Use of daratumumab in high risk multiple myeloma: A meta‐analysis

Abstract Daratumumab is approved for use in newly diagnosed and relapsed/refractory multiple myeloma (MM), however the patients most likely to benefit from its addition to standard anti‐myeloma therapy is unclear. This meta‐analysis included 2340 newly diagnosed MM patients (1982 with standard risk and 358 with high risk cytogenetics) and 673 patients with relapsed/refractory MM (513 with standard risk and 160 with high risk cytogenetics) to assess which cytogenetic subgroups derived PFS benefit from Daratumumab. Studies included were the CASSIOPEIA, MAIA and ALCYONE (for newly diagnosed MM) and the CASTOR and POLLUX trials (for relapsed/refractory MM). Daratumumab's addition led to a clear benefit in standard risk newly diagnosed MM (HR 0.43; 95% CI, 0.35‐0.53; P < .05) and both high and standard risk relapsed/refractory disease (HR 0.28; 95% CI, 0.21‐0.36; P < .05 and HR 0.48; 95% CI, 0.30‐0.76; P < .05, respectively). No clear benefit was seen in newly diagnosed high risk MM. These findings fail to demonstrate PFS benefit from Daratumumab's addition in high risk newly diagnosed MM. Data forthcoming from the GRIFFIN and MASTER trials may increase the power of the study and provide a definitive answer. Daratumumab remains important in standard risk upfront and relapsed/refractory MM and high risk relapsed/refractory MM.


INTRODUCTION
Among patients with newly diagnosed multiple myeloma (NDMM), nearly 20% present with high risk disease (HRD) features defined by cytogenetic/FISH analysis, namely del(17p) or p53, t(4:14) and t (14:16), with approximately 10% of patients meeting R-ISS Stage III criteria [1]. HRD increases in incidence during subsequent relapses and despite the advent of novel therapies, patients with HRD have only attained a modest increase in overall survival (OS) [2]. and in combination therapy [3][4][5][6][7]. Similarly, Dara has gained approval in NDMM in combination therapy [8][9][10]. Most approvals are based on phase 3 randomized control trials (RCTs) meeting primary endpoints of progression-free survival (PFS) improvement. The substantial financial implications and increased rates of adverse events like infections [3][4][5][8][9][10] associated with Dara make it important to identify which patients, and in which treatment line, would derive the greatest benefit and whether Dara can overcome the poor prognosis of high-risk patients.

Outcome measures
The primary endpoint was PFS. Other analyses included high quality responses (≥VGPR) and minimal residual disease (MRD) negativity rate. For analysis, patients were divided into ND and RR.

Statistical analysis
We used R version 3.6.1 (R Foundation) and the "Meta" package (version 4.9-7). ND and RR studies were stratified and analyzed separately, and pooled odds ratios (ORs) using inverse variance method,

RESULTS
We  Figure 1D) in HRD.

DISCUSSION
To our knowledge, this is the first meta-analysis examining the effect of Dara in HRD and SRD MM. In SRD, the addition of Dara provides a clear PFS benefit. In NDMM HRD, the addition of Dara indicates a favorable but not statistically significant PFS benefit. Currently, standard therapy for NDMM is bortezomib (V) with lenalidomide and dexamethasone (RD) that demonstrated superior PFS and OS compared to RD alone [11]. While the small sample size of HRD patients possibly contributed to the lack of statistical significance of the HR, until further data emerge from studies evaluating the addition of Dara to VRD or KRD (carfilzomib with lenalidomide and dexamethasone), we believe VRD remains the important backbone in NDMM HRD.
In RRMM, the addition of Dara led to a clear PFS benefit in patients with SRD with a HR of 0.28. In HRD, the improvement was less striking but still resulted in a significant HR of 0.48. This is comparable to the PFS benefit seen with use of KRD in HRD compared to RD (HR 0.7, P < .05) in the ASPIRE trial [12] as well as the ELOQUENT-2 trial comparing elotuzumab with RD to RD alone with a HR of 0.76 in del(17p) (both P < .05) and 0.56 in t(4:14) patients [13]. Overall, the PFS advantage with Dara combinations in the RRMM seems favorable or at least comparable to other regimens commonly used for relapsed disease.
While this study could not definitively show benefit of Dara in ND HRD, the admittedly smaller sample size resulted in wide confidence intervals. Another potential reason is that the relapsed/refractory studies (POLLUX and CASTOR) both have doublets in the control arm, which are inferior to triplets. In NDMM, the CASSIOPEIA and ALCY-ONE trial control arms are triplets leading to comparable outcomes to a four-drug combination in HRD. Since patients with NDMM are more chemo-sensitive regardless of cytogenetic risk, doublets (such a RD) or regimens without either IMIDs or PIs (such as VMP) perform better as compared to the relapsed/refractory patients with more pronounced effects.
In conclusion, our analysis shows that while clearly efficacious in SRD and RR HRD, the role of Dara in ND HRD is less clear. Preliminary data from the GRIFFIN and MASTER trials show higher rates of deep responses and MRD negativity with Dara + VRD compared to VRD alone and high rates of deep responses and MRD negative with Dara + KRD, respectively [14,15]. Stratification by cytogenetic group is eagerly awaited and will enhance the power of this study, perhaps leading to a definitive answer.