No abstract

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). This study evaluated addition of daratumumab (D) to RVd in ASCT-eligible NDMM patients. Patients (N=207) were randomized 1:1 to receive RVd ±D induction (4 cycles), ASCT, RVd ±D consolidation (2 cycles), and lenalidomide ±D maintenance (26 cycles). At the primary endpoint analysis, the stringent complete response (sCR) rate by the end of post-ASCT consolidation favored D-RVd over RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval [CI], 0.87-2.82; 1-sided P=0.068) and met the prespecified 1-sided alpha of 0.10. With longer follow-up (median, 22.1 months), responses continued to deepen; rates of sCR improved for D-RVd versus RVd (62.6% vs 45.4%; P=0.0177), as did rates of minimal residual disease negativity (10−5 threshold) in the intent-to-treat population (51.0% vs 20.4%; P<0.0001). Four (3.8%) and 7 (6.8%) patients in the D-RVd and RVd groups progressed, respectively, and 24-month progression-free survival rates were 95.8% (D-RVd) and 89.8% (RVd). Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but rates of grade 3/4 infections were similar. Median CD34+ cell yield was 8.2´106/kg for D-RVd and 9.4´106/kg for RVd, although plerixafor use was more common in the D-RVd arm. There was no difference in median times to neutrophil or platelet engraftment. In summary, daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. Clinicaltrials.gov NCT02874742.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T 0) was 50.1 months. The median overall survival (OS) from T 0 for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T 0 in 249 (90%) patients. Overall response rate to first regimen after T 0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n ‫؍‬ 50) and 62% and 48%, respectively, after Haplomarrow transplantation (n ‫؍‬ 50). The day ؉56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplomarrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies.