Unprecedented PFS Improvement in Relapsed Multiple Myeloma

Progression-free survival (PFS) in relapsed multiple myeloma almost doubled with the addition of the CD38 inhibitor isatuximab (Sarclisa) to a standard proteasome inhibitor (PI) regimen, according to long-term follow-up from a randomized trial.

Median PFS improved from 19.2 months with carfilzomib (Kyprolis) and dexamethasone (Kd) to an unprecedented 35.7 months with the addition of isatuximab (I-Kd). Second progression-free survival (PFS2) approached 4 years, reflecting durability of treatment effect.

Substantially more patients attained complete response and complete response with minimal residual disease (MRD)-negative status with the triplet regimen versus standard Kd, reported Philippe Moreau, MD, of University Hospital Hôtel-Dieu in Nantes, France, during the European Society for Medical Oncology (ESMO) Virtual Plenary.

“That is the longest PFS when using a proteasome inhibitor backbone in relapsed myeloma patients,” said Moreau. “This benefit in terms of PFS for isatuximab-Kd is observed across all subgroups of patients, and we also have impressive MRD-negativity rates with the triplet combination. PFS2 is also in favor of the triplet combination … and we are awaiting longer follow-up to draw conclusions regarding overall survival (OS).”

“Isatuximab-Kd is now a standard of care for relapsed multiple myeloma,” he said.

The results add to a treatment landscape for relapsed myeloma that has become increasingly complicated by availability of multiple options for different scenarios within the relapsed setting, said ESMO invited discussant Francesca Gay, MD, of the University of Turin in Italy. The options include various combinations of PIs, anti-CD38 antibodies, and second-generation immunomodulatory agents. The diverse settings encompass multiple prior lines of therapy and patients with lenalidomide (Revlimid)-refractory disease.

Different regimens and individual components of the regimens have different toxicity profiles, which must be taken into account when choosing a therapy.

“I think that it’s very difficult for us as clinicians to try to put all this data together and to try to understand what can be the best option for each patient,” said Gay. “The good thing is that there are several options that we can consider.”

“The treatment decision algorithm is complex and a multifactorial process that can include patient and disease features, thinking about sequences, prior therapies, the response achieved, and the toxicity,” she continued. “When we discuss with a patient what is an option for treatment, we consider compliance, the route of administration, the need to come periodically to the hospital more or less frequently.”

The key question is how to identify the optimal therapy for a specific patient, she added. Although several studies have demonstrated superiority for three drugs versus two, no triplet regimens have been compared directly in randomized trials.

Moreau reported follow-up data from the international, randomized, phase III IKEMA trial. Patients with one to three prior lines of therapy for myeloma were randomized 3:2 to I-Kd or Kd and continued treatment until progression or unacceptable toxicity. The primary endpoint was PFS. After a median follow-up of 20.7 months, the first planned interim analysis showed the control arm had a median PFS of 19.15 months versus not yet reached in the I-Kd arm (HR 0.53, 99% CI 0.32-0.89, P=0.0007).

Investigators initially randomized 302 patients, 27.4% of whom remained on I-Kd and 8.9% on Kd at the updated analysis at a median follow-up of 44 months. With an additional 2 years of follow-up, the advantage in favor of I-Kd persisted, as the 16.5-month absolute difference in PFS represented a 42% reduction in the hazard for progression or death (95.4% CI 0.42-0.79).

I-Kd led to an overall response rate of 86.6% versus 83.7% for Kd. Very good partial response or better occurred in 72.6% of the I-Kd arm and 56.1% of the Kd group, whereas 44.1% of I-Kd patients had complete response or better versus 28.5% with Kd. More than twice as many patients in the I-Kd arm achieved MRD-negative status (33.5% vs 15.4%).

Median time to next treatment was significantly prolonged with I-Kd (44.9 vs 25.0 months; HR 0.55, 95% CI 0.40-0.76), and median PFS2 was nearly a year longer with I-Kd (47.2 vs 35.6 months; HR 0.68, 95% CI 0.50-0.94).

The estimated survival at 36 and 42 months favored I-Kd (68.7% vs 62.9% and 66.3% vs 54.5%, respectively). The final OS analysis will occur 3 years after the interim analysis, said Moreau.

The safety analysis was consistent with results of the prior interim analysis. The addition of isatuximab did not increase the rate of fatal treatment-emergent adverse events or treatment-related discontinuation.