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

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.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

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.

High Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT) remains an important treatment option for transplant eligible patients. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction treatment can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time.

The role of consolidation treatment for newly diagnosed, transplant-eligible patients with multiple myeloma has not been conclusively established and needed prospective evaluation. The present prospective clinical trial was conducted to study the relevance of consolidation therapy using Bortezomib, Lenalidomide, and Dexamethasone (VRD) followed by Lenalidomide maintenance, compared with Lenalidomide maintenance alone, in transplant-eligible newly diagnosed multiple myeloma patients.

The EMN02/HOVON95 trial is an open-label, Phase III study, performed by the European Myeloma Network (EMN) in which 1197 previously untreated transplant-eligible patients with symptomatic Stages I-III Multiple Myeloma were randomly assigned initially to four cycles of Bortezomib, Melphalan, and Prednisone (VMP) or High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM/ASCT). Within 2 months after ASCT or last VMP treatment, 878 eligible patients underwent a second randomization to either two 28-day cycles of VRD consolidation treatment, which consisted of Bortezomib 1.3 mg/m2 either IV or SC once daily on days 1, 4, 8, and 11, combined with Lenalidomide 25 mg orally once daily, days 1-21 and Dexamethasone 20 mg orally once daily, on days 1, 2, 4, 5, 8, 9, 11, and 12 (N=451 – Arm B) or no consolidation (N=427 – Arm A). Patients then received Lenalidomide maintenance 10 mg orally once daily on days 1-21 of a 28-day cycle, starting 1-2 months after ASCT or consolidation, and treatment was continued until disease progression or toxicity. The Primary end point was Progression Free Survival (PFS) defined as time from second randomization to disease progression or death. Secondary end points included Partial Response or higher, Overall Survival (OS) from second randomization until death from any cause, and toxicity. Predefined high-risk prognostic subgroups for PFS were cytogenetic abnormalities defined by FISH and included deletion (17p) in 20% or more of enriched plasma cells, t(4;14) in 10% or more of enriched plasma cells, t(14;16) in 10% or more of enriched plasma cells; and amplification 1q. This was in addition to the standard clinical variables such as Hemoglobin level, Serum Creatinine and LDH. Disease assessment was performed before and after consolidation and every 2 months until progression. Bone marrow Minimal Residual Disease (MRD) assessment was performed by multicolor flow cytometry in bone marrow with a detection of 10−4 to 10−5.

At a median follow-up of 74.8 months after the second randomization, the median PFS was significantly prolonged in the VRD consolidation group, compared those who did not receive consolidation treatment (59.3 versus 42.9 months, HR=0.81; P=0.016). This PFS benefit was observed across most predefined subgroups, including Stage, standard-risk cytogenetics, and prior treatment groups. VRD consolidation was however not beneficial in patients with del(17p). Stage III disease and addition of chromosome 1q by FISH at diagnosis were significant adverse prognostic factors for PFS from second randomization. The median duration of maintenance treatment with Lenalidomide was 33 months. Complete Response (CR) or more after consolidation versus no consolidation, and before start of maintenance treatment was 34% versus 18%, respectively (P<0.001). Complete Response or more on protocol including maintenance treatment was 59% with consolidation and 46% without consolidation (P<0.001). Minimal Residual Disease analysis in a subgroup of 226 VRD-consolidated patients with CR or stringent CR or Very Good Partial Response before start of maintenance treatment demonstrated a 74% MRD-negativity rate. Toxicities related to VRD consolidation were acceptable and manageable.

It was concluded from this study that consolidation followed by maintenance treatment after either Bortezomib, Melphalan and Prednisone or High-Dose Melphalan and Autologous Stem Cell Transplantation, significantly improves Progression Free Survival and Overall Response Rate in transplant-eligible and Lenalidomide-naïve newly diagnosed patients with Multiple Myeloma, compared to maintenance treatment alone.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. Sonneveld P, Dimopoulos MA, Beksac M, et al. J Clin Oncol. 2021;39:3613-3622.

Anti-BCMA CAR T-Cell Therapy for Multiple Myeloma

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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable 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 median survival for patients with myeloma is over 10 years. 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.

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.
Anti-BCMA-CAR-T-Cell-Therapy-for-Multiple-Myeloma
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. In this study, 128 patients with persistent disease after at least three previous regimens including a Proteasome Inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, received ABECMA® target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells, after receiving lymphodepleting chemotherapy. Lymphodepletion therapy consisted of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV given on 3 consecutive days, followed by 2 days of rest before ABECMA® infusion. The median patient age was 61 years and the median time from diagnosis was 6 years. About 51% of patients had a high tumor burden (50% or more bone marrow plasma cells), 39% had extramedullary disease and 35% had a high-risk cytogenetic abnormalities, defined as del(17p), t(4;14), or t(14;16). Patients had received a median of 6 previous antimyeloma regimens and 94% had received previous Autologous Hematopoietic Stem Cell Transplants. The Primary end point was an Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and key Secondary end point was a Complete Response or better (comprising complete and stringent Complete Responses). Other efficacy endpoints include Time to Response, Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Minimal Residual Disease (MRD) evaluated by Next-Generation Sequencing (NGS) assay, and Safety.

At a median follow up of 13.3 months, the ORR was 73%, and 33% had a complete or stringent Complete Response. Of those with a complete or stringent Complete Response, 79% had MRD-negative status at a sensitivity level of 10−5, corresponding to 26% of the treated population. This benefit was consistently observed in most subgroups examined, including older patients, those who received bridging therapy, and those with aggressive disease features, including high-risk cytogenetics, triple or penta-refractory disease, a high tumor burden, and extramedullary disease. The median time to first response was 1.0 month and the median time to a Complete Response or better was 2.8 months. The estimated median Duration of Response was 10.7 months for all patients and 11.3 months among those receiving the highest target dose. The response duration increased with the depth of response. The median PFS was 8.8 months for all patients and 20.2 months in patients having a complete or stringent Complete Response. Data on Overall Survival are immature. Cellular kinetic analysis confirmed CAR+ T cells in 59% at 6 months and 36% at 12 months after infusion. Common toxicities included neutropenia, anemia and thrombocytopenia. Cytokine Release Syndrome was reported in 84% of patients including 5% Grade 3 or higher events. Neurotoxic effects developed in 18% of patients.

It was concluded that ABECMA® induced deep and durable responses in majority of heavily pretreated patients with Refractory and Relapsed myeloma, and fulfills a highly unmet need for this patient group. It should however be noted that although some subsets of patients may have sustained responses for long periods of time, most patients eventually relapse. This has been attributed to the loss of CAR T-cells, loss of antigen expression on the tumor cell surface, or to impaired activity of T cells in an immunosuppressive microenvironment. Studies are underway to overcome these shortcomings by optimizing CAR design, as well as preventing antigen escape and developing combination therapies.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. Munshi NC, Anderson LD, Shah N, et al. N Engl J Med 2021; 384:705-716

Infection Risk in Multiple Myeloma Patients Receiving New Generation Therapies

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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 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 will eventually relapse, requiring multiple lines of therapy for disease control. The availability of newer agents has transformed Multiple Myeloma into a chronic disease. Patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Infection is a leading cause of morbidity and mortality in patients with Multiple Myeloma. In a study of over 3000 newly diagnosed Multiple Myeloma patients, approximately 50% of early deaths (deaths occurring in less than 6 months following diagnosis) were associated with infections (J Clin Oncol. 2005;23:9219-9226). The increased susceptibility to infection in this patient group has been attributed to disease-related deficits in the innate or adaptive immune system, including hypogammaglobulinaemia, qualitative and quantitative abnormalities of dendritic cells, T cells, and Natural Killer cells, as well as renal function impairment, and therapies administered at different stages of the disease. Further, the introduction of new therapeutic agents such as Proteasome Inhibitors (PIs), Immunomodulatory drugs and monoclonal antibodies, with novel mechanisms of action, for first and later lines of therapy, for both Hematopoietic Stem Cell Transplantation eligible and ineligible patients, has significantly improved survival, but has also changed the spectrum of infections in patients with Multiple Myeloma. The epidemiology and risks for infection with the use of new therapeutic agents however remains unclear. The present study was conducted to determine patterns, risks and outcomes of infections in patients with Multiple Myeloma, managed with new therapeutic agents and monoclonal antibodies.

In this study, patients with Multiple Myeloma treated with second generation therapies and other monoclonal antibodies were identified from pharmacy and clinical databases, collected from 2 major tertiary referral centers for Multiple Myeloma management in Australia. Agents considered new generation therapies included Pomalidomide, Carfilzomib, Isatuximab, Daratumumab and Elotuzumab. Following commencement of new generation therapy, 60% of the patient’s had previously received Autologous Stem Cell Transplantation and 93% of the patient’s had Relapsed or Refractory Multiple Myeloma. Patients were then followed for episodes of infection, from the commencement of therapy with any newer agents, until completion of treatment, death or end of study, which ever occurred first. Prophylaxis with antibiotics for bacterial infections was not routinely used, but antiviral prophylaxis with Valaciclovir was used when patients received therapy with Proteasome Inhibitors. Patients received prophylaxis with Trimethoprim/Sulfamethoxazole for Pneumocystis jirovecii pneumonia when steroid doses exceeded 16-20 mg of Prednisone equivalent per day.

Each episode of infection was classified as Microbiologically Defined (MDI) when pathogens were isolated on microbiological testing, Clinically Defined (CDI) when sites of infection were identified but no pathogens were isolated on microbiological testing, and Fever of Unknown Focus (FUF) when patients had febrile episodes with no pathogen or site identified. Univariate and multivariate analyses were performed to determine risk factors for infection.

A total of 148 patients with Multiple Myeloma were followed for a median of 13.2 months, and 345 infection episodes were identified. Of these, 29% (100 out of 345) were defined as Microbiologically Defined Infections, 58% (200 out of 345) were defined as Clinically Defined Infections, and 13% (45 out of 345) were defined as Fever of Unknown Focus. Of those with Microbiologically Defined Infections, 50% of infections were attributed to viruses, whereas 45% were attributed to bacterial infection. Respiratory Syncytial Virus was the most frequently isolated virus accounting for 24% of episodes, followed by Rhinovirus at 16% and Influenza virus at 14%. E. coli was the most frequently isolated bacteria at 20%, followed by Haemophilus influenza at 11%. The most common infection site was the respiratory tract (56.8%), hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. Treatment with Proteasome Inhibitors resulted in 16.8 times increased risk for infections, combination of IMiD and PI was associated with 13.44 times higher risk, monoclonal antibody combination therapy was associated with 10.44 times higher risk, and more than 4 lines of therapy was associated with 7.72 times higher risk for infections (P<0.05).

It was concluded from this study that majority of infections are caused by viruses, in patients with Multiple Myeloma treated with newer therapeutic agents. Treatment with a Proteasome Inhibitor and more than 4 lines of therapy were associated with higher risk for infection.

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Lim C, Sinha P, Harrison SJ, et al. Clinical Lymphoma, Myeloma & Leukemia. 2021;21:444-450.

Subcutaneous DARZALEX® Plus POMALYST® and Dexamethasone Improves Progression Free Survival in Relapsed or Refractory Multiple Myeloma

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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 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, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

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. DARZALEX® has activity as both a single agent and when combined with other standard regimens. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID® (Lenalidomide), and has been shown to be active in REVLIMID® and VELCADE® refractory patients. In the EQUULEUS Phase Ib study, intravenous DARZALEX® in combination with POMALYST® and Dexamethasone in heavily pretreated relapsed or refractory Multiple Myeloma, resulted in a Very Good Partial Response (VGPR) or better in 42% of patients.Mechanism-of-Action-of-Daratumumab

Recently published studies have concluded that the subcutaneous formulation of DARZALEX® resulted in non-inferior pharmacokinetics and efficacy compared to the current IV formulation, and also importantly offers the potential for a fixed-dose administration, shorter administration times and a lower rate of infusion-related reactions with improved safety profile.

APOLLO study is an open-label, randomized, multicenter, Phase III trial, conducted by the European Myeloma Network investigators, to evaluate SubCutaneous (SC) formulation of DARZALEX® in combination with POMALYST® and Dexamethasone (D-Pd; N=151) versus POMALYST® and Dexamethasone (Pd; N=153) alone, in relapsed/refractory Multiple Myeloma patients who have received one or more prior lines of therapy including REVLIMID® and a Proteasome Inhibitor. This study enrolled 304 patients with relapsed or refractory Multiple Myeloma, and prior treatment with anti-CD38 antibody or POMALYST® was not permitted. Treatment for all patients consisted of POMALYST® 4 mg orally daily plus Dexamethasone 40 mg orally on days 1, 8, 15, and 22 (20 mg for patients aged 75 years or older), given every 28 days. Patients in the D-Pd group additionally received DARZALEX® 1800 mg SC co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.), given weekly for cycles 1 to 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter. The median age was 67 years, and 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). The median prior lines of therapy were 2, approximately 80% of patients were refractory to REVLIMID®, 48% of patients were refractory to a Proteosome Inhibitor, and 42% of patients were refractory to both agents. Treatment was continued until disease progression or unacceptable toxicity. The median duration of treatment was 11.5 months with D-Pd, compared with 6.6 months with Pd. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Very Good Partial Response (VGPR), Complete Response (CR), MRD negativity rate, Overall Survival (OS), and Safety.

The study met its Primary endpoint of improved PFS in the primary analysis at a median follow up of 16.9 months. The median PFS for the D-Pd group was 12.4 months versus 6.9 months for Pd group (HR=0.63; P=0.0018). This represented a 37% reduction in the risk of progression or death in patients treated with D-Pd. Among patients who were refractory to REVLIMID®, median PFS was 9.9 months in the D-Pd group versus 6.5 months in the Pd group. This benefit was seen across all subgroups of patients, regardless of age, stage, prior line of therapy, REVLIMID® refractoriness and cytogenetic risk. D-Pd regimen was also superior to Pd regimen in terms of other endpoints, including ORR (69% versus 46%), VGPR or better (51% versus 20%), CR (25% versus 4%), and MRD negativity (9% versus 2%). Survival data are immature and follow up is ongoing. Infusion-related events were rare, and seen in 6% of patients treated with D-Pd, and local injection-site reactions which were all Grade 1 were seen in 2% of patients in the D-Pd group. Treatment discontinuation due to treatment-related adverse events, were similar for the D-Pd and Pd groups (2% versus 3%).

It was concluded that Subcutaneous DARZALEX® given along with POMALYST® and Dexamethasone significantly reduced the risk of progression or death by 37% in patients with relapsed/refractory Multiple Myeloma, compared to POMALYST® and Dexamethasone alone. The infusion-related reaction rate was very low and median duration of injection administration was short at 5 minutes. Subcutaneous DARZALEX® thus has a high likelihood of changing clinical practice, increasing convenience for patients and decreasing treatment burden.

Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Dimopoulos MA, Terpos E, Boccadoro M, et al. Lancet Oncol. 2021;22:801-812. doi:10.1016/S1470-2045(21)00128-5

DARZALEX® with REVLIMID® and Dexamethasone Improves Overall Survival in Newly Diagnosed Multiple Myeloma

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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 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, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

REVLIMID® (Lenalidomide) based regimens are often prescribed for patients with newly diagnosed, transplant-ineligible Multiple Myeloma. REVLIMID®, a thalidomide analogue has immunomodulatory, tumoricidal, and antiangiogenic properties, and synergizes with Dexamethasone to enhance anti-myeloma activity. 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. DARZALEX® has activity as both a single agent and when combined with other standard regimens. The primary analyses of several Phase III studies (ALCYONE, MAIA, and CASSIOPEIA) demonstrated superior clinical efficacy of DARZALEX® in combination with standard-of-care regimens, compared to standard of care alone, for patients with newly diagnosed multiple myeloma. The MAIA study compared the efficacy and safety of DARZALEX® plus REVLIMID® and Dexamathasone (D-Rd) with REVLIMID® and Dexamathasone (Rd), in transplant-ineligible newly diagnosed Multiple Myeloma patients.Mechanism-of-Action-of-Daratumumab

The MAIA study is a multicenter, international, open-label, phase III trial, which included 737 newly diagnosed Myeloma patients who were not candidates for high-dose chemotherapy and Autologous Stem Cell Transplant (ASCT), due to age 65 years or older or comorbidities. Patients were randomly assigned 1:1 to receive REVLIMID® 25 mg orally on days 1-21 of each 28-day cycle and Dexamethasone 40 mg once a week, with or without DARZALEX®. Patients assigned DARZALEX® (D-Rd regimen) received 16 mg/kg weekly for the first 8 weeks (cycles 1 and 2), every other week for 16 weeks (cycles 3 to 6), and then every 4 weeks (cycle 7 and beyond) until disease progression or unacceptable toxicity. Treatment groups were well balanced. The median patient age was 73 years, 99% of patients were 65 years or older and 44% of patients were 75-90 years old. Cytogenetic risk level could be determined in 642 patients of the total population. Eighty-six percent (86%) of these patients were standard risk and 14% were considered high risk. The Primary end point was Progression Free Survival (PFS). Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity rate (10-5 sensitivity), and Safety.

In the primary analysis of the MAIA trial, D-Rd regimen reduced the risk of disease progression or death by 44%, compared to Rd. The authors now reported the updated efficacy and safety of D-Rd, compared to Rd, after almost 5 years of median follow up, in transplant-ineligible newly diagnosed Multiple Myeloma patients, from the prespecified interim OS analysis of MAIA.

After a median follow up of almost 5 years (56.2 months), the median OS was not reached (NR) in either treatment groups. The estimated 5-year OS rate was 66.3% with D-Rd and 53.1% with Rd (HR=0.68; P=0.0013). D-Rd reduced the risk of death by 32%. The updated median PFS was Not Reached with D-Rd versus 34.4 months with Rd. The estimated 5-year PFS rate was 52.5% with D-Rd and 28.7% with Rd (HR=0.53; P<0.0001). D-Rd reduced the risk of disease progression or death was reduced by 47%. The updated ORR was 92.9% with D-Rd versus 81.6% with Rd (P<0.0001).

The authors concluded that after almost 5 years of follow-up, the addition of DARZALEX® to REVLIMID® and Dexamethasone resulted in a significant improvement in Overall Survival, as well as significant reduction in the risk of disease progression or death, in newly diagnosed Multiple Myeloma patients, who are transplant-ineligible. The authors added that these results are more meaningful and support D-Rd as a new standard of care for this patient group, as this study population of elderly patients, never receive subsequent therapy.

OVERALL SURVIVAL RESULTS WITH DARATUMUMAB, LENALIDOMIDE, AND DEXAMETHASONE VERSUS LENALIDOMIDE AND DEXAMETHASONE IN TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: PHASE 3 MAIA STUDY. Facon T, Kumar SK, Plesner T, et al. Presented at: European Hematology Association Annual Meeting; June 9-17, 2021; Virtual. Abstract LB1901.