Orlowski Calls Linvoseltamab Results “the Best Single-Agent Data Ever in the History of Myeloma”

Among the attention-grabbing abstracts at the 67th American Society of Hematology Annual Meeting & Exposition were results for LINKER-MM4 (NCT03761108), presented by Robert Z. Orlowski, MD, PhD, who is chairman and interim director of myeloma, and professor of medicine in the departments of Lymphoma/Myeloma and Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. As the investigators note in their abstract, “treatment of [newly diagnosed multiple myeloma] relies on complex quads and triplets, highlighting a need for a simpler improved regimen.”¹
 

Enter LINKER-MM4, which investigators say is the first known trial of a bispecific antibody evaluated as a monotherapy in first-line MM. They reported an overall response rate (ORR) of 79% for 43 patients, with a median time to partial response or better of 1.2 months.¹ In addition, 92% of patients were found to be minimal residual disease (MRD) negative at or below 10^–5, with just 1 patient stopping therapy due to a treatment-emergent adverse event.

Efficacy responses among the evaluable patients were dose dependent. Investigator-assessed ORR included very good partial response or better at 56% and complete response or better at 26%. Patients receiving the 200 mg or 50 mg doses had ORR of 86%; investigators report that deeper responses may occur with longer follow-up, and all patients were progression-free at data cutoff.¹ Among safety results, there were no cytokine release syndrome (CRS) events of grade 2 or higher and only 1 grade 1 event of immune effector cell–associated neurotoxicity syndrome (ICANS) observed.

The FDA approved linvoseltamab (Lynozyfic; Regeneron) in July 2025 for patients with MM who have had at least 4 prior lines of therapy.²

The American Journal of Managed Care^® (AJMC^®) spoke with Orlowski in Orlando, Florida, during the meeting about the results of LINKER-MM4 as well as the trend of bispecifics in earlierlines of treatment.

This interview is edited lightly for length and clarity.

AJMC: Today, standard of care in newly diagnosed multiple myeloma calls for triplet or quadruplet therapy, depending on whether an anti-CD38 therapy is used. Your trial suggests patients could go from 4 medications down to a single bispecific in first-line treatment, through a different mechanism. Can you discuss the advantages of this approach?

Orlowski: As you know, the current standard of care for newly diagnosed patients is a quadruplet, if you're transplant eligible or transplant ineligible but fit, and a triplet, if you're ineligible but are a little bit more, shall we say, mature and may have a lot of comorbidities. So, we were interested in studying linvoseltamab as a single agent because of its really strong activity in the relapsed/refractory setting, where it is FDA approved.²

The thought was that by giving it earlier, we would take advantage of first, more drug-sensitive myeloma cells and second, a healthier immune system for the patient with better T cells, because they wouldn't have been exposed to years of therapy.

From a patient benefit perspective, the thought was that if we could get 1 drug to have an equivalent or better overall response rate, complete response, MRD negative rate, that one of the things we've learned in oncology over the years looking at 2 vs 3 drugs, or 3 vs 4 drugs, is the more drugs you add, the more side effects there are. And if you could get a similar outcome with 1 drug that would be wonderful—hopefully, a narrower profile of side effects—and you save those other drugs for use later in the patients who may relapse down the road. So, that gives you more options, and hopefully the cross-resistance between linvoseltamab and these other drugs may not be there.

AJMC: Let’s talk about the safety data. If we are talking about moving more bispecific antibodies into community practice, which is a goal to make these therapies more widely available, what do the safety data look like in first line vs later on in treatment?

Orlowski: This was a phase 1 study where after step-up dosing, patients got either 50 mg full dose, 100 mg full dose, or 200 mg full dose. There were no dose-limiting toxicities at any of the doses, no grade 5 events, which, of course, are death.¹ So that's wonderful.

In terms of specific side effects, there was CRS in 44% of people, but all of those events were grade 1, which is the mildest level. We did have 1 episode of ICANS, which is a neurologic toxicity, interestingly, at the lowest dose of 50 mg, and that also was grade 1. And the great advantage about grade 1 [events] is that those are much easier to manage for folks in the community. And by the way, none of these people got prophylactic tocilizumab.

AJMC: In the future, in a real-world setting, that’s something you could consider?

Orlowski: Yes.… In terms of other side effects, we saw infectious complications, which we see with triplets and quadruplets. About a third of patients had a grade 3 infection, most of which were sinus, bronchial, or pneumonia. There were 2 CMV [cytomegalovirus] reactivations, again, oddly at the lowest dose of 50 mg, but they were asymptomatic. Infections declined over time, in part because people began using intravenous immunoglobulin [IVIG] replacement therapy.

So overall, the safety profile was very consistent with what had been seen in the relapsed/refractory setting MM and something that should be able to be used in the community because of only grade 1 cytokine release, which is what we mostly worry about.

AJMC: How many days post treatment did you start to see the CRS?

Orlowski: Most of that was early during the step-up dosing and then did not happen later on.

AJMC: In the late-breaking session we will hear results for the use of teclistamab with daratumumab in multiple myeloma (the MajesTEC-3 trial (NCT05083169).³ And yesterday there was a presentation for linvoseltamab in combination with daratumumab in later lines of therapy.⁴ A question was asked of the lead investigator of the MajesTEC-3 trial, with these results and the results seen in EPCORE FL-1 (NCT05409066) with epcoritamab,⁵ do we really need some of these other drugs? The phrasing was, “Are we clinging to lenalidomide?” Are we using these older drugs unnecessarily when we should be moving more quickly to newer therapeutics?

Orlowski: That’s a great question. The study you're referring to, the MajesTEC-3 trial with daratumumab and teclistamab, which was on average, if I remember correctly, third-line patients and a very defined population, because almost all of them were daratumumab naïve. Which, frankly, is kind of hard to find, because [today] most of them get daratumumab either frontline or at least by second line. So, I'm not sure how applicable those data are to our routine practice, although certainly the data look great, and maybe using that up front would be important.

I do think that we are transitioning in the direction of using these immuno-oncology assets in appropriate combinations, and maybe transitioning away from immunomodulatory drugs, proteasome inhibitors, and even corticosteroids in early lines of therapy. And as long as we're getting similar to higher overall and complete response rates. We always want to try to give myeloma patients the best therapy we can give up front, because the faster we reduce their disease burden, the better they're going to feel. The deeper the response, the longer in remission they're going to stay. And especially if we're talking about transplant-ineligible patients, some of whom, unfortunately, because of other complications, don't get to second line or third line. That's another rationale to try to give the best treatment up front.

AJMC: Another major theme of this ASH meeting has been fixed-duration regimens. Would this be a regimen that is fixed-duration or continuous?

Orlowski: Great questions—we should talk about the efficacy data. At the 200-mg dose, which is what we recommend, there was an overall response rate of 86%, some of those will improve because the patients were still on treatment at the data cut off, and 43% were in complete remission.¹

If you look at MRD negativity across the entire study, 20 patients were evaluable; 19 of them were MRD negative at 10^-5, which is 95% and for those that were evaluable at 10^-6, it was 100% and it was also 100% at that 200-mg dose level. So those are pretty darn good levels of response. We do plan on expanding the trial further to see if additional data for single agent—and also we're exploring combinations—will lead to the possibility for compendia listing or perhaps even FDA approval in these settings.

AJMC: So, what are the next steps?

Orlowski: There are additional combinations that are being studied in terms of the duration of treatment.… Certainly there is a lot of interest in doing some of the MRD testing, especially the blood-borne assays, which maybe we can do more conveniently for patients and potentially think about a fixed-duration [regimen] based on sustained MRD negativity, which is defined now as either 1 year or 2 years of MRD negativity, and then after that to monitor and maybe restart treatment if there's disease recurrence. But we did not study that in the context of this trial, because at the time it was designed, that was really not considered an option.

This is really the best single-agent data ever in the history of myeloma.

AJMC: That’s quite a statement. I'm sure it's going to get a lot of attention.

References

1. Orlowski RK, Shah M, Chakraborty R, et al. Safety and efficacy of linvoseltamab as a simplified monotherapy first-line regimen in NDMM: initial results from the window of opportunity phase 1/2 LINKER-MM4 trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Paper 697.

2. Klein HE. FDA approves linvoseltamab to treat R/R multiple myeloma. Am J Manag Care. 2025;31(Spec 9):SP558-SP559.

3. Mateos MV, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclisatamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or bortezomib (DPd or DVd) in patients with relapsed refractory multiple myeloma (RRMM): results of MajesTEC-3. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract LBA-6.

4. Dimopoulos MA, Delimpasi S, Manier S, et al. Safety and efficacy of linvoseltamab combined with anti-CD38 monoclonal antibodies daratumumab or isatuximab in patients with relapsed/refractory multiple myeloma (RRMM): initial results from the multicohort phase 1b LINKER-MM2 trial. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Paper 2254.

5. Falci L, Nijland M, Huang H, et al. Primary phase 3 results from the EPCORE FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma. Presented at: 67th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 466.