Background
On the basis of the DREAMM‐2 study (ClinicalTrials.gov identifier NCT03525678), single‐agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple ...myeloma (RRMM) who received ≥4 prior therapies, including anti‐CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM‐2 after 13 months of follow‐up among patients who received belamaf 2.5 mg/kg.
Methods
DREAMM‐2 is an ongoing, phase 2, open‐label, 2‐arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti‐CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee.
Results
As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty‐one of 97 patients (32%; 97.5% confidence interval CI, 21.7%‐43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression‐free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6‐3.6 months), respectively. Response and survival outcomes in patients who had high‐risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow‐up.
Conclusions
Extended follow‐up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.
Extended follow‐up of patients enrolled in the ongoing phase 2 DREAMM‐2 study confirms sustained clinical activity without new safety signals in patients with relapsed or refractory multiple myeloma who receive belantamab mafodotin 2.5 mg/kg every 3 weeks. These data show that belantamab mafodotin has the potential to shift the treatment paradigm in this heavily pretreated, anti‐CD38 monoclonal antibody–exposed patient population, which has a poor prognosis and few alternative treatment options.
The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo ...antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). ...However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.
The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including
proteins crucial to cell cycle regulation and programmed cell death, or ...apoptosis. In preclinical cancer models, proteasome
inhibitors induce apoptosis, have in vivo antitumor efficacy, and sensitize malignant cells and tumors to the proapoptotic effects of conventional chemotherapeutics
and radiation therapy. Interestingly, transformed cells display greater susceptibility to proteasome inhibition than nonmalignant
cells. Therefore, proteasome inhibition holds promise as a novel approach to the treatment of cancer. Inhibitors of the proteasome
impact on cells in part through down-regulation of nuclear factor κB, but also through modulation of cell cycle proteins and
other pro- and antiapoptotic pathways. Bortezomib (VELCADE; formerly PS-341), the first such inhibitor to undergo clinical
testing, has demonstrated impressive antitumor activity and manageable toxicities in Phase I and II trials both as a single
agent, and in combination with other drugs. It has been approved recently by the Food and Drug Administration for therapy
of patients with multiple myeloma who have received at least two prior regimens and progressed on the last of these. Ongoing
preclinical evaluations of the mechanisms that underlie the antitumor effects of proteasome inhibitors, and clinical trials
in a variety of tumor types, will allow additional refinement of the role these agents will play in cancer therapy. Below
we discuss the rationale behind targeting the proteasome for cancer therapy, and review the preclinical and clinical data
on proteasome inhibitors alone, and in combination with conventional chemotherapeutics.
ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: ...NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.
Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion.
As of January 8, 2022, 124 patients (dose escalation 0.025-120 mg, n = 73; dose expansion 60 mg, n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively.
ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.
To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman ...disease.
In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.
Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response complete response (CR), n = 1; partial response (PR), n = 11, including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR.
No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.
Decreased p27Kip1 levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCFSkp2 E3 ligase function, resulting in enhanced p27 ubiquitination and ...proteasome-mediated degradation. While proteasome inhibitors stabilize p27Kip1, agents inhibiting SCFSkp2 may represent more directly targeted drugs with the promise of enhanced efficacy and reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered with SCFSkp2 ligase function in vitro, and induced specific accumulation of p21 and other SCFSkp2 substrates in cells without activating a heat-shock protein response. CpdA prevented incorporation of Skp2 into the SCFSkp2 ligase, and induced G1/S cell-cycle arrest as well as SCFSkp2- and p27-dependent cell killing. This programmed cell death was caspase-independent, and instead occurred through activation of autophagy. In models of multiple myeloma, CpdA overcame resistance to dexamethasone, doxorubicin, and melphalan, as well as to bortezomib, and also acted synergistically with this proteasome inhibitor. Importantly, CpdA was active against patient-derived plasma cells and both myeloid and lymphoblastoid leukemia blasts, and showed preferential activity against neoplastic cells while relatively sparing other marrow components. These findings provide a rational framework for further development of SCFSkp2 inhibitors as a novel class of antitumor agents.
The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with ...high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients.
SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1-14 every 21 days), bortezomib (1·3 mg/m
subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m
subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1-21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, on days 1 and 11 for cycles 3-8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEP
), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719.
100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57-70, range 36-85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEP
, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46-59), no difference in median progression-free survival was observed (RVd 33·64 months 95% CI 19·55-not reached, RVd-elotuzumab 31·47 months 18·56-53·98; hazard ratio 0·968 80% CI 0·697-1·344; one-sided p=0·45. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3-5 infections (four 8% of 52 in the RVd group, eight 17% of 48 in the RVd-elotuzumab group), sensory neuropathy (four 8% of 52 in the RVd group, six 13% of 48 in the RVd-elotuzumab group), and motor neuropathy (one 2% of 52 in the RVd group, four 8% of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator.
In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population.
National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.
Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits.
We report the Southwest Oncology Group randomized phase II ...trial (S1304) comparing twice weekly low-dose (27 mg/m
; arm 1) to high-dose carfilzomib (56 mg/m
; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811). The primary endpoint was progression-free survival (PFS), and patients on arm 1 could cross-over to arm 2 after progression on treatment.
Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms (
= 0.113). Also, neither the median PFS 5 months and 8 months, respectively; HR, 1.061; 80% Wald confidence interval (CI), 0.821-1.370;
= 0.384 nor the median overall survival were significantly different (26 and 22 months, respectively; HR, 1.149, 80% Wald CI, 0.841-.571;
= 0.284). Sixteen patients crossed over to arm 2 with a median PFS benefit of 3 months. Certain adverse events (AE) were more frequent in arm 2, including fatigue, thrombocytopenia, and peripheral neuropathy, but there was no significant difference in cardiopulmonary AEs.
This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/m
dosing of carfilzomib over the 27 mg/m
dose for the treatment of relapsed and/or refractory multiple myeloma. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.
Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race ...showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients.
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