Early Treatment Matters More Than Ever in Multiple Myeloma, Kumar Says

The multitude of options to treat multiple myeloma (MM) doesn’t change an important fact: the duration of a patient’s response to the first treatment will define the disease biology going forward—how well the disease is managed in the early going matters, according to Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center, who gave an update on MM management during Friday’s National Comprehensive Cancer Center (NCCN) annual meeting.

Fortunately, results from the GRIFFIN trial are showing what’s possible. Results presented at the December 2021 meeting of the American Society of Hematology showed positive outcomes after 24 months for newly patients who took quadruplet therapy after an autologous stem cell transplant (ASCT). The combination, which added daratumumab to the usual combination of lenalidomide, bortezomib, and dexamethasone (RVd) had better stringent complete responses (sCR, 66.0% vs 47.4%), along with higher minimal residual disease (MRD) negativity rates.

“This clearly appears to be translating into an improvement in progression-free survival (PFS),” Kumar said. It’s too soon to start treating every patient with newly diagnosed, transplant-eligible MM this way, but “given the high rates of MRD negativity that we see with Dara-RVd, this regimen is definitely one to consider for patients with high risk multiple myeloma.”

What about patients who are not transplant eligible, or need to wait? The IFM 2009 study compared giving ASCT right away with additional doses of therapy. Although ASCT clearly offered better PFS, there was not improvement in overall survival (OS), Kumar noted. Thus, “it is very reasonable to delay stem cell transplant to the time of first relapse.”

For these patients, daratumumab with lenalidomide and dexamethasone should be considered the standard, based on the MAIA study, he said.

Ongoing treatment. After initial treatment and lenalidomide maintenance, treatment choices are driven by whether patients are refractory to lenalidomide, Kumar explained. He shared a slide with multiple doublet and triplet options, and explained that triplets are now preferred, with one drug being dexamethasone. Prior treatments, age, comorbidities, frailty, and any lingering toxicity should be considered.

“In general, the approach—especially in the earlier lines of therapy—is to treat patients to maximum response, and then maintain them on at least one of the drugs from the combination until disease progression,” Kumar said. This is easier in the early lines of therapy, he acknowledged. Whether a patient is refractory on their initial therapy is a key differentiator is a “key differentiator” that guides treatment going forward.

Selinexor, an XP01 inhibitor, was approved in December 2020 for use with bortezomib and dexamethasone in patients who have had at least one prior therapy. Belantamab mafodotin, is an antibody drug conjugate that targets B-cell maturation antigen (BCMA), and could be used to treating patients that have been refractory to other major drug classes, including protease inhibitors. Long-term data from the DREAMM-2 study found that median duration of response, OS, and PFS were 11.0 month, 13.7 months, and 2.8 months.

A recent highlight is the FDA approval last month of a second chimeric antigen receptor (CAR) T-cell therapy for MM, ciltacabtagene autoleucel (cilta-cel) which also targets BCMA. In the CARTITUDE trial, results at 2 years showed median PFS and OS were not reached and sCR was 82.5%.

Kumar also reported on several clinical trials involving investigational therapies and new uses of existing therapies, including:

• Teclistamamb is a bispecific antibody that binds to CD3 on T cells and BCMA on plasma cells; the MajesTEC-1 sudy explored dosing and reported early data at ASH in December.
• Iberdomide is a novel CRBN E3 ligase modulator, or CELMoD, that is under development as a next-generation IMiD agent. A third patients with R/R MM responded in a first-in-human trial presented at ASH.
• Venetoclax, studied for several years in MM after success in other blood cancers, had previously showed improvement in PFS. More recently, Kumar said, his study group showed this benefit is seen in t(11;14) translocation, which is linked to the BCL-2 protein that venetoclax inhibits.