Myeloma Landscape Undergoing Dramatic Shift With Approvals, Pivotal Data

C. Ola Landgren, MD, PhD

Impactful clinical trial data that have led to approvals of novel agents and regimens over the last few years has led to a significant transformation in the multiple myeloma landscape, according to C. Ola Landgren, MD, PhD. The expert shared this insight during a lecture at the the 34th Annual Chemotherapy Foundation Symposium^TM.

Landgren, chief of Myeloma Service, Memorial Sloan-Kettering Cancer Center, began with the phase III ASPIRE trial, which included patients with relapsed myeloma. In the study, the combination of carfilzomib, lenalidomide, and dexamethasone had a median progression-free survival (PFS) of 26.3 months compared with 17.6 months with lenalidomide and dexamethasone alone (HR, 0.69; P <.0001). The complete response (CR) rates were 31.8% and and 9.3%, respectively.

Landgren next discussed the phase III TOURMALINE trial, in which the median PFS was 20.6 months when combining the oral proteasome inhibitor ixazomib with lenalidomide and dexamethasone, compared with 14.7 months with lenalidomide and dexamethasone alone (HR, 0.74; P = .012) in patients with relapsed/refractory myeloma. The CR rates were 11.7% and 6.6%, respectively.

Switching to monoclonal antibodies, Landgren reported the long-term data from the ELOQUENT-2 trial, in which the 3-year PFS rate was 26% with elotuzumab plus lenalidomide and dexamethasone compared with 18% with lenalidomide and dexamethasone alone. The CR rates were 5% and 9%, respectively.

In discussing the higher CR rate in the control arm, Landgren focused on monoclonal immunoglobulin (M protein) levels, an indicator of how active multiple myeloma is in a patient.

“If you give a monoclonal antibody, even to a healthy person, you can in the peripheral blood see an M-Spike (increased M protein levels). So, that lower complete response rate with the 3-drug combination is probably an [overestimate] of the drug as being residual [M protein]. This is a problem that we now have to deal with in the clinic when we start using monoclonal antibodies, in particular, for early lines of treatment—we have to be able to tease out the drug from the disease.”

Landgren also noted this phenomenon when discussing the POLLUX trial, in which combining daratumumab with lenalidomide and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma. The CR rates were 43% and 19%, respectively.

Commenting on why the CR rate in the control arm was so much higher than in the previous studies he discussed, Landgren said, “I’m not sure, exactly, because I do not have access to the data, but I know for a fact that this study used an assay to try and deal with the issue of monoclonal antibody drug versus disease. And my take on this is that maybe they were underestimating the amount of disease [in the control arm] and they said ‘this is probably the drug.’ So, again, this shed light on the fact that we now have a new problem to deal with in the clinic and we don’t really have a fixed solution.”

Landgren also had a word of caution for US physicians who are considering the pivotal data for novel myeloma agents.

“There are no published randomized studies that are clearly based on the the US treatment paradigm. Most of the patients enrolled in these pivotal clinical trials had not been treated with lenalidomide. As you’ve seen, lenalidomide is used consistently both in the control arm and the experimental arm. So, the progression-free survivals and the depth of responses are probably less profound for patients treated here in the US. But nevertheless, it seems that the 3-drug combinations are superior to the 2-drug combinations.”