieved minimal residual disease (MRD)-negativity after induction therapy compared with 35.6% assigned to RVd alone.

And updated 2-year follow-up results of the GRIFFIN trial showed ongoing deep responses for patients with transplant-eligible newly diagnosed multiple myeloma treated with daratumumab (Darzalex) plus RVd combined with autologous stem cell transplant followed by daratumumab plus lenalidomide maintenance. The stringent complete response rate was 66.0% for the quadruplet compared with 47.4% for triplet therapy (P=0.0096). In the intent-to-treat population, MRD-negativity (10^-5) was 64% for the quadruplet compared with 30% with the triplet (P<0.0001).

One patient factor that may sway a clinician toward a four-drug regimen versus a three-drug regimen is a patient’s age or goals of treatment, said Brandon Blue, MD, of Moffitt Cancer Center in Tampa, Florida.

“If I see a younger patient — which is a relative term — the patient may still have tons of time and want to do as much as they can to beat the disease,” Blue said. “In that case, I may give them four drugs.”

However, he noted that even that decision can vary patient by patient. For example, Blue said he recently was treating a woman who was a musician, for whom not being able to play would be considered a significant morbidity for her. Because of the risk of peripheral neuropathy, Blue chose to avoid bortezomib.

“We did lenalidomide, daratumumab, and dexamethasone without Velcade even though she is transplant eligible,” Blue said. “It is great that we have other medicines that can be substitutes.”

Generally speaking, there is enough data now for clinicians to confidently know that giving a patient a triplet-regimen is better than a doublet regimen, Garfall said. The question moving forward will be when to give four drugs.

“For me, four-drug regimens are something I reserve for a patient with an aggressive presentation,” Garfall said. “This is someone that I think has disease that may not respond to the first couple of weeks of therapy. We have to get the disease under control quickly.”

A four-drug regimen may also be a good option in patients started on a triplet regimen but who are not responding as expected, Garfall said.

Consider Comorbidities

When selecting which drugs should be in that three- or four-drug regimen, clinicians must also consider patient comorbidities.

“The classic situation is a patient who presents with acute renal failure, which is a common problem in newly diagnosed patients,” Garfall said. “It is difficult to give lenalidomide to those patients, because of dosing issues. In that case I would start with a regimen that does not include lenalidomide.”

Another comorbidity of concern is pre-existing peripheral neuropathy. This can occur in patients with diabetic neuropathy or in patients who have been treated with chemotherapy for another cancer. In these patients, Garfall said he would hesitate to use bortezomib.

Clinicians must also consider a patient’s fitness or frailty when considering different treatment options, according to Blue.

“Often this can be a bit of an arbitrary thing, but there are more efforts to try to standardize these assessments now,” Blue said.

At ASH, researchers presented the results of the Fitness study, which supported the feasibility of recruiting frail patients with newly diagnosed multiple myeloma into large clinical trials. By the International Myeloma Working Group (IMWG) frailty score, all patients older than 80 are classified as frail. When the researchers removed age as a factor, 42.6% of patients ages 80 or older would have been re-classified as fit and only 19.2% would have been considered frail.

“More work is needed to know if someone should be considered frail or not when it comes to myeloma treatments,” Blue said.

Biomarker-Directed Treatment

Unfortunately, multiple myeloma does not currently have a biomarker to help guide treatment decisions in newly diagnosed patients.

Patients who have an 11;14 translocation seem to have a significantly higher chance of responding to bortezomib, Garfall said, but that is not an option considered as part of first-line therapy.

Overtime, Garfall is hopeful that more biomarkers will emerge, such as tapping into the full potential of cell surface targets.

CAR T-cell therapy is also in early studies as a first-line therapy in myeloma and other hematologic malignancies.

“There is a lot of stress placed on this initial decision,” Garfall acknowledged. “The way I think about the big picture is that we have a lot of drugs for multiple myeloma, and my goal is to make sure that my patient, at some point in the course of the disease, gets a shot at all the good ones. I stress less about the order we do it.”

A patient cannot receive all of the active drugs at one time, Garfall said. Instead, clinicians should pick combinations that have an established record of safety and effectiveness.

“We have to use every tool in our kit,” he said “The more weapons we can throw at the disease, the longer we can keep it under control.”