Might Myeloma Trial Point to Novel Study Approach?

A novel study comparing outcomes from a phase II, single-arm trial with those from an earlier phase III clinical trial has shown that a five-drug regimen is more effective than conventional management in ultra-high-risk (UHR) multiple myeloma (J Clin Oncol 2023 Jun 14 [Epub ahead of print]). However, questions remain over whether the approach can be applied to other studies—and even whether the prior trial was a valid choice for comparison.

In the OPTIMUM trial, 107 patients with symptomatic, newly diagnosed UHR multiple myeloma received induction therapy with up to six cycles of the five-drug Dara-CVRd regimen (see sidebar with specifics of each regimen) and an autologous stem cell transplant (ASCT). This was followed by six cycles of Dara-VRd consolidation therapy, 12 cycles of Dara-VR consolidation therapy, and maintenance therapy with daratumumab and lenalidomide.

Given the relative rarity of UHR multiple myeloma, lack of a standard treatment, and high unmet therapeutic need, the team turned to a “digital comparator”—in this case, a comparison with results from 120 similar patients who received conventional care in the Myeloma XI study.

In this trial, KCRD induction therapy was compared with CRD therapy. This was followed by consolidation therapy—chosen based on the response to induction treatment—then ASCT, and finally maintenance with lenalidomide or no additional therapy. Tumor risk profiling and posttreatment assessments were performed using the same criteria and molecular methods—and in the same laboratory—for both trials.

Overall, 81.7% of patients in OPTIMUM and 65.9% of patients in Myeloma XI were alive with no disease progression at 18 months. Progression-free survival at 30 months was estimated at 77% for patients in the OPTIMUM trial versus 39.8% for those in Myeloma XI; overall survival at 30 months was estimated to be 83.5% and 73.5%, respectively.

The researchers say the novel protocol is an “effective treatment option for the clinical management” of UHR disease, but it is the eye-catching trial design that potentially raises questions over how to best approach evidence generation in rare subpopulations of patients.

Martin Kaiser, MD, of The Institute of Cancer Research in London, UK, notes that conducting a true randomized trial would have been difficult, as there was no internationally agreed-upon treatment standard for UHR disease for comparison.

Assigning patients with UHR multiple myeloma to a control regimen that would likely have worse outcomes than the study treatment is also ethically questionable, and “not very palatable for hematologists,” adds co-author Guy Pratt, MD, of the University of Birmingham in the UK.

Nevertheless, Kaiser and Pratt believe that they can be confident in their results, despite question marks over the possibility of time bias between OPTIMUM and Myeloma XI.

The baseline characteristics between the two cohorts were “very comparable,” Kaiser notes, reflecting the patients being treated in the same national health care system and in the same mix of hospitals.

However, questions remain over whether the study design could be applied outside of the centralized UK National Health Service or to other cancers.

Michael O'Dwyer, MD, of the University of Galway in Ireland, who was not involved in the study, believes it could. Although cross-trial comparisons frequently compare groups that are “not exactly the same,” there are several examples in which two trials employed a “consistent way of doing things, where they're using the same sort of reference laboratories and centralized molecular analysis,” and so are “comparing like with like.” But, he adds, “there is always going to be that time bias.”

The FDA and the European Medicines Agency are considering how best to design external comparator arm trials and incorporate them into the overall risk–benefit assessment.

In the current analysis, O'Dwyer says the high degree of comparability between two trials conducted within the same health care system means the results are “valid.”

However, he says the real issue is that the value of the results is limited because the comparator arm from Myeloma XI has long been superseded by more effective regimens.

That the regime in OPTIMUM would achieve better results than those in Myeloma XI is a “no-brainer,” he notes. –Liam Davenport