Tag: Multiple Myeloma

Late Breaking Abstract- ASCO 2023: BCMA-directed CAR T-cell therapy Cilta-cel in Lenalidomide Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed or Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

Ciltacabtagene autoleucel (Cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with Relapsed or Refractory multiple myeloma and was approved by the FDA in February 2022 for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including a Proteasome Inhibitor (PI), an Immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. The researchers in this study investigated the efficacy of cilta-cel in earlier treatment lines among patients with Lenalidomide-refractory disease.

CARTITUDE-4 is an open-label, multicenter, randomized Phase III trial conducted to compare cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

Treatment with cilta-cel resulted in a significantly lower risk of disease progression or death than standard-of-care (HR=0.26; P<0.001). The median PFS was not reached in the cilta-cel group and was 11.8 months in the standard-of-care group. Progression-free survival at 12 months was 75.9% in the cilta-cel group and 48.6% in the standard-of-care group. The ORR was 84.6% in the cilta-cel group and 67.3% in the standard-of-care group (P<0.001), the CR rate or better was 73.1% versus 21.8% (P<0.001), and MRD negativity was 60.6% versus 15.6% (P<0.001), respectively. Among the patients who had a response, an estimated 84.7% in the cilta-cel group as compared with 63.0% in the standard-of-care group continued to have a response for at least 12 months.

The most common Grade 3 or 4 adverse events in both groups were hematologic and most high-grade cytopenias in patients who received cilta-cel recovered to Grade 2 or less by day 60. Serious adverse events were reported in 44% of patients in the cilta-cel group and in 39% of patients in the standard-of-care group. Lower rates of cytopenias, Cytokine Release Syndrome, and CAR-T–related neurotoxicity were seen in this study compared to previous cilta-cel studies suggesting that cilta-cel may have a better side-effect profile when used earlier in treatment.

It was concluded that a single cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. San-Miguel J, Dhakal B, Yong K, et al. N Engl J Med 2023;389:335-347.

Overall Survival with DARZALEX®, REVLIMID®, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX)

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730 new cases will be diagnosed in 2023 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed or Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Previously published Phase I and II studies involving patients with Relapsed or Refractory multiple myeloma demonstrated promising efficacy of DARZALEX® when given as a single agent, as well as when given along with Lenalidomide (REVLIMID®) and Dexamethasone.

POLLUX is a multicenter, randomized, open-label, active-controlled, Phase III trial in patients with Relapsed or Refractory multiple myeloma. In this study, 569 patients who had Relapsed or Refractory multiple myeloma were assigned in a 1:1 ratio to receive either DARZALEX®, REVLIMID® and Dexamethasone (D-Rd group, N=286) or REVLIMID® and Dexamethasone (Rd group, N=283). Patients refractory to REVLIMID® were excluded. Patients in the DARZALEX® group received DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter. Both treatment groups received REVLIMID® 25 mg PO on days 1-21 of each cycle and Dexamethasone 40 mg PO weekly. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Time to disease progression, Response Rate, Time to response, Duration of Response, and percentage of patients with results below the threshold for Minimal Residual Disease (MRD). Minimal Residual Disease status was evaluated for patients who had a Complete Response by Next-Generation sequencing assay of bone marrow.

At a median follow-up of 13.5 months, the PFS at 12 months was 83.2% in the DARZALEX® group compared to 60.1% in the control group (HR=0.37; P<0.001). The Overall Response Rate was significantly higher in the DARZALEX® group than in the control group (92.9% versus 76.4%, P<0.001) and further, there was a higher rate of Complete Response or better (43.1% vs. 19.2%, P<0.001). In the DARZALEX® group, 22.4% of the patients had results below the threshold for MRD (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001).

The authors in this publication reported updated efficacy and safety results at the time of final Overall Survival (OS) analysis of POLLUX, after a follow-up of more than 6.5 years. After positive primary analysis and protocol amendment, patients receiving Rd were offered DARZALEX® monotherapy after disease progression. At a median follow-up of 79.7 months, D-Rd significantly prolonged OS, with a 27% reduction in the risk of death compared to Rd alone (median 67.6 versus 51.8 months, respectively; HR=0.73; P=0.0044). Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age 65 years or older and patients with one, two, or three prior lines of therapy, International Staging System Stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a Proteasome Inhibitor. MRD negativity rates in this final analysis were nearly five times higher with D-Rd versus Rd (33.2% versus 6.7%) and regardless of the treatment group, MRD negativity was associated with improved OS, emphasizing the importance of achieving MRD negativity.

The most common Grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia, anemia, pneumonia, thrombocytopenia and diarrhea. Even though the incidence of Grade 3/4 infections was higher with D-Rd versus Rd, the discontinuation rate was similar in both treatment groups. No new safety concerns were observed with longer follow up.

It was concluded that in this updated analysis of the POLLUX study, DARZALEX® in combination with REVLIMID® and Dexamethasone significantly extended Overall Survival compared to REVLIMID® and Dexamethasone, in patients with Relapsed or Refractory multiple myeloma. The authors added that the POLLUX study reported the longest median Overall Survival observed to date in Phase III studies of REVLIMID® and Dexamethasone-based triplets in Relapsed or Refractory multiple myeloma. These results complement and strengthen the Overall Survival data recently reported with DARZALEX® plus VELCADE® (Bortezomib) and Dexamethasone in the Phase III CASTOR study in Relapsed or Refractory multiple myeloma.

Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial. Dimopoulos MA, Oriol A, Nahi H, et al. J Clin Oncol 2023;41;1590-1599

Real World Experience of Anti-BCMA CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730 new cases will be diagnosed in 2023 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR) by transducing with a gene encoding the engineered CAR via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. The KarMMa trial however had stringent eligibility criteria, which was likely not representative of real-world population.

The researchers conducted this study to evaluate safety and efficacy of Standard of Care ABECMA® for the treatment of Relapsed and Refractory multiple myeloma in a real-world population. This retrospective, multicenter, observational study included 196 patients planned for Standard of Care ABECMA® for Relapsed and Refractory multiple myeloma from 11 US medical centers. Unlike the KarMMa trial which had stringent eligibility criteria, not representative of real-world patient population, the present study included patients with comorbidities that would have made them ineligible for the KarMMa trial. A total of 159 patients successfully received ABECMA®. The median age was 64 years, and 35% of patients had high-risk cytogenetics (del(17p), t(4;14) and t(14;16), the median number of prior lines of therapy was seven and 44% of patients had penta-refractory disease. In this real-world experience study, 21% had prior anti-BCMA therapy, 84% had prior Autologous Stem Cell Transplant and 6% had Allogeneic Stem Cell Transplant. Approximately 75% of patients in this study would not have met KarMMa eligibility criteria. Further, relative to KarMMa trial, this real-world cohort had more patients with extramedullary and penta-refractory disease.

The median time from leukapheresis to ABECMA® infusion was 47 days. The CAR T-cells manufacturing failure rate in real-world patients was higher than that seen in KarMMa trial and this was attributed to poor bone marrow reserve among patients in this study, probably related to prior treatment, including alkylators, which can result in T-cell depletion. Nonetheless, 90% of eligible patients were administered ABECMA®, which is comparable with 91% in the KarMMa trial. The median follow up from infusion was 6.1 months.

Overall, the efficacy of ABECMA® in the real-world population was comparable with that in the KarMMa trial group of patients. The Overall Response and Complete Response rates with Standard of Care ABECMA® were 84% and 42%, which are comparable with 73% and 33% noted in the KarMMa trial. The median DOR was 8.6 months in the present study versus 10.7 months in the KarMMa trial and the median time to response was 1 month. The median PFS in this study was 8.5 months, similar to that observed in the KarMMa trial and the median Overall Survival was 12.5 months. In a multivariable analysis of this study, prior use of BCMA targeted therapy, high-risk cytogenetics, ECOG PS 2 or more, lymphodepletion, and younger age were independent predictors of inferior Progression Free Survival. Any grade and Grade 3 or more Cytokine Release Syndrome and neurotoxicity occurred in 82%/3% and 18%/6%, respectively.

It was concluded from this trial that safety and efficacy of ABECMA® in patients with Relapsed and Refractory multiple myeloma in the Standard of Care setting were comparable with those in the Phase II pivotal KarMMa trial, even though majority of patients in this study did not meet KarMMa trial eligibility criteria. This real-world population study also suggested that if BCMA chimeric antigen receptor-T-cell treatment is planned, prior exposure to BCMA-targeted therapy should be avoided.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. Hansen DK, Sidana S, Peres LC, et al. DOI: 10.1200/JCO.22.01365 Journal of Clinical Oncology. Published online January 09, 2023.

TECVAYLI® (Teclistamab-cqyv)

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The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory Multiple Myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. TECVAYLI® is a product of Janssen Biotech, Inc.

Unprecedented Progression Free Survival with SARCLISA® plus KYPROLIS® and Dexamethasone in Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. CD38 is a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with KYPROLIS® and Dexamethasone in 2020, for the treatment of patients with multiple myeloma, who had received 1-3 prior lines of therapy. This was based on the CANDOR open label, Phase III trial, in which the triplet combination of DARZALEX®, KYPROLIS® and Dexamethasone resulted in a 37% reduction in the risk of progression or death, compared with KYPROLIS® and Dexamethasone. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation, by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

SARCLISA® (Isatuximab-irfc) is a CD38-targeting IgG1monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome. The FDA in 2021, approved SARCLISA® in combination with KYPROLIS® (Carfilzomib) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy.

IKEMA trial is a multicenter, randomized, open label, Phase III study, in which the efficacy and safety of SARCLISA® in combination with KYPROLIS® and Dexamethasone was evaluated among patients with relapsed and/or refractory multiple myeloma, who had received 1-3 prior lines of therapy. In this study, 302 eligible patients were randomized 3:2 to receive SARCLISA® plus KYPROLIS® and Dexamethasone (N=179) or KYPROLIS® and Dexamethasone alone (N=123). SARCLISA® was given at 10 mg/kg IV weekly for 4 weeks and then every 2 weeks. KYPROLIS® was given at 20 mg/m2 IV on days 1 and 2 and then at 56 mg/m2 IV thereafter twice weekly for 3 of 4 weeks and Dexamethasone was given at 20 mg twice weekly. Treatment was continued until disease progression or unacceptable toxicity. The median age was 64 years, 23% had 3 or more prior lines of therapy, 90% of patients had prior treatment with Proteasome Inhibitor, 78% had prior treatment with Immunomodulatory drug (IMiD) and 24% had high-risk cytogenetics. The Primary endpoint was Progression Free Survival (PFS) as determined by an Independent Review Committee (IRC). Key Secondary endpoints included Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity rate (10-5 by NGS), and Overall Survival (OS). The authors have now reported updated efficacy and safety results from IKEMA trial.

At a median follow-up of 44 months, the median PFS was 35.7 months in the SARCLISA® group and 19.2 months in the KYPROLIS® and Dexamethasone group (HR=0.58; 95.4% CI). The PFS benefit with SARCLISA® group was consistent across subgroups, including among patients with high-risk cytogenetics and those who were refractory to Lenalidomide. SARCLISA® plus KYPROLIS® and Dexamethasone also delayed the time to next treatment and prolonged PFS2. The median time to next treatment was 44.9 months with SARCLISA® combination and 25.0 months with KYPROLIS® and Dexamethasone (HR=0.55; 95% CI). The median PFS2 was 47.2 months and 35.6 months respectively (HR=0.68; 95% CI). The Complete Response (CR) rate or stringent CR rate was 44.1% in the SARCLISA® combination group and 28.5% in the KYPROLIS® and Dexamethasone group. MRD negativity was achieved in 33.5% of patients in the SARCLISA® combination group and 15.4% in the KYPROLIS® and Dexamethasone group. The rate of MRD negativity among patients with a CR or stringent CR was 26.3% in the SARCLISA® combination group and 12.2% in the KYPROLIS® and Dexamethasone group. No new safety signals were identified.

It was concluded that the addition of SARCLISA® to KYPROLIS® and Dexamethasone resulted in unprecedented median Progression Free Survival, Complete Response Rate and MRD negativity with a non-Lenalidomide regimen, and is the longest Progression Free Survival with a Proteasome Inhibitor backbone in the relapsed multiple myeloma setting. The authors added that SARCLISA® combination was well tolerated with manageable safety and a favorable benefit-risk profile, and this updated efficacy data support SARCLISA® in combination with KYPROLIS® and Dexamethasone as a standard of care treatment for patients with relapsed or refractory multiple myeloma.

VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Moreau P, Dimopoulos MA, Mikhael J, et al. ESMO Virtual Plenary. May 19-20, 2022. DOI:https://doi.org/10.1016/j.annonc.2022.04.013

XPOVIO® (selinexor): A Treatment Approved for Multiple Myeloma as Early as First Relapse

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Author: Cristina Gasparetto, MD
Sponsored by: Karyopharm Therapeutics, Inc.
Dr. Gasparetto is a paid consultant for Karyopharm Therapeutics, Inc. and has been compensated.

Multiple myeloma (MM) remains an incurable hematologic cancer due to the clonal nature of the disease.1 With each relapse, cancer cells undergo clonal evolution and acquire new mutations that render them resistant to certain treatments.1 Triplet therapies combining proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38-mAbs) have improved patient outcomes and their use has steadily increased over the past decade.2,3 When patients relapse after exposure to daratumumab (a CD38-mAb), the prognosis becomes unfavorable; even if patients previously responded to PIs or IMiDs, median survival may not reach one year.3 A significant unmet need therefore remains for providing durable disease control for patients with MM.1

For patients with previously-treated MM, the National Comprehensive Cancer Network® (NCCN®) recommends a new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months.4 For patients with MM who are triple class exposed, a selective inhibitor of nuclear export (SINE) may be a potential treatment class to consider in early relapsed (1-3 prior therapies) MM.4 Once-weekly XPOVIO® (selinexor), is a first-in-class, oral SINE compound approved as early as first relapse in MM that reversibly inhibits exportin 1 (XPO1).5 This action leads to accumulation of tumor suppressor proteins in the nucleus and reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells.5 Oral, once weekly selinexor (XPOVIO®) in combination with bortezomib and dexamethasone (XVd) is recommended by the NCCN as a Category 1 therapeutic option in early relapsed (1 to 3 prior therapies) MM.4

The efficacy and safety of XPOVIO was assessed in a phase 3, randomized, open-label trial comparing XPOVIO (100 mg once weekly) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) with Vd alone in patients exposed to one to three prior lines of therapy.6 Patient disease characteristics were well balanced in both treatment groups and the primary endpoint was progression-free survival (PFS).5,6 Patients in the XVd group demonstrated a median PFS of 13.9 months (95% CI: 11.73-NE) compared with 9.5 months (95% CI: 8.11-10.78) in the Vd group (HR 0.70 [95% CI: 0.53-0.93], P=0.0075).6 In patients treated with XVd, a greater median PFS was consistently observed in certain subgroups compared with patients treated with Vd (Figure 1).6,7 When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and a higher incidence of serious adverse reactions (56% vs 47%).5

XPOVIO-Combination-Demonstrated-Sustained-PFSFigure 1. Median PFS in the XVd and Vd treatment groups (primary endpoint) and in select patient subgroups in the XVd trial.

Oral, once-weekly XPOVIO dosage may be adjusted to help mitigate potential adverse reactions (ARs).5 The indicated starting dose of XPOVIO is 100 mg once weekly and the dose may be reduced to 80 mg, 60 mg, or 40 mg based on ARs.5 Dose reductions were permitted in the XVd trial to help mitigate ARs – 65% of patients in the XVd group had a dose reduction and the median dose of XPOVIO in that group was 80 mg once weekly.5,7 Patients in my clinical practice typically get reduced from 100 mg to 60 mg once weekly and experience minimal tolerability issues at 60 mg. In an exploratory post-hoc analysis of the XVd trial, efficacy was maintained with XPOVIO dose reductions (Figure 2).7

Efficacy-Maintained-Even-With-XPOVIO-Dose-ReductionFigure 2. Median PFS in XPOVIO dose-reduced patients in the XVd trial.

XVd was not associated with serious organ toxicities of the cardiac, pulmonary, renal, or hepatic systems.6,7 Warnings and precautions include life-threatening thrombocytopenia and neutropenia, gastrointestinal toxicities, severe life-threatening hyponatremia, serious infection, and life-threatening neurological toxicities.5 The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting (Figure 3).5 The XVd trial protocol required a prophylactic 5-HT3 antagonist to address nausea but allowed for other interventions as required.7 Nausea events were reported in 50% of patients, however, treatment-related nausea associated with XPOVIO diminished over time; 92% of nausea cases were resolved/resolving in the first month of treatment.7 Patients should be counseled on what to expect with XPOVIO therapy and monitored throughout treatment, with more frequent monitoring during the first three months of treatment.5

Figure 3. Adverse reactions reported in the XVd trial.

Below we consider 2 hypothetical patients where XPOVIO may be considered.

Patient A is a 66-year-old woman with relapsed/refractory MM. She was started on lenalidomide, bortezomib, and dexamethasone, and received autologous stem cell transplant (ASCT) followed by lenalidomide maintenance, which she did well on for 16 months. Upon relapsing, she was given daratumumab, pomalidomide with dexamethasone, and after 7 months, imaging confirmed that her MM progressed again. Given her DPd exposure, Patient A (RVd → ASCT → R → DPd) may be a candidate for a class switch to XVd.

Patient B is a 74-year-old man with a history of hypertension and was diagnosed with MM 2 years ago. Because of his hypertension, he was unable to start a PI due to risk of cardiotoxicity and he is ASCT ineligible. His healthcare provider started him on daratumumab, lenalidomide, and dexamethasone (DRd), but after 2 years, he has relapsed. A class switch to XPOVIO could be considered for Patient B as his second-line therapy.

Healthcare providers should consider patients’ individual clinical characteristics when making treatment decisions. Consider switching class with XPOVIO® (selinexor) for patients at relapse, including those who have been exposed to a CD38-mAb–based regimen.5 Based on the results of the XVd trial and considering the clonal nature of MM, switching patients to XPOVIO may be an option to consider.

INDICATIONS
XPOVIO® (selinexor) is a prescription medicine approved:
• in combination with bortezomib and dexamethasone to treat adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma.
Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of bleeding. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection.
Monitor more frequently during the first 3 months of treatment. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients.

Nausea/Vomiting/Diarrhea: Provide prophylactic antiemetics or treatment as needed.

Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout treatment and provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia.
Monitor sodium level at baseline and throughout treatment.

Serious Infection: XPOVIO can cause serious and fatal infections. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Advise patients to refrain from driving and engaging in hazardous occupations or activities until the neurological toxicity fully resolves. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity: XPOVIO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

Cataracts: New onset or exacerbation of cataract has occurred during treatment with XPOVIO. The incidence of new onset or worsening cataract requiring clinical intervention was reported.

ADVERSE REACTIONS

The most common adverse reactions (ARs) (≥20%) in patients with multiple myeloma who received XVd were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting.

Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia.

Fatal ARs occurred in 6% of patients within 30 days of last treatment. Serious ARs occurred in 52% of patients. Treatment discontinuation rate due to ARs was 19%. The most frequent ARs requiring permanent discontinuation in >2% of patients included fatigue, nausea, thrombocytopenia, decreased appetite, peripheral neuropathy and vomiting. Adverse reactions led to XPOVIO dose interruption in 83% of patients and dose reduction in 64% of patients.

USE IN SPECIFIC POPULATIONS

No overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥65 years old had a higher incidence of discontinuation due to an adverse reaction (AR) and a higher incidence of serious ARs than younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

Please see full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

© 2022 Karyopharm Therapeutics Inc. US-XPOV-10/22-00003

References
1. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18(2):71-84. doi:10.1038/s41571-020-0427-6
2. Braunlin M, Belani R, Buchanan J, Wheeling T, Kim C. Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011-2019 oncology clinic electronic health record data. Leuk Lymphoma. 2021;62(2):377-386. doi:10.1080/10428194.2020.1827253
3. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.5.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed October 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
5. XPOVIO (selinexor) [prescribing information]. Karyopharm Therapeutics Inc. https://www.karyopharm.com/wp-content/uploads/2019/07/NDA-212306-SN-0071-Prescribing-Information-01July2019.pdf
6. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. The Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
7. Data on File. Karyopharm Therapeutics Inc. 2021. Published online 2021.

FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505

Overall Survival Benefit with SARCLISA® Plus POMALYST® and Dexamethasone in Relapsed and Refractory Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

CD38 is a transmembrane glycoprotein, abundantly expressed on malignant plasma cells, and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38 and was approved for use in combination with POMALYST® (Pomalidomide) and Dexamethasone in 2017, for the treatment of patients with multiple myeloma, who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

SARCLISA® (Isatuximab) is a CD38-targeting monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome.

The FDA approval of SARCLISA® in 2020 was based on ICARIA-MM trial, which is an open-label, randomized, multicentre Phase III study in which 307 adult patients with Relapsed and Refractory multiple myeloma who had received at least two previous lines of treatment, including REVLIMID® and a Proteasome Inhibitor were eligible. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. Patients were randomly assigned 1:1 to receive either SARCLISA® along with POMALYST® and low-dose Dexamethasone (N =154) or POMALYST® and low-dose Dexamethasone alone (N = 153). Treatment consisted of 28-day cycles of SARCLISA® 10 mg/kg given IV on days 1, 8, 15, and 22 in the first cycle and days 1 and 15 in subsequent cycles. Both groups received POMALYST® 4 mg orally on days 1 to 21 of each cycle and Dexamethasone 40 mg (20 mg for patients aged 75 years or older) orally or IV on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The Primary endpoint was Progression Free Survival (PFS), determined by an Independent Response Committee, and assessed in the intent-to-treat population.

At a median follow up of 11.6 months, the median PFS was 11.5 months in the SARCLISA® group versus 6.5 months in the control group (HR= 0.596; P=0.001). This PFS improvement represented an approximately 40% reduction in the risk of disease progression or death in the SARCLISA® group and was noted in all poor prognostic patient subgroups, including patients who were refractory to REVLIMID®, a Proteasome Inhibitor or both.

The researchers in this publication reported prespecified updated Overall Survival analysis, at 24 months after the primary analysis (second interim analysis). The median follow-up at data cutoff was 35.3 months. The median Overall Survival was 24.6 months in the SARCLISA® group and 17.7 months in the control group (HR=0.76; P=0.028, not crossing prespecified stopping boundary). Final Overall Survival analysis follow up is ongoing. Updated median PFS was 11.1 months in the SARCLISA® group versus 5.9 months in the control group (HR= 0.60; P<0.0001).

Approximately 60% of patients in the SARCLISA® group and 72% in the control group received subsequent therapy after disease progression. Median time to next treatment was longer in the SARCLISA® group (P<0.0001). Among these patients, 24% received DARZALEX® as subsequent therapy versus 58% in the control group. In a post hoc analysis, median overall survival was 19.9 months among control group patients who received DARZALEX® and 17.4 months among those who did not. Overall, median PFS on subsequent therapy or death was 17.5 months in the SARCLISA® group versus vs 12.9 months in the control group (HR=0.76; P=0.02).

The most common Grade 3 or worse treatment-related adverse events in the SARCLISA® group versus the control group were neutropenia (50% versus 35%), pneumonia (23% versus 21%), and thrombocytopenia (13% versus 12%). No new safety concerns were identified with SARCLISA® plus POMALYST® and Dexamethasone, with longer follow up.

The authors concluded that the addition of SARCLISA® to POMALYST® and Dexamethasone resulted in an approximately 7 month difference in median Overall Survival compared with POMALYST® and Dexamethasone, and is a new standard of care for REVLIMID® and Proteasome Inhibitor-refractory or relapsed multiple myeloma.

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Richardson PG, Perrot A, San-Miguel J, et al. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5

Late Breaking Abstract – ASCO 2022: RVd Plus Autologous Stem Cell Transplantation and REVLIMID® Maintenance Improves PFS in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

In patients with newly diagnosed Myeloma who are eligible for transplant, the optimal use of triplet/quadruplet induction regimens, Autologous Stem Cell Transplantation (ASCT), and REVLIMID® (Lenalidomide)-based maintenance, continues to evolve. In the IFM 2009 French trial, REVLIMID® maintenance treatment was admininstered for one year and after a median follow-up of 89.8 months, the median Progression Free Survival (PFS) was 47.2 months with RVd plus ASCT and 35 months with RVd alone, but there was no Overall Survival (OS) benefit.

DETERMINATION ((Delayed vs Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy) trial is a randomized Phase III trial, conducted to determine whether Autologous Stem Cell Transplantation (ASCT) enhances the efficacy of first line triplet induction therapy or whether it should be kept in reserve for select group of patients. In this study, 722 patients with symptomatic newly diagnosed Myeloma were enrolled. All patients received 3 cycles of RVd followed by stem cell mobilization (for possible ASCT if disease progressed). Patients were then randomly assigned to receive 5 additional cycles of RVd (RVd-alone arm, N=357) or Melphalan at 200 mg/m2, followed by ASCT and 2 additional cycles of RVd (RVd+ASCT arm, N=365). Each RVd cycle consisted of REVLIMID® 25 mg orally on days 1-14, VELCADE® (Bortezomib) 1.3 mg/m2 IV or SC on days 1, 4, 8, 11, and Dexamethasone given orally on days 1, 2, 4, 5, 8, 9, 11, 12, given as 21 day cycles. Dexamethasone was dosed at 20 mg/day for first 3 cycles and 10 mg/day for remaining cycles. Both treatment groups then received REVLIMID® maintenance at 10-15 mg orally daily, until disease progression or drug related toxicities. Both treatment groups were well balanced. The median age of enrolled patients was 56 years, approximately 14% of patients had ISS Stage III Multiple Myeloma and 18% had high-risk cytogenetics such as t(4;14), t(14;16), del17p. Approximately 19% of trial participants were African American, which is the highest representation of this subset of patients in any Phase III Myeloma trial. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Response Rates, Duration of Response (DOR), time to progression, Overall Survival (OS), Quality of Life, and Safety.

At a median follow up of 76 months, the median PFS was 46.2 months in the RVd alone group versus 67.6 months in the RVd plus ASCT group (HR=1.53; P<0.0001). The estimated 5-year PFS rates were 41.5% and 55.6% respectively. The 5 year Overall Survival was similar and not statistically different and was 79.2% and 80.7% respectively. The authors attributed the lack of Overall Survival in the RVd plus ASCT group to the availability of many highly effective treatment options now available after first-line therapy including salvage ASCT, next-generation immunomodulatory drugs, Proteasome Inhibitors, and monoclonal antibodies.

When evaluated by cytogenetic risk, for the standard risk group, the median PFS was 82.3 months in the RVd plus ASCT group versus 53.2 months in the RVd alone group, whereas for patients with high risk cytogenetics, the median PFS was 55.5 versus 17.1 months, respectively. Further, patients with t(4;14) derived more PFS benefit from RVd plus ASCT than those with del(17p). The PFS benefit with RVd plus ASCT was inferior among the African American enrollees and individuals with a Body Mass Index greater than 25 kg/m2.

Even though the Response Rates and quality of responses were similar between the two treatment groups, the Duration of Response was longer in the RVd plus ASCT group at 56.4 months, compared to 39.9 months in the RVd alone group.

More patients in the RVd plus ASCT group achieved MRD (Minimal Residual Disease) negativity compared to RVD alone (54.4% versus 39.8%), despite similar Complete Response Rates in both treatment groups. These MRD negative patients had favorable 5-year PFS, regardless of their treatment assignment. However, RVd plus ASCT improved PFS by 67% among the MRD positive patients.

Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without ASCT than with, at 78% versus 94% respectively. Secondary malignancies occurred in 10% of the RVd-alone group and 11% of the RVd plus ASCT group. Following RVd plus ASCT, 10 patients developed Myelodysplastic syndrome and/or Acute Myeloid Leukemia, compared with none in the RVd-alone group, and this was statistically significant (P=0.002).

The authors concluded that a combination of REVLIMID®, VELCADE® and Dexamethasone (RVd) plus ASCT as initial therapy followed by REVLIMID® maintenance until progression, demonstrated a significant improvement in PFS compared to RVd alone, followed by REVLIMID® maintenance, in patients with newly diagnosed Multiple Myeloma. There was no Overall Survival advantage observed to date. The researchers added that given the lack of benefit in OS and potential toxicities associated with ASCT, these data provide support for personalized treatment approaches, and helps patients make informed decision to delay transplant. Additionally, the significantly longer PFS for both treatment groups in the DETERMINATION study compared to the IFM 2009 (preplanned comparison), suggests that there is a clear benefit to continuous REVLIMID® maintenance until disease progression.

Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): The phase 3 DETERMINATION trial. Richardson PG, Jacobus SJ, Weller E, et al. J Clin Oncol. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4

DARZALEX® plus KYPROLIS® and Dexamethasone in Relapsed or Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients are expected to die of the disease. Multiple Myeloma (MM) in 2022 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

The efficacy of KYPROLIS® and DARZALEX® along with Dexamethasone was evaluated in two clinical trials, CANDOR and EQUULEUS. CANDOR is a global, multicenter, open-label, randomized Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). Patients were stratified by disease stage, previous Proteasome Inhibitor or anti-CD38 antibody exposure, and number of previous therapies. The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0.0027). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. The FDA in August , 2020, approved KYPROLIS® (Carfilzomib) and DARZALEX® (Daratumumab), in combination with Dexamethasone, for adult patients with Relapsed or Refractory multiple myeloma, who have received one to three lines of therapy.

The analysis in the present publication was a preplanned interim analysis for Overall Survival. However the Overall Survival data were not mature at the time of data cutoff. The authors provided updated PFS and safety data, with 11 months of additional follow up. At a median follow up was 27.8 months, the median PFS was 28.6 months in the KdD group and 15.2 months in the Kd group (HR=0.59; P<0.0001), representing a 41% reduction in the risk of progression or death in the KdD group. Treatment-related Adverse Events were consistent with the primary analysis. Grade 3 or more adverse events occurred in 87% patients in the KdD group and 76% in the Kd group and were most commonly thrombocytopenia (25% versus 16%), hypertension (21% versus 15%) and pneumonia (18% versus 9%), respectively.

The authors concluded that with longer follow up, a combination of KYPROLIS® along with Dexamethasone and DARZALEX® provided a clear and durable Progression Free Survival benefit over KYPROLIS® and Dexamethasone alone, making KdD an emerging standard of care for patients with relapsed or refractory multiple myeloma.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Usmani SZ, Quach H, Mateos M-V, et al. The Lancet Oncology 2022;23:65-76.