Isatuximab, Melflufen Combos Seek to Move the Needle in Relapsed/Refractory Myeloma

Novel combinations are paramount for patients with relapsed/refractory multiple myeloma who are in second relapse or beyond; some isatuximab-irfc–containing regimens have the potential to move to the frontline setting and combining melphalan flufenamide with proteasome inhibitors and anti-CD38 monoclonal antibodies is an active area of interest.

Novel combinations are paramount for patients with relapsed/refractory multiple myeloma who are in second relapse or beyond, according to Saad Z. Usmani, MD, FACP, who added that some isatuximab-irfc (Sarclisa)–containing regimens have the potential to move to the frontline setting and combining melphalan flufenamide (Melflufen) with proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies is an active area of interest.

Isatuximab has proven to have activity both as a monotherapy and in combination with PIs. In the phase 3 IKEMA trial (NCT03275285), the agent was combined with carfilzomib and dexamethasone (Kd) and the median progression-free survival (PFS) had not yet been reached compared with 19.15 months with Kd alone (HR, 0.531; 99% CI, 0.318-0.889; P = .0007) in patients with multiple myeloma who had received 1 to 3 prior lines of therapy.1

In the phase 3 ICARIA-MM trial (NCT02990338), isatuximab in combination with pomalidomide and dexamethasone (Pd) led to a median PFS of 11.53 months vs just 6.47 months with Pd alone (HR, 0.596; 95% CI, 0.436-0.814; P = .001) in those who received 2 or more prior lines of treatment.2 “The future of isatuximab moving to the frontline setting with other novel combinations, and several clinical trials are in early phases that are looking at that,” Usmani said.

Melflufen, which was FDA approved in February 2021 has been explored in combination with dexamethasone as part of the phase 2 HORIZON trial (NCT02963493) and in combination with dexamethasone and either bortezomib (Velcade) or daratumumab (Darzalex) as part of the phase 1/2 ANCHOR trial (NCT03481556). “Melflufen is being combined with proteasome inhibition and anti-CD38 monoclonal antibodies,” Usmani added. “It is an option for patients with advanced myeloma, but the future would be determining how best to partner this agent with other therapies.”

In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer webinar on multiple myeloma, Usmani, the chief of Plasma Cell Disorders and director of Clinical Research in Hematologic Malignancies, Levine Cancer Institute, Atrium Health, discussed key considerations when selecting treatment at first and second relapse, updates with isatuximab regimens, and next steps for research with Melflufen.

OncLive®:At first relapse, what are the key factors that you consider when selecting among available options?

Usmani: The factors to consider include patient preference, prior therapies received, the kinds of responses and adverse effects [AEs] they have experienced, and the pattern of relapses that they are having, particularly whether it is a slow, biochemical, or aggressive, clinical relapse with high-risk features. All those factors play a role from a therapy selection standpoint. Another thing that we do pay attention to is whether a patient is lenalidomide [Revlimid] refractory or not; that information helps us tease out what kind of regimens we can utilize, because we have both lenalidomide-based triplet regimens, as well as some non–lenalidomide-based triplets. We have more choices and that affords us the ability to pick the best option for our patients that will provide them with the longest duration of response possible.

What is your approach for the second-relapse setting and beyond?

In the second relapse and beyond we try to combine 2 therapies, or mechanisms of action, that the patients have not been exposed to before, or at least 1 mechanism of action in combination with something else they may have been exposed to in the past, but not with the prior relapse. We are trying to figure out the best combination. We obviously try to enroll patients on clinical trials with novel therapies in that setting, but we do have certain options for those advanced patients. Belantamab mafodotin-blmf [Blenrep] was approved last year for the triple-class refractory patient population. Additionally, selinexor [Xpovio] and dexamethasone, and now, Melflufen, have been approved in that setting, as well.

Could you highlight some of the data that established isatuximab as a combinable agent?

We learned about the anti-CD38–directed activity of isatuximab in myeloma several years ago. [The agent] is active both as monotherapy, with a response rate of approximately 23.9%, and [in combination] with dexamethasone, where that rate jumps to over 40%. In smaller studies, [isatuximab] has been combined with both carfilzomib [Kyprolis] and dexamethasone, as well as pomalidomide [Pomalyst] and dexamethasone, and has shown a response rate of about 60%; this includes many patients who are lenalidomide refractory, as well as triple-class refractory.

[These data] led to the design of the phase 3 IKEMA and ICARIA-MM trials. It is important to put this in context; when these studies were being designed, a doublet standard of care was fair game. It would be more challenging to have a 3-drug vs 2-drug combination study now.

The bottom line was that early signals seen in the phase 1b setting read out in the phase 3 trial. The PFS of the isatuximab/Kd combination in the IKEMA study has not been reached, whereas it was reached for the Kd arm, at a little over 20 months. Depth of response was superior in the isatuximab arm of the study. Investigators have done many subgroup analyses to look at patients with renal insufficiency and those with high-risk cytogenetics, and it appears that the benefit [with this regimen] is seen in all those subgroups, as well as in older patients.

The patient population is a bit different for IKEMA vs ICARIA-MM. IKEMA [included patients who received] 1 to 3 prior lines [of treatment], while ICARIA-MM [included patients who had received] 2 or more prior lines of treatment. The PFS, you see with isatuximab plus Pd [in ICARIA-MM] is approximately 11.5 months compared with about 6 months in the Pd arm.

As such, isatuximab has efficacy, it is a different patient population [with] many lenalidomide-refractory patients, but this shows us that it is active. [Isatuximab] appears to be safe, and goes along with the theme of anti-CD30 [agents] combining well with PIs and immunomodulatory drugs [IMiDs]. We see similar signal to what has been reported with daratumumab in the past; however, the way that we give isatuximab is different, and there are preclinical differences in the epitopes that it binds to, compared with daratumumab.

What are the next steps for this agent?

Now that we have the FDA approval for isatuximab in the relapsed/refractory setting, it will be utilized in different community settings. Again, having less frequent dosing in that first year is something that may be appealing to some patients and providers, so there is some advantage there. Both the drugs in the isatuximab/carfilzomib combination are being given intravenously [IV], so that may be motivation to pick this vs a daratumumab-based combination. If someone has had exposure to daratumumab in the frontline setting, and has not been exposed to an anti-CD38 agent, that would be another setting where isatuximab can be employed with the current indications. In the future, isatuximab [will likely move] to the frontline setting with other novel combinations.

Melflufen was approved in February 2021. How has this regulatory decision impacted this setting and how do you foresee the field integrating this option into practice?

Alkylator-based therapies have been employed for patients with advanced myeloma. We have utilized cyclophosphamide and melphalan for those patients in combination with other therapies in the past. The big innovation with this formulation is the delivery mechanism of a peptide-drug conjugate and the safety profile; it is given IV once every cycle of 28 days. The agent appears to be active. We know melphalan is an active drug, but the safety profile appears to be encouraging, a bit better than then other alkylators. We see hematologic AEs, but not many grade 3 or 4 AEs. We do see infections and neutropenia, but that is what we expect with alkylator therapy.

What are some of the novel combinations under exploration with this agent?

The therapy appears to be active, but you do have a higher chance of infection and neutropenia. Again, combining this peptide-drug conjugate with other mechanisms of action that make sense from a disease-biology perspective would be the key. The dosing and the schedule may be a bit different with different drugs, so we will see how this plays out.


  1. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB3603.
  2. Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15): 8004. doi:10.1200/JCO.2019.37.15_suppl.8004