Real-world patients often differ from those eligible for clinical trials, and comparing results in both populations is a key step in fine-tuning treatment strategies for multiple myeloma.
Populations in clinical trials and real-world patients are often different, and multiple myeloma (MM) trials are no exception. Considering the differences between these patient groups, drug trials may not always be representative of patients overall. Therefore, a review published in Frontiers in Oncology examined the last 10 years of comparable and discrepant 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 have often shown a good degree of reproducibility for key outcomes like progression-free survival, overall survival, and overall response rate (ORR). However, there are significant differences in the management of MM patients in clinical trials versus in the real world that can impact real-world safety and efficacy.
The current review compared real-world data and clinical trial results in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) treatments to gain a better understanding of effective treatment strategies.
In newly diagnosed patients ineligible for autologous stem-cell transplantation (ASCT), clinical trial results led to the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) in combination with anti-CD38 monoclonal antibodies (mAbs) in the induction phase before transplantation and during maintenance treatment. The IMiD lenalidomide is approved in combination with dexamethasone (Rd) in transplant-ineligible (NTE) patients, and adding the mAb daratumumab to 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 IMiD and PI efficacy. The standard of care options for this patient population are fixed-duration bortezomib-melphalan-prednisone (VMP) for 9 cycles, Rd until disease progression or intolerance, or bortezomib-Rd (VRd) for 6 cycles followed by Rd until progression or intolerance. These regimens have not been compared in clinical trials, however, and each has pros and cons — including renal toxicity with lenalidomide and neurotoxicity with bortezomib.
An ongoing randomized trial comparing Rd and VMP is ongoing and may provide clarity on the optimal strategy. Thus far, outcomes in the real-world — 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 treatment of patient subsets.
VRd has been shown more effective in clinical trial settings but might have problematic toxicity in older real-world patients who would be excluded from trial settings. A reduced dose and less intense regimen of VRd has shown better toxicity responses in a phase 2 trial, although longer time-to-next-treatment (TTNT) was associated with longer treatment duration overall. 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 real-world data on Dara-Rd in the first line to compare with clinical trials.
In transplant-eligible (TE) patients, VRd is approved for pre-ASCT induction treatment. Results in clinical trials and the real world have been similar, even in real-world cohorts with a significant proportion of older 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 patients who are high-risk.
In the RRMM setting, pomalidomide, a third-generation IMiD, plus dexamethasone (Pd) is authorized for patients who are relapsed or refractory to lenalidomide. ORR with Pd was approximately 30% in 2 large clinical trials and was similar or higher in real-world data. Other trials have had varied outcomes, and pomalidomide-based triplets are a future direction that can be assessed 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 considering its favorable safety profile. Overall, both drugs have shown results in the real world that are similar to findings in clinical trials as far as main outcomes.
Dara as monotherapy is another option in heavily pretreated patients, but with safety concerns regarding hematologic adverse events and infusion-related reactions (IRRs). Trials and real-world data showed have shown significantly different IRR incidence, with less reported in real-world settings. Another mAb, elotuzumab (Elo), has not shown efficacy as monotherapy but may be effective combined with Rd or Pd (Elo-Rd and Elo-Pd). While Elo has shown positive results in trials and similar results in real-world studies so far, previous lenalidomide exposure generally leads to subpar response and thus limits its applicability in the real-world RRMM setting.
Among novel agents are venetoclax, selinexor, and belantaab mafodotin, all of which still have scarce real-world data.
“Prospective multinational studies exploring standards of care in the RW setting are ongoing, and new studies are still needed to detect all possible discrepancies between clinical trials and RW practice, together with the validation of new tools or composite metrics incorporating these additional considerations,” the authors concluded.
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