Pivotal OPTIMISMM Trial Shows Benefits of Pomalyst Triple Combo Therapy

Treatment with Pomalyst (pomalidomide) in combination with Velcade (bortezomib) and dexamethasone prolongs survival without disease worsening in patients with multiple myeloma who have failed prior treatments, including Revlimid (lenalidomide), results from a pivotal clinical trial show.

Building on this data, the European Commission recently approved the triple combo as an early therapy for adults whose myeloma came back (relapsed) or continued to progress (refractory) after prior treatment.

The triple regimen showed no major safety concerns, supporting the potential of this combination for treatment-resistant myelomas.

“A growing population of patients with [Revlimid]-pretreated multiple myeloma, including those considered [resistant to Revlimid], need early-line treatment after relapse or refractory disease develops,” researchers said.

The trial’s results were reported in a study titled “Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial,” published in the journal The Lancet Oncology.

Combining agents with different mechanisms of action offers a viable approach to overcoming tumor diversity and drug resistance. Such a strategy allows clinicians to combine therapies that directly target the tumor, such as Velcade and dexamethasone, with other agents such as Pomalyst that will stimulate the immune system to specifically attack and kill cancer cells.

Similarly to Revlimid, Pomalyst (sold as Imnovid in Europe) is an immunomodulatory agent with both potent tumor-killing and immunostimulatory effects. However, it has a distinct mechanism of action and pharmacological properties.

One important property is that Pomalyst is active against Revlimid-resistant myeloma cells, which has been demonstrated in cancer models in the lab as well as in clinical trials with patients.

Results from a Phase 1/2 trial (NCT01212952) demonstrated that Pomalyst combined with Velcade and dexamethasone — a standard therapy combination for myeloma — could prolong survival without signs of tumor progression in patients with Revlimid-resistant disease.

Based on these promising results, researchers proceeded to confirm the triple combo’s efficacy and safety in the open-label Phase 3 OPTIMISMM trial (NCT01734928).

The study was sponsored by Celgene and conducted at several clinical sites worldwide. It was designed to compare Pomalyst-Velcade-low-dose dexamethasone triple regimen versus Velcade plus low-dose dexamethasone in patients with relapsed or refractory myeloma who failed to respond to prior lines of therapy.

A total of 559 patients were randomly assigned to 21-day cycles of either one of those treatment regimens, until disease progression or unacceptable toxicity. Approximately 70% of the participants were refractory to Revlimid.

Patients receive the therapies for a median of 8.8 months with the triple combo and 4.9 months with the dual therapy.

At a median follow-up time of 15.9 months, triple Polamyst combo showed to significantly prolong patients’ lives without disease progression compared with the dual regimen (median of 11.2 months versus 7.1 months), effectively reducing the risk of disease progression or death by 39%.

A similar benefit was reported in patients with Revlimid-resistant disease, who also lived significantly longer without signs of disease worsening (median of 9.53 months versus 5.59 months), as well as for patients who relapsed or did not respond to one prior treatment (median of 20·73 months vs. 11·63 months).

Other clinically relevant groups also had improvements in progression-free survival, including high-risk patients with certain genetic abnormalities (median 8.44 months versus 5.32 months) and those who failed treatment with proteasome inhibitors (median 10.91 months versus 6.31 months).

The Pomalyst-based combination also led to more “durable and deeper responses,” researchers noted, with about three times as many patients achieving a very good partial response or better (52.7%), compared with patients receiving Velcade plus dexamethasone (18.3%).

A very good partial response (VGPR) is defined as a 90% or greater drop in M protein, an antibody that serves as a marker of myeloma.

In general, the safety of Pomalyst triple therapy was consistent with the well-established safety profiles of each individual agent, without new safety issues being reported. The most common severe or life-threatening adverse events were low neutrophil count (a type of white blood cell), infections, and low platelet levels.

Serious negative effects were noted in 57% versus 42% of the patients receiving the Pomalyst-based triple regimen and the dual control therapy, respectively.

During the trial, eight deaths related to treatment were reported, six of which happened in the triple therapy group and were caused by pneumonia, cardiac arrest, cardiorespiratory arrest or unknown cause. Two deaths occurred in the dual therapy group due to pneumonia and hepatic encephalopathy (a brain disorder that develops in some people with liver disease).

At data cutoff (October 2017), 185 of 278 patients assigned to the Pomalyst combo and 225 of 270 patients in the Velcade-dexamethasone control group had discontinued treatment, mainly due to disease progression or adverse events.

The trial data “support sequencing of a [Pomalyst]-based regimen immediately after [Revlimid] treatment failure for management of relapsed or refractory multiple myeloma and suggest that a switch in class of agent is not warranted for patients with previous [Revlimid] exposure or who have become refractory to [Revlimid],” researchers stated.

The team said that Pomalyst combined with Velcade and dexamethasone could “be considered an effective treatment option in this setting.”