Lakshman, Arjun

AbstractPatients with multiple myeloma who are refractory to currently available effective therapies have short expected survival. Modalities harvesting the knowledge of the immune characteristics and microenvironment of myeloma such as chimeric antigen receptor (CAR) T‐lymphocytes, bispecific antibodies (bsAbs), and antibody‐drug conjugates (ADCs) have shown potential in early phase trials. Based on data from phase 2 studies, idecabtagene vicleucel (ide cel), an anti‐B‐cell maturation antigen CAR T‐product and belantamab mafodotin (belamaf), an ADC are currently approved in the relapsed/refractory setting. bsAbs have shown promise with quick and deep responses. In this review, we summarize the available evidence on these treatments from clinical trials.

Abstract The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

Abstract The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy-nine (26%) patients had an elevated PCPI (>0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P < .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials.

AbstractExperience with intensive chemotherapy for relapsed/refractory multiple myeloma (RRMM) using VDT PACE regimen and its modifications (VDT PACE‐like regimens: VPLRs) outside TOTAL THERAPY trials is limited. We analyzed the outcomes of 141 patients with RRMM who received VPLRs at our center between 2006 and 2017 in an intent‐to‐treat analysis. Median age was 59.7 years and 66.7% of patients were male. A median of 2.2 years (range 0.02‐11.4) separated diagnosis of myeloma and inititation of VPLR. High‐risk cytogenetics were present in 52.4% patients. Patients received a median of 4 (range 1‐14) prior therapies, including stem cell transplant (SCT) in 66.7% patients. Ninety‐five (67.4%) patients received VDT PACE, 20 (14.2%) patients received VD PACE and 26 (18.4%) patients received other VPLRs. Patients received a median of 1 cycle (range 1‐9) of VPLR. We observed ≥ minimal response in 68.4%, ≥ partial response (PR) in 54.4% and ≥ very good PR in 10.3% patients. Median progression‐free survival was 3.1 months (95% CI, 1.9‐3.9) and median overall survival (OS) was 8.1 months (CI, 6.2‐9.9). One‐hundred and sixteen (82.3%) patients received some therapy after VPLR; 71 (61.2%) received systemic chemotherapy, while 45 (38.8%) underwent SCT. Median OS for those who received SCT after VPLR was 15.1 months (CI, 10.3‐20.8). Age ≥ 60 years (hazard ratio [HR] 2.3 [CI, 1.4‐3.7]; P = 0.0008) and R‐ISS III stage (HR‐ 2.4 [CI, 1.3‐4.0]; P = 0.003) predicted shorter OS in patients receiving VPLR. VPLRs are effective in heavily pre‐treated RRMM. In fit patients, SCT can be used to consolidate the response to VPLR.

AbstractOutside of clinical trials, experience with daratumumab‐based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43‐93) years. High‐risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1‐14) and time to first DCT from diagnosis was 4.3 years (range, 0.4‐13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty‐two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and “other” DCTs, respectively. Overall response rate was 47%. Median follow‐up was 5.5 months (95% CI, 4.2‐6.1). Median progression‐free survival (PFS) was 5.5 months (95% CI, 4.2‐7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta‐refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1‐2.4] vs 3.1 [95% CI, 2.1‐NR] vs 5.9 [95% CI, 5.0‐NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1‐6.0] vs 8.2 [95% CI, 4.6‐NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7‐5.9] vs NR [95% CI, NR‐NR]; P = .002). Non‐hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.