Quadruplet Shows ‘Excellent Activity’ in Myeloma Patients Who Defer HSCT

Adding the CD38 monoclonal antibody isatuximab (Sarclisa) to a backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) induced deep and durable responses in a multiple myeloma study of untreated transplant-eligible patients, although the phase II trial missed its primary endpoint of complete response.

The quadruplet regimen was active with and without hematopoietic stem cell transplant (HSCT) and regardless of standard-risk or high-risk disease status, reported Elizabeth O’Donnell, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues.

Of 50 patients in the intent-to-treat population, 32% achieved a complete response after four cycles of therapy. The overall response rate (ORR) was 90%, and 78% achieved at least a very good partial response (VGPR).

After completion of consolidation — upfront HSCT plus two more cycles of therapy or deferred HSCT plus four more cycles — 58% of patients achieved a complete response, the ORR was maintained at 90%, and 86% achieved a VGPR or better.

While the study did not meet the prespecified threshold for the primary endpoint of complete response rate, the combination “did show excellent activity comparable with that of other four-drug regimens,” O’Donnell and coauthors wrote in Lancet Haematology.

For example, they pointed out that the complete response rate of 32% was similar to that in the MASTER trial, in which patients who received the anti-CD38 antibody daratumumab (Darzalex) with KRd after four cycles had a 36% complete response rate.

O’Donnell and colleagues also emphasized that of the 45 patients who were evaluable for response after four cycles of treatment, just five proceeded to undergo high-dose melphalan (Alkeran) and autologous HSCT, with the remaining 40 choosing to receive a total of eight cycles of isatuximab plus KRd while keeping HSCT as an option for later on.

The ORR among those 40 patients was 100%, with 65% achieving a complete response (stringent complete response and complete response) and 98% a VGPR or better.

“We show that deep and durable responses can be achieved without high-dose melphalan and also provide a regimen for high-risk patients with extended duration of isatuximab and carfilzomib,” the authors said.

In a commentary accompanying the study, Natalie Callander, MD, of the Wisconsin Institutes for Medical Research in Madison, suggested that use of triplet combinations for newly diagnosed multiple myeloma have “nearly been supplanted by four-component regimens, typically including an immunomodulatory drug, a proteasome inhibitor, a steroid, and the newest addition, an anti-CD38 antibody.”

She observed that results from the GRIFFIN and PERSEUS trials that used the combination of lenalidomide, bortezomib (Velcade), dexamethasone, and daratumumab, as well as the MASTER trial, “have led to the expectation that regimens for newly diagnosed multiple myeloma need to offer an ORR in excess of 90%.”

However, she also noted that these trials incorporated melphalan with HSCT, which is “an intervention that has come into question” after failing to improve overall survival in the DETERMINATION trial.

Furthermore, Callander noted that there are concerns that mutagenesis of hematopoietic DNA caused by high-dose melphalan could be associated with the development of secondary malignancies in multiple myeloma patients who undergo HSCT.

Thus, she suggested that the current study “should give encouragement to those who continue to search for highly effective regimens that could offer prolonged myeloma disease control without the routine incorporation of HSCT.”

The so-called SKylaRk study was a single-arm, phase II trial conducted at three cancer centers. Patients had a median age of 59 years (range 40-70), 54% were male, and 46% had high-risk cytogenetics.

The evaluable patients (45 of 50 who initiated therapy) completed four cycles of isatuximab plus KRd and underwent stem cell collection. The upfront HSCT group then underwent high-dose melphalan and autologous HSCT, followed by two additional cycles of treatment, while the transplant-deferred group received four additional cycles of isatuximab plus KRd. Patients who achieved a partial response or better continued on to maintenance therapy (determined based on cytogenic risk).

In addition to the response rates described above, results for minimal residual disease (MRD) were available after completion of four cycles of therapy for 28 patients achieving a VGPR or better. Of those, 43% were MRD negative at a threshold of one in 10^-5 nucleated cells and 18% (five patients) at a threshold of 10^-6.

After completion of eight cycles, 66% of the 41 patients with MRD results were negative using a threshold of 10^-5 and 17% at 10^-6.

The 24-month progression-free survival rate reached 91.3% (95% CI 83.4-99.8) and overall survival was 95.8% (95% CI 90.2-100).

Regarding safety, the most common grade 3/4 side-effects included neutropenia (26%), elevated alanine aminotransferase (12%), fatigue (6%), thrombocytopenia (6%), acute kidney injury (4%), anemia (4%), and febrile neutropenia (4%).

Grade 1/2 infusion-related reactions occurred in 20% of patients. There were two deaths assessed as unrelated to treatment.

Along with the single-arm, non-randomized trial design, another limitation of the study was that, while response after four cycles has been used in some studies of newly diagnosed multiple myeloma, other trials have used responses after high-dose melphalan and transplantation, the authors pointed out.

“A later timepoint could have allowed for additional treatment to deepen responses further and increase the likelihood of achieving the primary endpoint (with or without high-dose melphalan),” they suggested.

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