Characteristics of Relapse Affect Treatment Choices in Multiple Myeloma

The number of patients diagnosed with multiple myeloma is rising worldwide, and not just because of an aging population, Natalie S. Callander, MD, director of the University of Wisconsin Carbone Cancer Center Myeloma Clinical Program, said to open her talk March 31 at the National Comprehensive Cancer Network (NCCN) 2023 Annual Conference.

With this increased incidence in multiple myeloma comes a rise in patients living with myeloma after initial treatment—about 150,000 in the United States alone, according to National Cancer Institute data.

Natalie S. Callander, MD

A defining pattern of multiple myeloma is that patients relapse, and “We're going to be seeing more and more relapsed patients,” Callander said. The number of ways to treat these patients has expanded, too, and examining the characteristics of each relapse is key to deciding what to do, she said.

Defining relapse. As Callander noted, disease progression can be characterized by laboratory parameters—specifically, thresholds of myeloma protein (>0.5 mg/dL), urinary monoclonal protein (>200 mg/24 hours) or >10 mg/dL of involved light chain. Progression also be defined by an event, such as anemia, renal insufficiency, bone lesions or fractures, or new medullary deposits. She noted that a refractory relapse occurs when a patient progresses while on therapy or within 60 days of completing therapy.

Standard vs high risk. In some cases, patients at standard risk can be observed before starting treatment after relapse, but those at high risk need to be treated quickly, usually with a triplet combination. Previously collected stem cells may be used for an autologous transplant if this treatment was not used in the past (or if the patient’s last transplant was more than 24 months ago), Callander said. A “functional high risk” patient would be one whose transplant lasted only about 1 year, which she said, ‘is considered a bad prognostic sign.”

Early vs late relapse. This is the key point of departure in deciding treatment options, as Callander explained. Often, patients will be on lenalidomide maintenance at the time of a first relapse; increasing the dose offers “no real benefit,” she said, but adding dexamethasone may offer a benefit. “Now, [pomalidomide with dexamethasone] is not a bad choice,” she said. “But you have to be prepared that only a third of patients are going to respond to that maneuver, and that it’s not necessarily going to last very long.”

Instead, Callander said, recent trials show that “introduction of monoclonal antibody in a triplet should be strong consideration.”

She reviewed multiple FDA-approved triplet combinations for patients with 1 to 2 prior treatments, including:

• Daratumumab, lenalidomide, and dexamethasone, as seen in the phase 3 POLLUX trial, for relapsed or refractory (R/R) patients who are lenalidomide experienced but not lenalidomide refractory. Patients taking the combination with daratumumab had progression-free survival of 44.5 months compared with 17.5 months for the arm taking lenalidomide and dexamethasone only.
• Daratumumab, carfilzomib, and dexamethasone, as seen in the phase 3 CANDOR trial, involving relapsed or refractory patients who had received 1 to 3 prior treatments. Median PFS was 28.6 months compared with 15.2 months for patients receiving carfilzomib and dexamethasone only.3
• Isatuximab, pomalidomide, and dexamethasone, as seen in the phase 3 ICARIA-MM trial, for R/R patients previously treated with at least 2 lines of therapy including lenalidomide and a proteasome inhibitor (PI). Median overall survival (OS) was 24.6 for the isatuximab group and 17.7 months for the group taking pomalidomide and dexamethasone only.
• Isatuximab, carfilzomib, and dexamethasone, as seen in the phase 3 IKEMA trial, for R/R patients previously treated with 1-3 lines of therapy but not carfilzomib. After a median follow-up of 44 months, median PFS was 35.7 months for the isatuximab arm vs 19.2 months for patients taking carfilzomib and dexamethasone only.
• Elotuzumab, pomalidomide, dexamethasone, as seen in the phase 2 ELOQUENT-3 trial for R/R patients treated with 1-3 lines of therapy, including at lenalidomide and a PI. Compared with the pomalidomide/dexamethasone only group, those in the elotuzumab group had 46% improved PFS and 38% improved OS.

Callander noted that in addition to the clinical trial data, physicians take into account factors such as how the drug is administered and the ability to give the drug once a week—or, in some cases, once a month. “Isatuximab combined with carfilzomib probably has the highest response rate in terms of PFS here—35.7 months-which is just great,” she said. However, this therapy is still given intravenously. “Most patients tolerate it pretty well in my experience. There is an on-body formulation that seems to be coming… that may make the choice between daratumumab and isatuximab not as clear cut for many people.”

She also reviewed multiple combinations for early relapsed patients previously exposed to monoclonal antibodies, including:

• pomalidomide, carfilzomib, and dexamethasone
• pomalidomide, bortezomib, and dexamethasone
• bortezomib, panobinostat, and dexamethasone
• selinexor, bortezomib, and dexamethasone
• lenalidomide, carfilzomib, and dexamethasone
• lenalidomide, cyclophosphamide, and dexamethasone
• carfilzomib, cyclophosphamide, and dexamethasone

Callander said treatment with an antibody has other considerations: data show that using it at the first relapse does not preclude its use later on, “which is obviously something we want to know.” And data show carfilzomib seems to be a better choice for higher risk patients, she said.

Considerations after third-line treatment. But what happens once patients start to run through treatments, and including various antibody drugs?There are many questions to ask: Is the patient now “triple-class refractory,” to antibodies, PI, and immunomodulatory drugs? Does the patient need a quick response? What is the patient’s fitness level—are they still walking 3-4 miles a day? And how close is an academic center that might offer cellular therapy? Callander reviewed the following:

• Selinexor, a XPO1 inhibitor.
• Belanatamab mafodotin, which Callander discussed even though GlaxoSmithKline has begun the process of withdrawing the therapy from the market after phase 3 results did confirm data that supported accelerated approval.
• Idecabtagene vicleucel (ide-cel), one of a pair of chimeric antigen receptor (CAR) T-cell therapies that target BCMA, the other being ciltacabtagene autoleucel.
• Teclistamab, a bispecific T-cell engager, the first of its kind.

Callander explained that CAR T-cell therapy in multiple myeloma is not the same as in large B-cell lymphoma. “One of the things to remember is right now, it’s not curative,” she said. CAR T has a useful role, but patient selection is crucial here, because the manufacturing time is 4 to 6 weeks—and reports of manufacturing challenges in the multiple myeloma space have been significant. So, patients who cannot wait are not candidates for this therapy.

She reviewed the data for the trials, which show that CAR T-cell do give patients “this nice break,” but patients are told “we are anticipating at some point we are going to have to do something else. Now that is something that might give you a little bit of a pause if you consider that these therapies are coming in at about a half a million dollars each.”

“Now, how about cellular therapies for early relapse?” Callander asked, “This has been a theme in my entire career in myeloma—newer drugs get moved up.”

She reviewed data from KarMMa-3 for ide-cel, which showed a survival advantage of 13.3 months vs 4 months for standard of care. Some looked at the data and were impressed and others were not moved. “So, I guess it’s in the eye of the beholder,” she said.

“Stay tuned.” Bispecific antibodies, both the approved product and those in development, offer the advantage of being “off the shelf,” meaning patients do not have to wait for a manufacturing process. Results for talquetamab were presented in December 2022 at the American Society of Hematology.

Callander is excited about some newer treatments under development: next generation immunomodulatory drugs called cereblon E3 ligase modulators or CELMoDs, including iberdomide and mezigdomide, as well as modakafusp alfa (TAK-573), which is a first-in-class immunocytokine that delivers attenuated interferon in a laser-like manner to immune and tumor cells.

And, she noted, there are improvements in the works to existing therapies. “There’s so many CAR T’s out there under development. One of the things that’s being looked at…is a shorter production time,” she said. “Patients are just not healthy enough to last through that 6 week period, and you really can’t find what we call bridging therapy that makes sense—or that they respond to.”

Some treatments under study could have a turnaround time of a week or less, “which would actually change things quite a bit,” Callander said. “Just stay tuned is probably the answer.”