MM treatment landscape review compares clinical trials to real-world results

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Clinical trial populations and real-world patients are often different, and multiple myeloma (MM) trials are no exception. Given the differences between these patient groups, drug trials may not always be representative of all patients. Thus, a review published in Frontiers in oncology reviewed the last 10 years of comparable and discordant results from clinical trials and real-world settings.

Clinical trials have led to the approval of new drug options and combinations in MM in recent years, and real-world data has often shown a good degree of reproducibility for key outcomes such as free survival. progression, overall survival and overall response rate (ORR). However, there are significant differences in the management of patients with MM in clinical trials versus the real world that may impact real-world safety and effectiveness.

The current review compared real-world data and clinical trial results in treatments for newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) to better understand effective treatment strategies.

In newly diagnosed patients ineligible for autologous stem cell transplantation (ASCT), clinical trial results have led to the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) in combination with monoclonal antibodies against -CD38 (mAb) in the induction phase before transplantation and during maintenance treatment. IMiD lenalidomide is approved in combination with dexamethasone (Rd) in patients not eligible for transplant (NTE), and the addition of the mAb daratumumab to the Rd (Dara-Rd) has become a new standard in these patients. Lenalidomide plus bortezomib is also approved in combination with dexamethasone (VRd) in the induction phase before ASCT as well as in the maintenance phase after ASCT.

For NTE patients, there has not yet been a direct comparison between the effectiveness of IMiD and PI. Standard treatment options for this patient population are bortezomib-melphalan-prednisone (VMP) fixed duration for 9 cycles, Rd until disease progression or intolerance, or bortezomib-Rd (VRd) for 6 cycles followed from Rd until progression or intolerance. However, these regimens have not been compared in clinical trials, and each has advantages and disadvantages, including renal toxicity with lenalidomide and neurotoxicity with bortezomib.

An ongoing randomized trial comparing Rd and VMP is ongoing and may provide insight into the optimal strategy. So far, real-world results—where MM is more heterogeneous than in clinical trials—results have been mixed with VMP and Rd, and it is difficult to develop detailed guidelines for the treatment of patient subsets.

VRd has been shown to be more effective in clinical trials, but could have problematic toxicity in real-world elderly patients who would be excluded from trial settings. A reduced dose and less intense regimen of VRd showed better toxicity responses in a phase 2 trial, although longer time to next treatment (TTNT) was associated with longer treatment duration in all. Two phase 3 trials of VMP or Rd versus the same combinations plus Dara showed better results with the addition of Dara. However, there are no actual data on Dara-Rd in first-line to compare with clinical trials.

In transplant-eligible (TE) patients, VRd is approved for pre-ASCT induction therapy. Clinical trial and real-world results have been similar, even in real-world cohorts with a significant proportion of elderly patients and a high number of African American patients, who are often underrepresented in clinical trials. In the post-ASCT setting, real-world data support the use of lenalidomide, especially in high-risk patients.

Under the RRMM, pomalidomide, a third-generation IMiD, combined with dexamethasone (Pd) is authorized in patients who have relapsed or are refractory to lenalidomide. ORR with Pd was around 30% in 2 large clinical trials and was similar or higher in real-world data. Other trials have had varying results, and pomalidomide-based triplets are a future direction that can be evaluated as more real-world data potentially confirm clinical trial results.

PIs are another option in RRMM, with carfilzomib and ixazomib both approved in this disease setting. Elderly, frail, or cardiovascular risk patients may be better suited to ixazomib given its favorable safety profile. Overall, both drugs showed real-world results that are similar to clinical trial results when it comes to primary outcomes.

Dara monotherapy is another option in heavily pretreated patients, but with safety concerns regarding haematological adverse events and infusion-related reactions (IRRs). Trials and real-world data showed significantly different incidence of RRI, with fewer reports in real-world settings. Another mAb, elotuzumab (Elo), did not show efficacy as monotherapy but may be effective in combination with Rd or Pd (Elo-Rd and Elo-Pd). Although Elo has shown positive results in trials and similar results in real-world studies so far, prior exposure to lenalidomide generally leads to a sub-average response and thus limits its applicability in the real-world setting. of the RRMM.

Newer agents include venetoclax, selinexor and mafodotin belantaab, all of which still have little real data.

“Prospective multinational studies exploring standards of care in RW are ongoing, and further studies are still needed to detect any possible discrepancies between clinical trials and RW practice, as well as validation of new tools or composite measures incorporating these additional considerations,” the authors conclude.

Reference

Bertamini L, Bertuglia G, Oliva S. Beyond clinical trials in patients with multiple myeloma: A critical review of real-world results. front oncol. Published online May 11, 2022. doi:10.3389/fonc.2022.844779

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