In the first official report of the phase 3 BOSTON study (abstract 8501), selinexor, bortezomib, and dexamethasone (SVd) was evaluated vs bortezomib and dexamethasone (Vd) in patients who had received 1 to 3 prior lines of therapy. Some very exciting results emerged from this study; for instance, once-weekly SVd significantly improved progression-free survival (PFS) and overall response rates compared with twice-weekly Vd. In fact, SVd was associated with a median PFS that was nearly 4.5 months longer than that of Vd, with better overall response rates as well. Further, although SVd was linked to some increases in adverse events (eg, thrombocytopenia, fatigue, nausea), the rates of peripheral neuropathy were lower. This study did not specifically look at patients with high-risk disease; however, it was interesting to see a consistent PFS benefit across subgroups, particularly in the group with high-risk cytogenetics, such as 17p deletion (del[17p]).

Updated data from the phase 3 BELLINI trial were presented in abstract 8509. This study evaluated the addition of venetoclax vs placebo to Vd in patients with relapsed/refractory disease who had received 1 to 3 prior lines of therapy. The results were positive for patients with t(11;14), with outstanding durable responses in this group. Although t(11;14) is not typically felt to be a high-risk cytogenetic feature, some studies suggest that these patients may not do as well as standard-risk patients. For the non-t(11;14) patients, there was, unfortunately, much less benefit, significant toxicity, and increased mortality associated with the venetoclax combination.

Abstract 8540 reported the results of a meta-analysis of phase 3 trials of multiple myeloma regimens that included daratumumab. The analysis included trials in both the relapsed/refractory and frontline settings, and high-risk disease was defined as t(4;14), t(14;16), or del(17p). The authors concluded that high-risk patients had a substantial benefit from daratumumab-based regimens as compared with non–daratumumab-based  regimens. However, to better understand high-risk disease and its response to any therapy, the ideal is to have a dedicated trial with treatment arms balanced for the specific high-risk features. Also, the high-risk patients still did not do as well as the standard-risk patients, indicating that further treatment advances would be welcome. 

In my opinion, the BOSTON study group was courageous to compare a weekly regimen (SVd) with a biweekly regimen (Vd) because there was a risk, not least from a regulatory standpoint, that the control arm, with its more dose-intense use of proteasome inhibition, might outperform the experimental combination with selinexor. I agree with Dr Orlowski that the important takeaways include that weekly bortezomib was highly active and feasible with selinexor and that, with respect to peripheral neuropathy, the tolerability of SVd was much improved.

Regarding the BELLINI study, venetoclax appears to be outstanding in the t(11;14) population. However, it remains critical to understand why outcomes were worse in the non-t(11;14) patients, including worse myeloma-related outcomes after relapse. Was this related to tolerability issues, or did it have something to do with disease biology, or both? That needs to be better understood.

In the meta-analysis, results showing the benefit of daratumumab-based regimens in high-risk patients are consistent with other data, and this was very gratifying to see. One important area that requires further study and understanding is extramedullary disease, which is a high-risk presentation in the relapsed/refractory setting and is typically enriched for del(17p). Although the data are limited, daratumumab does not appear to be particularly effective for advanced extramedullary multiple myeloma, and we do not know the significance of these findings. Anecdotally, there is a mechanistic difference between isatuximab and daratumumab that may have relevance (ie, there are stronger apoptotic features with isatuximab preclinically), but we do not yet know whether it will translate into a difference clinically, and in particular with respect to high-risk presentations.

Regarding the BOSTON trial, the 4.5-month incremental PFS gain with SVd is similar to what we have seen previously with older multiple myeloma therapies that have become successful. It is quite promising, and this was surprising to me, as I have not been a much of a selinexor enthusiast in the past. 

In the BELLINI study, it is important to note that the positive results were for patients with t(11;14). The study had a total of 291 patients, of which only 35 had t(11;14). Increased mortality with the venetoclax combination regimen was primarily seen in the non-t(11;14) group. Now, a combined analytic category was created, consisting of patients with either t(11;14) or high BCL2 expression (ie, BCL2^high), and the results for BCL2^high, non-t(11;14) patents were not reported separately. In patients with t(11;14), venetoclax seems to be safe and was associated with a significant reduction in the risk of progression; however, similar conclusions cannot be drawn about the BCL2^high patients at this point. And it should be emphasized that venetoclax should be avoided in non-t(11;14) patients based on these data.

Finally, with regard to the daratumumab meta-analysis, I would say that, in general, outcomes are improved to a lesser degree in the setting of high-risk disease vs standard-risk disease, but this is essentially true for any therapy. So, I think the analysis demonstrates that daratumumab is effective in both newly diagnosed and relapsed multiple myeloma, but I agree that dedicated trials are needed for definitive conclusions.