Pretreated Refractory Multiple Myeloma Research Articles

Magnetismm-4: An Open Label, Phase 1B/2 Umbrella Study of Elranatamab in Combination with Other Anti-Cancer Treatments for Patients with Multiple Myeloma

Background Elranatamab (PF-06863135) is a humanized bispecific molecule that targets multiple myeloma (MM) cells via B-cell maturation antigen (BCMA) and T cells via CD3 to induce T cell-mediated cytotoxicity. In MagnetisMM-1 (NCT03269136), an ongoing, phase 1 study in patients with relapsed or refractory MM (RRMM), subcutaneous (SC) elranatamab yielded an overall response rate (ORR) of 64% and had a manageable safety profile (Jakubowiak et al, J Clin Oncol, 2022). In the phase 2 MagnetisMM-3 (NCT04649359) study in patients with heavily pretreated RRMM, SC elranatamab was well tolerated and yielded an ORR of 61% at the recommended phase 2 dose (Lesokhin et al, J Clin Oncol, 2022). Study Design and Methods MagnetisMM-4 (NCT05090566) is a phase 1B/2, open label, non-randomized, multicenter, umbrella study of elranatamab in combination with other anti-cancer treatments for patients with MM. The estimated enrollment is 105 patients. The study is split into 2 sub-studies (Figure 1). In each sub study, a 2 step-up priming dose of elranatamab will be employed to mitigate the risk of cytokine release syndrome and a Bayesian logistic regression model will be utilized for dose escalation. Sub-study A (SSA) is comprised of 2 phases in which patients will receive elranatamab + the gamma-secretase inhibitor (GSI) nirogacestat. Studies have shown that GSIs block BCMA cleavage and can potentially enhance BCMA-directed therapy (Eastman et al, Blood, 2019; Pont et al, Blood, 2019; Cowan et al, Blood, 2019). Phase 1 of SSA is designed to evaluate the safety, tolerability and select a recommended dose and regimen for the combination of elranatamab and nirogacestat. The primary endpoint for SSA Phase 1 is dose limiting toxicity (DLT) up to 35 days. Phase 2 of SSA will further evaluate the efficacy and safety of the combination of elranatamab and nirogacestat. The primary endpoint for SSA phase 2 is objective response rate (ORR) assessed every 4 weeks for ~2 years. A key secondary endpoint in both phases of SSA is the incidence of treatment-emergent adverse events (TEAEs). In sub-study B (SSB), patients will receive elranatamab + lenalidomide + dexamethasone. The dose escalation part of SSB is designed to assess the safety and tolerability of elranatamab in combination with lenalidomide and dexamethasone. The primary outcome of the dose escalation part is DLT up to 42 days. The dose expansion part of SSB is designed to evaluate the overall safety profile of elranatamab in combination with lenalidomide and dexamethasone. The primary endpoints of the dose expansion part of SSB are incidence of TEAEs and laboratory abnormalities across the duration of the study. A key secondary endpoint in SSB is ORR. Additional secondary endpoints in both SSA and SSB are time to response, duration of response, complete response (CR) rate, duration of CR, progression-free survival, overall survival, minimal residual disease negativity rate, immunogenicity to elranatamab, and elranatamab pharmacokinetics. Inclusion criteria in SSA and SSB include age ≥18 years, RRMM with ≥3 prior lines of therapy, refractory to at least one immunomodulatory drug, one proteasome inhibitor, and one anti-CD38 antibody, measurable disease by serum M-protein ≥0.5g/dL, urinary M-protein excretion ≥200mg/24h, or serum immunoglobulin free light chain (FLC) ≥10mg/dL and abnormal serum immunoglobulin kappa to lambda FLC ratio, and Eastern Cooperative Oncology Group performance status ≤1 (Table 1). Exclusion criteria include active plasma cell leukemia, amyloidosis, stem cell transplant within 12 weeks prior to enrolment or active graft-versus-host disease, POEMS syndrome, any active uncontrolled infection, impaired cardiovascular function or clinically significant cardiovascular disease within 6 months prior to enrolment, and previous administration with an investigational drug within 30 days or 5 half-lives preceding the first dose of study treatment. In SSA, patients who received prior treatment with a BCMA-bispecific antibody are excluded, and in SSB, patients who received prior treatment with BCMA-directed therapy are excluded. The study is enrolling the Phase 1 portions and is being opened at multiple sites in the United States and Canada. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Belantamab mafodotin for relapsed or refractory multiple myeloma.

Objective: Refractory multiple myeloma (MM) presents poor responses to therapies. New drugs for highly pretreated MM are a hope for this clinical context with limited treatment options. We developed a comparative commentary on the evidence about the use of belantamab mafodotin in heavily pretreated relapsed or refractory MM with respect to other therapies. Data sources: Regimen data were extracted from pivotal clinical trials. Data summary: Response rates were the main efficacy outcomes reported in trials. Overall response was achieved by approximately 30% of patients trated with belantamab mafodotin. Response rates of different regimens must be supported by more relevant data, such as overall survival or progression-free survival. Subgroups of patients with extramedullary disease and revised International Staging System III should be thoroughly evaluated in phase III comparative clinical trials with larger sample sizes. Belantamab mafodotin presented specific adverse events (visual disturbances and kerathopathies). Grade 3-4 adverse events involved high percentages of patients treated with the different schemes. The budgetary impact of different treatments for heavily pretreated refractory MM would be very high. Literature suggested increased efficiency of belantamab mafodotin versus chimeric antigen receptor T-cell therapies. Conclusions: Belantamab mafodotin and other regimens are promising drugs for MM, especially for triple-class refractory patients. Comparative studies are necessary to perform a reliable therapeutic positioning.

Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma.

Simple SummaryDefining the specificity and biological sequalae induced by receptors differentiated expressed in multiple myeloma cells are critical for the development of effective immunotherapies based on monoclonal antibodies. Ongoing studies continue to discover new antigens with superior tumor selectivity and defined function in regulating the pathophysiology of myeloma cells directly or indirectly in the immunosuppressive bone marrow microenvironment. Meanwhile, it is urgent to identify mechanisms of immune resistance and design more potent immunotherapies, alone and/or with best combination partners to further prolong anti-MM immunity.The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment. Recently, targeting B cell maturation antigen (BCMA), an even MM-specific antigen, has shown high therapeutic activities by chimeric antigen receptor T cells (CAR T), antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), as well as bispecific antibody (BiAb), with some already approved for heavily pretreated RRMM patients. New antigens, such as orphan G protein-coupled receptor class C group 5 member D (GPRC5D) and FcRH5, were identified and rapidly moved to ongoing clinical studies. We here summarized the pathobiological function of key MM antigens and the status of the corresponding immunotherapies. The potential challenges and emerging treatment strategies are also discussed.

Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, Disclosures Chen:Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity9s Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma

Abstract 77 Background:The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have shown initial results that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy (Rossi et al, ASCO 2012). We now report updated results from a phase 2 trial of large group of patients treated with ClaPD in RRMM. Methods:One hundred patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1–21 of a 28-day cycle, and dexamethasone 40mg on days 1,8,15,22. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results:Ninety-seven patients had completed at least 1 cycle of ClaPD and were eligible for disease response and safety analysis. Patients had undergone a median of 5 (range 3–15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide +bortezomib) refractory were 73%, 70%, and 64% respectively. The median number of ClaPD cycles received was 4 (range 1–23). Response to ClaPD was progressive disease (PD): 9.3%, stable disease (SD): 32%, minimal response (MR): 5.2%, partial response (PR): 32%, very good partial response (VGPR): 17.5%, stringent complete remission (sCR): 4.1%, giving an overall response rate (ORR, ≥PR) of 53.6% and a ≥VGPR rate of 21.6%. Clinical benefit (≥SD) was achieved in 90.7%. Median time to PR and maximum response was 1 (range 1–7) and 2 (range 1–14) cycles, respectively. After a mean follow up time of 10.1 months, 41 patients (42%) remain on study free from disease progression, with a median progression free survival of 8.2 months (95% CI: 5.1, 10.3). Median overall survival has not been reached with 72 patients (74%) alive at last follow-up. The most common grade 3 and 4 toxicities included anemia (25%), neutropenia (40%), hyperglycemia (11%), and fatigue (6%). Febrile neutropenia was uncommon at 2%. There were 4 cases of lower extremity venous thrombosis (4.1%, 1 at grade 1, 3 at grade 2) and no instances of pulmonary embolism. There was no treatment related mortality. Conclusions:ClaPD is a highly effective regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPD is rapid and sustained at > 8 months in the majority of subjects. The tolerability profile is comparable to lenalidomide and incidence of thromboembolic events was low with low-dose aspirin prophylaxis. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures:Mark:Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium Inc.: Speakers Bureau. Off Label Use: Pomalidomide is not indicated to treat multiple myeloma. This drug is a next-generation immunomodulatory agent. We are investigating its activity and safety for use in relapsed or refractory myeloma. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Niesvizky:Onyx, Millenium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding.