Tag: Multiple Myeloma

SUMMARY: The FDA on May 7, 2018 approved DARZALEX® (Daratumumab) in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone VMP regimen), for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT). Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). With a record number of regulatory approvals for myeloma treatment over the past 12 years, the median survival for patients with myeloma is over 10 years.

The incidence of multiple myeloma increases with age and the median age of patients diagnosed with multiple myeloma is approximately 70 yrs. Elderly patients with myeloma in the US are often treated with a combination of REVLIMID® (Lenalidomide) and Dexamethasone, whereas Melphalan, Prednisone, and Thalidomide (MPT) and VELCADE® (Bortezomib), Melphalan and Prednisone (VMP) are the most widely used regimens outside the US. These regimens are associated with a PFS of 18-24 months and an OS of 4-5 years. For patients with newly diagnosed multiple myeloma who are ineligible for ASCT, treatment with VMP regimen has been a standard effective regimen, based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial. 

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 have a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. In previously treated patients with myeloma, DARZALEX® in combination with REVLIMID® and Dexamethasone (POLLUX trial) as well as in combination with VELCADE® and Dexamethasone (CASTOR trial), induced higher Response Rates and significantly prolonged PFS, reducing the risk of disease progression or death by over 60% in previously treated myeloma patients.

ALCYONE is a multicenter, randomized, open-label, active-controlled, phase III trial in which DARZALEX® given along with VELCADE®, Melphalan and Prednisone (VMP regimen) was compared with VMP alone (control group), in patients with newly diagnosed multiple myeloma, who were ineligible for Autologous Stem Cell Transplantation (ASCT). Of the 706 enrolled patients, 350 were assigned to the DARZALEX® group and 356 to the control group. The median age was 71 yrs. All the patients received up to nine 6 week cycles of VELCADE® 1.3 mg/m2 SQ, twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), Melphalan 9 mg/m2 orally, once daily on days 1-4 of each cycle, and Prednisone 60 mg/m2 once daily on days 1-4 of each cycle. In the study group, patients received DARZALEX® 16 mg/kg IV administered with Dexamethasone 20 mg oral or IV (to manage infusion reactions), once weekly for a total of 6 doses, every 3 weeks for a total of 16 doses and every 4 weeks thereafter until disease progression or unacceptable toxicity. The Primary end point was PFS. Secondary end points included Overall Response Rate, rates of Very Good Partial Response, Complete Response rate, Minimal Residual Disease negativity and Overall Survival.

At a median follow up of 16.5 months in a prespecified interim analysis, the 18-month PFS was 71.6% in the DARZALEX® group and 50.2% in the control group (HR=0.50; P<0.001). This meant a 50% reduction in the risk of disease progression or death when DARZALEX® was added to VMP regimen. The median PFS for DARZALEX® plus VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone. The Overall Response Rate was 90.9% in the DARZALEX® group, as compared with 73.9% in the control group (P<0.001), and the rate of Complete Response or better (including stringent Complete Response) was 42.6%, versus 24.4% (P<0.001). In the DARZALEX® group, 22.3% of the patients were negative for Minimal Residual Disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events were cytopenias noted in both treatment groups, and with the exception of infections (23% versus 15%), combining DARZALEX® with VMP regimen did not increase overall toxicities. DARZALEX® associated infusion-related reactions occurred in 28% of the patients.

It was concluded that DARZALEX® is the first monoclonal antibody approved for newly diagnosed multiple myeloma patients who are not eligible for a Autologous Stem Cell Transplant, and in combination with VMP regimen significantly improved Progression Free Survival and Response Rates. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. Mateos MV, Dimopoulos MA, Cavo M, et al. for the ALCYONE Trial Investigators. N Engl J Med 2018; 378:518-528

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, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Overall Survival (OS) in the relapsed setting.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. Most of the recent phase III trials in Relapsed or Refractory Myeloma have used Progression Free Survival (PFS) as the Primary end point, with the exception of the phase III trial ENDEAVOR trial in which patients treated with KYPROLIS® and Dexamethasone achieved a statistically significant 7.6-month improvement in median Overall Survival (OS) compared to those patients treated with VELCADE® and Dexamethasone (HR=0.79; P=0.01). REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed Multiple Myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with Relapsed or Refractory Multiple Myeloma.

Based on this background, a randomized, open label, multicenter, phase III study (ASPIRE) was conducted, in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KRd) was compared with a combination of REVLIMID® and weekly Dexamethasone (Rd), in patients with Relapsed or Refractory Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KRd (N=396) and Rd (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID® and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The Primary end point was Progression Free Survival (PFS) and secondary end points included Overall Survival (OS), the rate of overall response (partial response or better), response duration, health-related quality of life, and safety.

The study met its Primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median PFS for those patients in the KRd group compared to the Rd (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Further, patients in the KYPROLIS® group reported superior health-related quality of life.

The authors in this prespecified analysis reported the final Overall Survival (OS) data and updated safety results. The median follow up was 67.1 months. The median OS was 48.3 months in the KRd group and 40.4 months in the Rd group (HR=0.79; P=0.0045). This represented a 7.9 month prolongation of OS and 21% decrease in the risk of death with KRd. Among patients who had received one prior line of therapy, KRd improved median OS by 11.4 months and among those who had received 2 or more prior lines of therapy, KRd improved median OS by 6.5 months, compared to Rd. Among patients who had received one prior line of VELCADE® based therapy, the median OS was improved by 12 months with KRd versus Rd, with a 18% reduction in the risk of death, and among patients with prior transplantation at first relapse, the median OS was improved by 18.6 months with KRd versus Rd, with a 29% reduction in the risk of death. The OS benefit with KRd was noted across all age, Creatinine Clearance (CrCL) and ECOG PS subgroups, including those 75 years or older, patients with impaired renal function (CrCL 30 to less than 60 mL/min), and patients with decreased Performance Status (ECOG PS, 2). The median time to next treatment from time of randomization was 39.0 months for patients who received KRd and 24.4 months for those who received Rd (HR=0.65; P<0.001).

An updated median PFS with longer follow up (median , 48.4 months) was 26.1 months in the KRd group versus 16.6 months in the Rd group (HR=0.66; P<0.001). Grade 3 or higher adverse events were reported in 87% and 83.3% of patients in the KRd and Rd groups, respectively.

It was concluded that treatment with KRd resulted in a statistically significant and clinically meaningful reduction in the risk of death, compared to Rd, among patients with Relapsed or Refractory Myeloma. This analysis supports the early use of KYPROLIS® at first relapse, regardless of prior treatment with VELCADE® or transplantation. Because each subsequent line of therapy can result in shorter response duration and increased treatment resistance, the authors suggested that early treatment with an effective regimen is important to maximize Overall Survival and KRd regimen should be considered a preferred treatment option in Relapsed or Refractory Multiple Myeloma. Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. Siegel DS, Dimopoulos MA, Ludwig H, et al. J Clin Oncol. 2018;36:728-734

SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. MGUS is defined as the presence of a serum monoclonal protein (M protein) at a concentration of 3 g/dl or less, urine with none or only modest amounts of monoclonal light chains, absence of CRAB features that are related to the M protein (Hypercalcemia, Renal insufficiency, Anemia, and Bone lesions) and 10% or fewer monoclonal plasma cells in the bone marrow. MGUS occurs in approximately 3% of individuals 50 years of age or older and in 5.3% of those 70 years of age or older.

MGUS is classified into two major subtypes, IgM and non-IgM. This is because the clonal cell that is involved and the nature of progression, differ between these two types. The origin of IgM MGUS is typically from a CD20 positive Lymphoplasmacytic cell that has not undergone Switch Recombination (Class-Switch Recombination or CSR, is a biological mechanism that changes a B cell production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG.), and this disease type is associated with a risk of progression to Lymphoma or Waldenström’s macroglobulinemia. In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone Switch Recombination and is associated with a risk of progression to Multiple Myeloma. Both disease types can progress to AL Amyloidosis.

There is limited information regarding malignant transformation of MGUS to Multiple Myeloma as well as Overall Survival, after diagnosis is made. Further, the risk of progression to Multiple Myeloma among the two major biologic subtypes of MGUS, IgM and non-IgM, is different, and data regarding the prognosis and risk stratification associated with these entities have not been well characterized. The authors in this publication, which is a longer follow up of previously reported findings, studied 1384 patients with MGUS, who were identified in a well-defined geographic area, from 1960-1994. The median follow up was 34.1 years. The Primary end point was progression to Multiple Myeloma or another Plasma-cell or Lymphoid disorder.

During 14,130 person-years of follow up, the rate of progression of MGUS to Multiple Myeloma was 6.5 times as high as the rate in the control population. The risk of progression to Multiple Myeloma was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. The risk of progression varied depending on the biologic subtypes of MGUS and other adverse risk factors. Among patients with IgM MGUS, the presence of two adverse risk factors – an abnormal serum free light chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein level (1.5 g/dl or greater), was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression to Multiple Myeloma at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. More importantly, patients with MGUS had shorter survival compared to age and sex matched control population (median 8.1 versus 12.4 years, P<0.001).

It was concluded that there were significant differences noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS and Overall Survival was shorter among patients with MGUS than was expected in a matched control population. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. Kyle RA, Larson DR, Therneau TM, et al. N Engl J Med 2018; 378:241-249

SUMMARY: The FDA on June 16, 2017 approved the use of DARZALEX® (Daratumumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,280 new cases will be diagnosed in 2017 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. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, 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. The FDA approved DARZALEX® in November 2015 as monotherapy for Myeloma patients who had received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an Immunomodulatory agent or who are double refractory to a PI and an Immunomodulatory agent. In November 2016, DARZALEX® was approved in combination with REVLIMID® and Dexamethasone, or VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID®, and has been shown to be active in REVLIMID® and VELCADE® refractory patients.

This new FDA approval was based on data from the phase Ib (MMY1001, EQUULEUS) study of DARZALEX® in combination with POMALYST® and Dexamethasone in relapsed or refractory Multiple Myeloma. This open-label study included 103 patients with Multiple Myeloma who had received prior treatment with a Proteasome Inhibitor and an Immunomodulatory agent. Treatment consisted of 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 until disease progression. POMALYST® 4 mg PO was administered daily for 21 days along with Dexamethasone 40 mg weekly (20 mg for patients over 75 years of age). The median patient age was 64 years and patients had received a median of 4 prior lines of therapy. About 75% of the patients had prior Autologous Stem Cell Transplant, 90% of patients were refractory to REVLIMID®, 70% were refractory to VELCADE®, and 64% were refractory to both agents.

The Overall Response Rate in this study was 59% with Very Good Partial Response (VGPR) noted in 28% of patients. Complete Response was achieved in 6% of patients and stringent Complete Response was achieved in 8% of patients. The median time to response was 1 month and the median duration of response was 13.6 months. The most common toxicities were infusion reactions, nausea, vomiting, diarrhea, fatigue, fever, upper respiratory tract infection, muscle spasms, cough and dyspnea. The most common grade 3/4 toxicities were cytopenias including lymphopenia.

It was concluded that DARZALEX® in combination with POMALYST® and Dexamethasone is a new combination therapy, with significant clinical benefit, for patients who relapse or become resistant to Proteasome Inhibitors and Immunomodulatory agents. This combination may be a viable option for patients who progress on a combination of REVLIMID®, VELCADE® and Dexamethasone (RVD) regimen, which is often given as first line therapy. A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With Backbone Treatments for the Treatment of Patients With Multiple Myeloma. ClinicalTrials.gov Identifier: NCT01998971 https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761036orig1s005ltr.pdf.

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, about 30,330 new cases will be diagnosed in 2016 and 12,650 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. Nonetheless, patients 75 years or older, are often under-represented in clinical trials because of increased comorbidities and altered pharmacodynamics. This group of elderly, newly diagnosed Multiple Myeloma patients, who are ineligible for Stem Cell Transplantation (SCT), are often treated with combination therapies such as Melphalan, Prednisone, and Thalidomide (MPT), VELCADE® (Bortezomib), Melphalan, and Prednisone (VMP) or REVLIMID® (Lenalidomide) and low dose Dexamethasone (Rd). However there is limited data regarding the efficacy and safety of front line use of REVLIMID® in this patient group.

The FIRST (Frontline Investigation of REVLIMID® Plus Dexamethasone Versus Standard Thalidomide) trial is a randomized, global, phase III trial, in which the efficacy and safety of REVLIMID® and Dexamethasone, given until disease progression or for a fixed number of cycles, was compared with MPT given for a fixed number of cycles, in patients with newly diagnosed Multiple Myeloma, who were ineligible for Stem Cell Transplantation. A total of 1,623 patients were randomly assigned patients in a 1:1:1 ratio to receive REVLIMID® and Dexamethasone (Rd continuous) in 28 day cycles until disease progression, REVLIMID® and Dexamethasone (Rd18) in 28 day cycles for 72 weeks (18 cycles), or MPT in 42 day cycles for 72 weeks (12 cycles). In both REVLIMID® groups, patients received REVLIMID® 25 mg orally daily on days 1 – 21 of each 28 day cycle, and Dexamethasone 40 mg orally on days 1, 8, 15, and 22. Patients in the MPT group received Melphalan 0.25 mg/kg/day orally on days 1- 4, Prednisone 2 mg/kg/day orally on days 1- 4 and Thalidomide 200 mg orally daily, administered in 42 day cycles. The median patient age was 73 years and 35% of the patients were older than 75 years. Patients were stratified by age (75 years or less versus more than 75 years) and disease stage. The Primary end point was Progression Free Survival (PFS) and Secondary end point included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), time to first response and Time to Treatment Failure. The primary objective was to compare the efficacy of Rd continuous with MPT.

In this updated analysis after a median follow up of 45.5 months, Rd continuous reduced the risk of progression or death by 31% compared with MPT (HR=0.69; P<0.001) overall. In patients 75 years or younger, Rd continuous reduced the risk of progression or death by 36% (HR=0.64; P<0.001) and by 20% (HR=0.80; P=0.08) in those older than 75 years. Patients in the Rd continuous group also had a longer median Overall Survival than those in the MPT group regardless of age, and there was a 14 month Overall Survival advantage for the group of patients 75 years or older. In the Rd continuous group, grade 3-4 adverse events were similar across age groups although older patients had more frequent REVLIMID® dose reductions.

The authors concluded that the FIRST study results, with the largest cohort of patients 75 years or older, support Rd continuous treatment as a new standard of care for Stem Cell Transplantation-ineligible patients with newly diagnosed Multiple Myeloma. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial Hulin C, Belch A, Shustik C, et al. J Clin Oncol 2016;34:3609-3617

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, about 30,330 new cases will be diagnosed in 2016 and 12,650 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. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®).

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.

The authors now report the results of a prespecified interim analysis of a phase III trial of DARZALEX®, REVLIMID® and Dexamethasone in patients with relapsed or refractory multiple myeloma. In this randomized, open-label, multicenter, phase III study, 569 patients who had relapsed or refractory multiple myeloma were assigned in a 1:1 ratio to receive either DARZALEX®, REVLIMID® and Dexamethasone (Daratumumab group, N=286) or REVLIMID® and Dexamethasone (Control group, N=283). Patients refractory to REVLIMID® were excluded. Patients in the Daratumumab 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 the time to disease progression, Response Rate, time to response, duration of response, Overall Survival (OS) and percentage of patients with results below the threshold for Minimal Residual Disease. 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 Daratumumab group compared to 60.1% in the control group (HR=0.37; P<0.001). The Overall Response Rate was significantly higher in the Daratumumab 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 Daratumumab group, 22.4% of the patients had results below the threshold for Minimal Residual Disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001), and those with results below the threshold for Minimal Residual Disease had improved outcomes. The most common grade 3 or 4 adverse events were cytopenias. Approximately 48% of the patients in the Daratumumab group experienced grade 1 or 2 infusion-related reactions.

The authors concluded that the addition of DARZALEX® to REVLIMID® and Dexamathasone significantly improves Progression Free Survival among patients with relapsed or refractory multiple myeloma. This impressive efficacy data may warrant the use of this triplet combination for first relapse, in this group of patients, provided their disease is not refractory to REVLIMID®. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. Dimopoulos MA, Oriol A, Nahi H, et al. for the POLLUX Investigators. N Engl J Med 2016;375:1319-1331