- |||||||||| Darzalex IV (daratumumab) / J&J
Review, Journal, IO biomarker: CD38-Directed Therapies for Management of Multiple Myeloma. (Pubmed Central) - Jul 9, 2021
Antibody-based therapies targeting the surface marker CD38, namely daratumumab and isatuximab, have emerged as being highly effective as single agents as well as in combination regimens for both newly diagnosed and relapsed settings. Herein, the authors summarize the most recent data with both the current and emerging CD38-directed therapies in multiple myeloma.
- |||||||||| Darzalex Faspro (daratumumab/hyaluronidase) / J&J
Review, Journal, Combination therapy: Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. (Pubmed Central) - Jul 9, 2021
A subcutaneous formulation of daratumumab has also been approved in the EU and USA (DARZALEX FASPRO™) for use in MM...The addition of daratumumab had a minimal effect on overall toxicity and the most common grade ≥ 3 adverse events with daratumumab combination therapy were haematological (e.g. neutropenia, lymphopenia). The approval of daratumumab as combination therapy in patients with newly diagnosed, transplant-eligible MM expands the range of MM treatment settings in which daratumumab is an option and the availability of the subcutaneous formulation will likely be of benefit to patients.
- |||||||||| Darzalex IV (daratumumab) / J&J
Review, Journal: Realization of Osteolysis, Angiogenesis, Immunosuppression, and Drug Resistance by Extracellular Vesicles: Roles of RNAs and Proteins in Their Cargoes and of Ectonucleotidases of the Immunosuppressive Adenosinergic Noncanonical Pathway in the Bone Marrow Niche of Multiple Myeloma. (Pubmed Central) - Jul 4, 2021
Via EVs, mesenchymal stem cells allow myeloma cell dissemination and confer PI resistance, whereas myeloma cells promote angiogenesis, myeloid-derived suppressor cell proliferation, and osteoclast differentiation and inhibit osteoblast differentiation. In this review, to understand key processes of MM development involving communication between myeloma cells and other cells in the tumor microenvironment, EV cargo and the non-canonical adenosinergic pathway are introduced, and ectoenzymes and EVs are discussed as potential druggable targets for the treatment of MM patients.
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J
Clinical, Retrospective data, Review, Journal: Efficacy of Daratumumab-Based Regimens Compared to Standard of Care in Transplant-Eligible Multiple Myeloma: A Meta-Analysis. (Pubmed Central) - Jun 23, 2021
The GRIFFIN trial underlined the efficacy of dara, lenalidomide (R), and Vd in the dara group versus RVd in the control group...However, an increased risk of neutropenia (RR: 1.80; 95% CI: 1.60-2.03; p < 0.01) and decreased risk of peripheral neuropathy (RR: 0.92; 95% CI: 0.86-0.99; p = 0.02; I = 52%) were observed in the dara group. Dara addition to the standard of care regimen for transplant-eligible NDMM has promising outcomes with increased efficacy and safety profile and manageable toxicity.
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J
Journal: Current status and future prospects of immunotherapy for multiple myeloma (Pubmed Central) - Jun 11, 2021
Therefore, it is expected that combination therapy with anti-CD38 antibodies and IMiDs may enhance anti-tumor immunity. Furthermore, chimeric antigen receptor (CAR) T cell therapy, antibody drug conjugates (ADC), and bispecific antibodies (BsAbs) are in the process of their introduction to the clinic as novel immunotherapies for MM.
- |||||||||| Abecma (idecabtagene vicleucel) / bluebird bio, BMS
Clinical, Review, Journal: The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma. (Pubmed Central) - Jun 10, 2021
After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.
- |||||||||| Darzalex IV (daratumumab) / J&J
Review, Journal: Antibody treatment in multiple myeloma. (Pubmed Central) - Jun 3, 2021
BCMA-targeted antibody-drug conjugates and bispecific antibodies, which are the newest antibody therapies to be investigated, provide additional therapeutic options for patients with heavily pretreated MM. This article reviews how antibody therapy has influenced the treatment of MM, describes the unique adverse event profiles of each relevant drug class, and explains how to incorporate antibody therapy into practice.
- |||||||||| Darzalex IV (daratumumab) / J&J
Review, Journal: Monoclonal Antibody Therapies in Systemic Light-Chain Amyloidosis. (Pubmed Central) - Jun 2, 2021
Daratumumab has been investigated and has clinical efficacy in upfront or refractory settings...Rituximab is usually integrated into the treatment regimen for IgM amyloidosis. Anti-amyloid therapies have shown preclinical proof of principle, but lack confirmation of improvement.
- |||||||||| Darzalex Faspro (daratumumab/hyaluronidase) / J&J
Journal: An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma. (Pubmed Central) - May 27, 2021
Subcutaneous daratumumab is non-inferior to conventional intravenous daratumumab with lower risk of infusion-related reactions and decreased administration time. Based on these data, and the recent FDA and European Commission approvalsthe widespread use of the subcutaneous formulation for both conventional and investigational practice is supported.
- |||||||||| Blenrep (belantamab mafodotin) / GSK
[VIRTUAL] Novel BCMA Targeted ADCs, Bispecific and Trispecific Antibodies () - May 20, 2021 - Abstract #SOHO2021SOHO_203;
Belantamab mafodotin (Belamaf) is the first FDA approved, B-cell maturation antigen (BCMA) targeting ADC in triple-class exposed, relapsed and/or refractory MM beyond four prior lines of therapy...Although there are BsAbs in preclinical development exploring CD16 in place of CD3 to help direct natural killer cells towards the tumor cells, the present talk will summarize clinical data on BsAbs in MM that have been reported at recent international congresses. Lastly, the trispecific antibodies are in preclinical development with dual MM surface markers targeting in an attempt to increase MM cell specificity
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J
[VIRTUAL] Infection in the CD38 and Anti-BCMA Era: Prevention and Treatment () - May 20, 2021 - Abstract #SOHO2021SOHO_76;
Treatment with these agents may be associated with lymphopenia, pneumonia, and reactivation of viral infections, particularly VZV and opportunistic infections, especially in heavily pretreated patients.3–5 Several ways of targeting B-cell maturation antigen (BCMA) including with cellular therapy (CAR T-cells), bispecific T-cell engagers and antibody drug conjugates like belantamab mafodotin are currently under investigation.6 All of these strategies result in immune suppression given that they target the antibody-producing B and plasma cells...Discussion and Conclusion We will review the data on infectious complications and will come up with guidelines for infection prophylaxis in this specific treatment population. We will also provide guidelines for treatment of infections in this patient population.
- |||||||||| fludarabine IV / Generic mfg.
Journal, IO biomarker: Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia. (Pubmed Central) - May 15, 2021
The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen...In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38-CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.
- |||||||||| Journal, IO biomarker: Delineation of target expression profiles in CD34+/CD38- and CD34+/CD38+ stem and progenitor cells in AML and CML. (Pubmed Central) - May 15, 2021
Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.
- |||||||||| Darzalex IV (daratumumab) / J&J, Zarzio (filgrastim biosimilar) / Novartis
[VIRTUAL] DARATUMUMAB, AN ORIGINAL APPROACH FOR TREATING REFRACTORY AUTOIMMUNE CYTOPENIA () - May 13, 2021 - Abstract #EHA2021EHA_1934;
Patients received a median number of 6 [range 4-11] weekly infusions of daratumumab at 16mg/kg of body weight with dexamethasone premedication...As most patients experienced transient hypogammaglobulinemia, the risk of infection should be weighted in the therapeutic decision. Prospective studies are needed to confirm these preliminary data.
- |||||||||| nirogacestat (PF-03084014) / SpringWorks Therap
[VIRTUAL] DREAMM-5 PLATFORM TRIAL: BELANTAMAB MAFODOTIN (BELAMAF) IN COMBINATION WITH FIVE DIFFERENT NOVEL AGENTS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) () - May 13, 2021 - Abstract #EHA2021EHA_1799;
P1/2, P2
Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment...Conclusion . Funding: GSK (Study 208887, NCT04126200); belamaf drug linker technology licensed from Seagen Inc; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics and isatuximab produced by and used in collaboration with Sanofi.
- |||||||||| Darzalex IV (daratumumab) / J&J, Zarzio (filgrastim biosimilar) / Novartis
[VIRTUAL] DARATUMUMAB MONOTHERAPY IN NEWLY DIAGNOSED PATIENTS WITH STAGE 3B LIGHT CHAIN (AL) AMYLOIDOSIS: A PHASE II MULTICENTER STUDY BY THE EUROPEAN MYELOMA NETWORK () - May 13, 2021 - Abstract #EHA2021EHA_1694;
Pts who do not achieve at least a hematologic VGPR, or hematologic PR with cardiac or renal response, may receive at Investigator’s discretion additional treatment with Bortezomib (weekly for a maximum of 6 months) and low dose dexamethasone from Cycle 4...Conclusion This early analysis shows that DARA monotherapy is safe with no treatment-related safety events or any signal of cardiac toxicity in patients with stage 3B disease. The enrollment in the study continues and more data will be available on safety and efficacy with the inclusion of additional patients in the updated analysis.
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J, Zarzio (filgrastim biosimilar) / Novartis
[VIRTUAL] RESULTS ON EFFICACY AND SAFETY OF DARATUMUMAB WITH DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND SEVERE RENAL IMPAIRMENT: THE DARE STUDY () - May 13, 2021 - Abstract #EHA2021EHA_1686;
Eligible adult pts had documented RRMM and severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m2 or requiring dialysis), who had ≥2 previous treatments of both bortezomib- and lenalidomide-based regimens, had progressive disease after their last treatment and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2...Notably, responses were similar in pts regardless of being on dialysis or not. No new safety signals were observed but antibiotic prophylaxis may potentially reduce infection risk.
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J
[VIRTUAL] UPDATED ANALYSIS OF DARATUMUMAB PLUS LENALIDOMIDE AND DEXAMETHASONE (D-RD) VERSUS LENALIDOMIDE AND DEXAMETHASONE (RD) IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (TIE-NDMM): THE PHASE 3 MAIA STUDY () - May 12, 2021 - Abstract #COMy2021COMy_154;
P3
INTRODUCTION AND Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor1-4 and immunomodulatory5-7 mechanism of action DARA is approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care (SOC) for RRMM and (NDMM)8,9 The addition of DARA to SOC regimens in phase 3 studies has consistently improved progression-free survival (PFS) and has led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity, compared with SOC10-14 In the primary analysis of the phase 3 MAIA study (median follow up, 28.0 months), a significant PFS benefit (median, not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; 95% CI, 0.43-0.73; P 3-fold increase in MRD-negativity rates (10–5 sensitivity threshold; 24.2% vs 7.3%; P <0.001) were observed with the combination of DARA plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in patients with transplant-ineligible (TIE) NDMM13 With a longer follow up (median, 36.4 months), D-Rd maintained a PFS benefit and deeper and more durable responses versus Rd alone15 Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow up Study Design Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplant due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA Stratification factors were International Staging System stage (I vs II vs III), region (North America vs other), and age (<75 vs ≥75 years) All patients received 28-day cycles of Rd (lenalidomide, 25 mg orally once daily on Days 1-21; dexamethasone, 40 mg orally or intravenously [IV] on Days 1, 8, 15, and 22) In the D-Rd arm, DARA (16 mg/kg IV) was given weekly during Cycles 1 and 2, every 2 weeks during Cycles 3 through 6, and every 4 weeks thereafter (Figure 1) Patients in both treatment arms were treated until disease progression or unacceptable toxicity Endpoints and Assessments The primary endpoint was PFS. After a median follow up of 47.9 months, the addition of DARA to Rd continues to demonstrate a superior PFS benefit and more patients continue to have deeper and more durable responses, including a tripling of the MRD-negativity rate, versus Rd alone in patients with TIE NDMM – The estimated 48-month PFS rate was substantially higher for D-Rd than Rd – D-Rd showed a PFS benefit and improvement in MRD-negativity rate in patients with high cytogenetic risk The longer follow up also demonstrated a significant benefit in PFS2 favoring D-Rd versus Rd alone No new safety concerns were observed with longer follow up.
- |||||||||| Revlimid (lenalidomide) / BMS, Darzalex IV (daratumumab) / J&J
Preclinical, Journal: VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo. (Pubmed Central) - May 7, 2021
Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy (P < 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.
- |||||||||| Darzalex IV (daratumumab) / J&J
Review, Journal: Current antibody-based therapies for the treatment of multiple myeloma. (Pubmed Central) - May 7, 2021
The accelerated approval of belantamab mafodotin represents an important milestone in antibody development; its ability to target B-cell maturation antigen (BCMA) in advanced disease is now established. Here, we present an overview of the currently available monoclonal antibody treatments in MM and discuss the clinical value, significant potential, and possible limitations of these immunotherapeutic approaches to driving deeper responses and achieving longer overall survival among patients with a challenging disease.
- |||||||||| Abecma (idecabtagene vicleucel) / bluebird bio, BMS, Sarclisa (isatuximab-irfc) / Sanofi
Journal: Approvals Expand Multiple Myeloma Treatment Options. (Pubmed Central) - Apr 29, 2021
Two recent FDA approvals broaden the treatment landscape for multiple myeloma. The approvals include the first CAR T-cell therapy for the disease, idecabtagene vicleucel, and a monoclonal antibody targeting CD38, isatuximab-irfc.
- |||||||||| Melflufen (melphalan flufenamide) / Oncopeptides, Darzalex IV (daratumumab) / J&J
[VIRTUAL] LIGHTHOUSE (OP-108): A phase 3 study of melflufen in combination with dexamethasone (dex) and daratumumab (dara) versus dara in relapsed/refractory multiple myeloma (RRMM) patients (pts). () - Apr 28, 2021 - Abstract #ASCO2021ASCO_2907;
P3
Other secondary endpoints: clinical benefit rate (≥ minimal response), time to response, time to progression, time to next treatment, and overall survival . Exploratory endpoints include: minimal residual disease in pts achieving ≥ very good PR, PFS following next line of treatment (PFS-2), pt-reported outcomes, pharmacokinetics, translational biomarkers, response rate in pts with extramedullary disease, and efficacy (including ORR) in Arm B pts who receive Arm A triplet therapy after PD.
- |||||||||| iberdomide (CC-220) / BMS, Blenrep (belantamab mafodotin) / GSK
Journal, Combination therapy: Current developments in the combination therapy of relapsed/refractory multiple myeloma. (Pubmed Central) - Apr 24, 2021
Therapeutic strategies continue to evolve in myeloma, with the application of existing platforms (e.g., antibody-drug conjugates) to target relevant biology (e.g., B cell maturation antigen). Within the next year, there will be additional agents approved for those with advanced disease, and combinations as well as placement in sequencing will deepen responses and improve outcomes for patients.
- |||||||||| Darzalex IV (daratumumab) / J&J
Journal, IO biomarker: Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma. (Pubmed Central) - Apr 23, 2021
The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.
- |||||||||| Sarclisa (isatuximab-irfc) / Sanofi
Journal, PD(L)-1 Biomarker, IO biomarker: Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells. (Pubmed Central) - Apr 13, 2021
Finally, isatuximab-induced CDC was observed in cell lines with high CD38 receptor density (>250,000 molecules/cell) and limited expression of inhibitory complement regulatory proteins (CD46, CD55, and CD59; <50,000 molecules/cell). Taken together, our findings highlight mechanistic insights for isatuximab and provide support for a range of combination therapy approaches that could be tested for isatuximab in the future.
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