Ninlaro as Oral Combo Therapy Fails at Trial in Heavily Treated Patients

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by Steve Bryson PhD |

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Adding Ninlaro (ixazomib) to cyclophosphamide and dexamethasone does not improve progression-free survival for multiple myeloma patients who relapsed after several lines of treatment, a Phase 2 trial reported.

The study, “Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results,” was published in the journal Blood Cancer Journal.

Ninlaro is an oral therapy developed to treat multiple myeloma, a rare cancer that affects a type of immune cell that produces antibodies to fight infections.

The treatment is designed to block the activity of proteasomes, cellular components that break down and recycle damaged proteins. Ninlaro ensures that fast-growing cancer cells cannot repair damaged proteins, leading to protein accumulation and cancer cell death.

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Ninlaro is often prescribed in combination with the oral immunomodulatory treatment Revlimid (lenalidomide) and the corticosteroid dexamethasone for patients who have undergone at least one prior therapy.

Clinical studies confirmed that the combination is effective and well-tolerated in newly diagnosed multiple myeloma. Ninlaro  given alongside other oral immunomodulatory therapies, such as Thalomid (thalidomide) and Pomalyst (pomalidomide), have also yielded encouraging results.

However, immunomodulatory therapies may not be effective for some patients, including those with severe kidney disease, a higher risk of blood clots, or whose disease has progressed despite these treatments.

Switching immunomodulatory treatment for another oral medication with a different mode of action, such as alkylating agents that include the chemotherapy cyclophosphamide, is a potential three-combination approach supported by outcomes in newly diagnosed patients or those who do not respond to other treatments (relapsed-refractory disease).

Researchers at the University of Leeds, in the U.K., conducted a Phase 2 clinical trial, dubbed MUKeight (ISRCTN58227268), to evaluate cyclophosphamide and dexamethasone with or without Ninlaro in myeloma patients who relapsed after treatment with Thalomid, Revlimid, and a proteasome inhibitor.

The trial enrolled 112 people with a median age of 80. Of them, 58 were randomly assigned to the triple combination therapy (ICD group), while 54 received cyclophosphamide and dexamethasone alone (CD group). Participants had a median of four previous lines of treatment, and 74% were classified as frail.

The study’s primary goal was progression-free survival (PFS) — the time from randomization to the first evidence of disease progression or death.

Analysis found the progression-free survival of patients receiving the triple combination was 5.6 months compared to 6.7 months with cyclophosphamide and dexamethasone. This difference was not statistically significant.

Response rates, a secondary goal, were similar between the two groups: 42.1% with ICD versus 39.6% with CD. The median duration of response to treatment with or without Ninlaro was also similar (6.3 vs. 10.8 months), as was the median time to progression (5.8 vs. 6.7 months).

In addition, overall survival was not significantly different between the two groups, and the frailty of participants had no impact on the efficacy of either treatment. At the time of analysis, 31 patients treated with the triple combination and 23 in the dual combination group had died.

Those who discontinued treatment mostly did so due to disease progression, with seven ICD patients (13.5%) and five CD patients (10.0%) stopping because of side effects.

Higher rates of severe or medically significant adverse events were seen in the triple combination group, including low levels of platelets or immune neutrophil cells, sensory nerve impairment, fatigue, and infections. More people treated with the CD combination experienced low blood pressure and high blood sugar.

Sixty-five serious adverse events were reported in 34 (59.6%) people in the ICD group compared with 51 events in 26 CD (49.1%) participants. Serious adverse reactions resulted in the death of three patients in the ICD group.

Due to disease progression, 20 CD group patients switched to triple combination therapy. Here, the median progression-free survival of crossover treatment was 4.6 months. Among these people, 17 had cancer progression by the time of the final analysis.

“In summary, the addition of [Ninlaro] to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial,” the researchers wrote.