Although new drug classes have significantly extended survival of patients with multiple myeloma, they continue to experience multiple relapses and/or become refractory to treatment. Therefore, novel ...therapies and treatment combinations with different mechanisms of action are needed to improve the outcomes of patients with relapsed/refractory multiple myeloma.
Here, the authors review the published data regarding the development and clinical investigation of isatuximab, a CD38 monoclonal antibody, for treatment of patients with relapsed/refractory multiple myeloma. The mechanisms of action, clinical efficacy, and safety of isatuximab treatment are summarized.
Isatuximab is approved in combination with pomalidomide/dexamethasone for the treatment of adults with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Isatuximab displays a manageable safety profile, with infusion reactions being the most common adverse events. Isatuximab is currently being further evaluated in combination with other backbone regimens in relapsed/refractory and newly diagnosed multiple myeloma.
Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly ...improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 95.4% Cl, 0.68-1.00; P = 0.0408 less than allotted α of 0.046), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.
Dose modifications in response to adverse events (AEs) can maintain tumor response and improve therapy tolerability. We conducted a post-hoc analysis of the efficacy and safety of reduced selinexor ...doses in the BOSTON trial (NCT03110562).
Efficacy, safety, and quality of life (QoL) in 195 patients with relapsed/refractory multiple myeloma randomized to once-weekly (QW) selinexor (100 mg), QW subcutaneous bortezomib (1.3 mg/m2), and twice-weekly dexamethasone (20 mg) were compared between patients with dose reductions and those without.
In total, 126 patients (65%) had selinexor dose reductions (median dose 71.4 mg/wk). In patients with dose reductions versus those without median progression-free survival was 16.6 months (95% CI 12.9-not evaluable NE) versus 9.2 months 95% CI 6.8-15.5), overall response rate was 81.7% (95% CI 73.9-88.1%) versus 66.7% (95% CI 54.3-77.6%), ≥very good partial response was (51.6% 95% CI 42.5-60.6% vs. 31.9% 95% CI 21.2-44.2), median duration of response was not reached (95% CI 13.8-NE) versus 12.0 months (95% CI 8.3-NE), and time to next treatment was 22.6 months (95% CI 14.6-NE) versus 10.5 months (95% CI 6.3-18.2). Mean best change from baseline on the EORTC QLQ-C30 Global Health Status/QoL scale was 10.0 ± 20.5 versus 4.0 ± 20.9. Duration-adjusted AE rates that were lower after selinexor dose reduction included thrombocytopenia (62.5% before vs. 47.6% after), nausea (31.6% vs. 7.3%), fatigue (28.1% vs. 9.9%), decreased appetite (21.5% vs. 6.4%), anemia (17.9% vs. 10.3%), and diarrhea (12.9% vs. 5.2%).
Appropriate dose reductions in response to AEs of the 100 mg selinexor starting dose in the BOSTON study were associated with improved efficacy, reduced AE rates and improved QoL.
Efficacy and tolerability data of 195 patients with relapsed/refractory multiple myeloma who were randomized to once-weekly selinexor (100 mg), once-weekly subcutaneous bortezomib, and twice-weekly dexamethasone in the BOSTON study were compared between patients who had selinexor dose reductions (n = 126) and those who did not (n = 69). Selinexor dose reduction was associated with longer progression-free survival, better overall response, lower duration-adjusted adverse event rates and improved quality of life.
In this study, the addition of carfilzomib to lenalidomide and dexamethasone improved response rates and overall survival among patients with relapsed multiple myeloma.
Survival rates have improved ...for patients with multiple myeloma, yet relapse remains common,
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indicating an ongoing need for new therapeutic approaches. The immunomodulatory agent lenalidomide in combination with high-dose dexamethasone is approved for use in relapsed multiple myeloma on the basis of phase 3 trials showing superiority to dexamethasone alone, with a median progression-free survival of 11.1 months and an overall response rate of 60%.
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In previously untreated patients, lower weekly doses of dexamethasone proved less toxic and more effective than high-dose dexamethasone.
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Indeed, in a recent phase 3 study, lenalidomide with weekly dexamethasone, administered until disease progression, was . . .
Objective: The anti-CD38 antibody Isa in combination with Kd is approved in various countries for patients (pts) with relapsed MM after ≥1 prior therapy, based on primary interim analysis (IA) of the ...Phase 3 IKEMA study (NCT03275285). Here we report updated efficacy and safety Results from IKEMA. Methodology: This prespecified final analysis (Isa-Kd 179, Kd 123 pts) evaluated updated PFS (primary endpoint), PFS2, CR rate, MRD- rate, and MRD- and CR rate in ITT population, and safety with 2 additional years of follow-up. Isa 10mg/kg was given IV qw for 4 wks and then q2w; Kd 20/56mg/m² biw, 3/4 weeks. Hydrashift Isa IF assay was used to rule out potential Isa interference in CR determination. At cutoff (14Jan2022; median follow-up 44 mo), 49 (27.4%) Isa-Kd, 11 (8.9%) Kd pts were still on treatment. Results: Updated PFS was consistent with primary IA Results, showing significant benefit of Isa-Kd (vs Kd): PFS HR 0.58; PFS2 HR 0.68. Final CR rate (Isa-Kd vs Kd) was 44.1% vs 28.5%, MRD- rate 33.5% vs 15.4%, MRD- and CR rate 26.3% vs 12.2% (Table). Serious TEAEs were reported in 70.1% Isa-Kd vs 59.8% Kd pts. The most common, any-grade non-hematologic TEAEs in Isa-Kd were infusion reactions (45.8%), diarrhea (39.5%), hypertension (37.9%) and upper respiratory tract infection (37.3%). Conclusion: These Results show unprecedented mPFS, CR rate, MRD- and MRD- CR rates in a non-lenalidomide containing regimen with benefit maintained through subsequent therapies and a manageable safety profile. Safety profiles and efficacy Results in both arms were consistent with prior IKEMA findings. Our findings support Isa-Kd as a standard of care treatment for pts with relapsed MM.
The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). ...The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.
•KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM.•KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.
In a study involving patients with refractory multiple myeloma, the anti-CD38 antibody daratumumab in combination with bortezomib and dexamethasone resulted in longer progression-free survival and a ...higher rate of response than bortezomib and dexamethasone alone.
Multiple myeloma is associated with organ dysfunction, including bone lesions, anemia, renal insufficiency, and hypercalcemia.
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Proteasome inhibitors (e.g., bortezomib) in combination with glucocorticoids are standard regimens for relapsed or relapsed and refractory multiple myeloma
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(definitions of these terms are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org) and have contributed considerably to patient survival.
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Nevertheless, almost all patients will have a relapse.
Daratumumab is a human IgGκ monoclonal antibody that targets CD38, which is highly expressed on myeloma cells and other hematopoietic cell types.
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Daratumumab has direct and indirect antitumor activity and diverse . . .
Maintenance therapy prolongs progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) not undergoing autologous stem cell transplantation (ASCT) but has generally been ...limited to immunomodulatory agents. Other options that complement the induction regimen with favorable toxicity are needed.
The phase III, double-blind, placebo-controlled TOURMALINE-MM4 study randomly assigned (3:2) patients with NDMM not undergoing ASCT who achieved better than or equal to partial response after 6-12 months of standard induction therapy to receive the oral proteasome inhibitor (PI) ixazomib or placebo on days 1, 8, and 15 of 28-day cycles as maintenance for 24 months. The primary endpoint was PFS since time of randomization.
Patients were randomly assigned to receive ixazomib (n = 425) or placebo (n = 281). TOURMALINE-MM4 met its primary endpoint with a 34.1% reduction in risk of progression or death with ixazomib versus placebo (median PFS since randomization, 17.4
9.4 months; hazard ratio HR, 0.659; 95% CI, 0.542 to 0.801;
< .001; median follow-up, 21.1 months). Ixazomib significantly benefitted patients who achieved complete or very good partial response postinduction (median PFS, 25.6
12.9 months; HR, 0.586;
< .001). With ixazomib versus placebo, 36.6% versus 23.2% of patients had grade ≥ 3 treatment-emergent adverse events (TEAEs); 12.9% versus 8.0% discontinued treatment because of TEAEs. Common any-grade TEAEs included nausea (26.8%
8.0%), vomiting (24.2%
4.3%), and diarrhea (23.2%
12.3%). There was no increase in new primary malignancies (5.2%
6.2%); rates of on-study deaths were 2.6% versus 2.2%.
Ixazomib maintenance prolongs PFS with no unexpected toxicity in patients with NDMM not undergoing ASCT. To our knowledge, this is the first PI demonstrated in a randomized clinical trial to have single-agent efficacy for maintenance and is the first oral PI option in this patient population.
Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of ...resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir's effectiveness in the treatment of multiple myeloma.
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