Modified Quadruplet Regimen Effective in Older Myeloma Patients

A modified version of the regimen combining the anti-CD38 monoclonal antibody isatuximab (Sarclisa) with bortezomib (Velcade), lenalidomide (Revlimid), and limited dexamethasone was safe and effective for older multiple myeloma patients ineligible for autologous hematopoietic stem cell transplantation, according to results from the phase II REST trial.

Among 51 patients ages 70 to 88, measurable residual disease (MRD)-negative complete response was observed in 37%, reported Frida Bugge Askeland, MD, of Oslo University Hospital in Norway, and colleagues in Lancet Haematology.

Of note, the overall response rate was 100%; 47% of patients had a complete response or better, and 82% had a very good partial response or better. Median progression-free survival (PFS) was not reached, while the 12-month PFS rate was 86%. The 12-month overall survival rate was 90%.

Moreover, Askeland and colleagues said that the modified regimen appeared to mitigate the risk of increased toxicity — including infection — that might be expected with the full regimen.

The quadruplet was previously shown to be effective in the phase III IMROZ study, which included patients with a median age of 72 and excluded those over the age of 80. In REST, the investigators included patients up to the age of 88 and treated them with a version of the regimen in which dexamethasone was omitted after two cycles and bortezomib was scheduled weekly instead of twice a week.

The authors noted that these results complement those of the IMROZ study, concluding that “our results support that a modified version of the IMROZ regimen is effective and tolerable for older patients in more frail condition.”

In a commentary accompanying the study, Tanya M. Wildes, MD, of the University of Nebraska Medical Center in Omaha, wrote that while phase III trials of quadruplets that contain an anti-CD38 monoclonal antibody with bortezomib, lenalidomide, and dexamethasone have shown a superior depth of response — and in the case of IMROZ and CEPHEUS, longer PFS — compared with triplet regimens, “several features of the treatments as delivered in these studies might not be ideal in frail older adults.”

“In a population of less fit older adults with newly diagnosed multiple myeloma, the REST trial demonstrates that how anti-myeloma treatments are given is an important consideration, and that some simple modifications, including weekly bortezomib and omitting dexamethasone after cycle 2, could allow more individuals to be considered quad-eligible,” Wildes added.

REST was a single-arm trial conducted at five sites across Norway and Denmark. The 51 patients in the trial had a median age of 77 years, and 53% were women. About half had an Eastern Cooperative Oncology Group performance status of 1 or higher, and 45% were categorized as frail.

In 28-day cycles, these patients received isatuximab (10 mg/kg intravenously on days 1, 8, 15, and 22 of cycle 1, and days 1 and 15 of cycles 2-18), bortezomib (1.3 mg/m² subcutaneously on days 1, 8, and 15 of cycles 1-8), and lenalidomide (25 mg orally on days 1-21, until progressive disease). Dexamethasone was given orally at 20 mg on days 1, 8, 15, and 22, and discontinued after the two first cycles.

During the first 18 cycles of treatment, the most common grade 3 or 4 adverse events were neutropenia (55% of patients), infections (41%), and thrombocytopenia (22%).

Askeland and colleagues noted that the incidence of grade 3 or 4 neutropenia in REST was consistent with that observed in IMROZ (54%), and that while the incidence of grade 3 or 4 infection was lower than the 32% rate in the MAIA trial — which evaluated the triplet combination of daratumumab (Darzalex), lenalidomide, and dexamethasone — the 38% rate in IMROZ was “consistent with the incidence in our trial, which had a considerably older population.”

A total of 14 (27%) patients discontinued treatment before cycle 19, most commonly because of progressive disease (16%) and adverse events (8%). Two deaths (one from pneumonia and one from sepsis) were assessed as possibly related to study treatment.

The authors acknowledged that while it would be expected that eliminating dexamethasone after two cycles would reduce short-term and long-term toxicity and improve quality of life, “those benefits could not be properly evaluated without a control arm.”

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