Elotuzumab in Combination With Carfilzomib Lenalidomide and Dexamethasone (E-KRd) Versus KRd in MM

  • STATUS
    Recruiting
  • End date
    Aug 3, 2029
  • participants needed
    576
  • sponsor
    Wuerzburg University Hospital
Updated on 3 March 2021

Summary

Of the next-generation compounds, the monoclonal antibodies (moAbs) have recently attracted a lot of interest in MM. The anti-SLAMF7 directed moAb elotuzumab has completed phase III trials in MM patients. One phase III trial in MM patients with one to three prior lines of therapy compared elotuzumab-Rd with standard Rd. The triple combination was shown to significantly prolong PFS in this patient cohort with a greater proportion of patients in at least very good partial response (VGPR) when compared to subjects on Rd. Notably, the rate of infusion-related reactions with this specific moAb was very low, with an overall rate of 10% in premedicated patients and only 1% of Grade 3 severity. Grades 4/5 infusion-related reactions were absent and only 1% of patients on elotuzumab discontinued for infusion-related reactions. Of particular interest is the observation in this trial, that response and PFS were independent of cytogenetic high-risk features, i.e., deletion of chromosome 17p and translocation t(4;14). This effect distinguishes elotuzumab from most, if not all, other drug-based approaches.

The investigators assume that incorporating the moAb into the KRd triple induction regimen should result in an even higher rate of deep (negative for MRD in conjunction with at least very good partial response [VGPR] as defined by the International Myeloma Working Group [IMWG]) with these responses occurring independently of cytogenetic risk. Due to potential interference of elotuzumab with serum immune fixation, the investigators chose VGPR rather than complete response (CR) to exclude false-positive immunofixation results. Furthermore the investigators hypothesize that combining elotuzumab with lenalidomide should prolong PFS further.

Description

Multiple myeloma (MM) is a cancer originating from the antibody-secreting plasma cell and characterized by abnormal accumulation of clonal plasma cells in bone marrow. In Europe, 3.8 new cases of MM and 2.2 deaths per 100,000 individuals (age-standardized rate) due to MM were estimated in 2012.

Treatment options for myeloma patients have markedly improved during the last decades.

For frontline treatment, high-dose myeloablative chemotherapy followed by reinfusion of autologous peripheral blood stem cells has been a standard of care since 1996. Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide led to improvement in remission rates and survival in newly diagnosed patients. However, high-dose chemotherapy remains essential for achievement of long-lasting remissions even in the era of novel agents.

While high-dose melphalan chemotherapy (HDT) plus autologous stem cell transplant (ASCT) remains a standard in eligible, medically fit subjects, defining an optimal pre- and post HDT approach is subject to rapidly evolving novel-compound based options. In 2010, a group from the U.S. presented results on the combination of lenalidomide, bortezomib, and dexamethasone (VRd) in newly diagnosed patients with an overall response rate of 98%, however without systematic consolidation by HDT. The next-generation proteasome inhibitor carfilzomib is more active and very well tolerated in terms of peripheral neuropathy and gastrointestinal adverse effects. A randomized phase III trial in pretreated myeloma patients found the triple regimen of carfilzomib and lenalidomide/dexamethasone (Rd) to be superior to standard-Rd in terms of depth of response; progression-free survival (PFS) and, most importantly, overall survival (OS). At the 2015 annual meetings of the American Society of Clinical Oncology as well as the European Society of Hematology, this regimen (KRd) was found to be exceptionally effective in a phase 2 trial when given in newly diagnosed patients in a prolonged fashion: patients received four KRd induction cycles prior to HDT. The latter was followed by an additional 4 consolidation and 8 maintenance cycles with KRd, followed by lenalidomide maintenance thereafter. The most appealing effect was the high rate of deep remissions: stringent complete response (sCR) rate increased from 22% following 4 x KRd and HDT to more than 80% following all 18 cycles. Notably, the vast majority of patients in sCR also were negative for minimal residual disease (MRD) as assessed by 10-color flow cytometry. MRD negativity probably has a major impact on long-term disease control as was recently shown in a French prospective trial investigating in the combination of VRd prior and post HDT followed by lenalidomide maintenance.

Of the next-generation compounds, the monoclonal antibodies (moAbs) have recently attracted a lot of interest in MM. The anti-SLAMF7 directed moAb elotuzumab has completed phase III trials in MM patients. One phase III trial in MM patients with one to three prior lines of therapy compared elotuzumab-Rd with standard Rd. The triple combination was shown to significantly prolong PFS in this patient cohort with a greater proportion of patients in at least very good partial response (VGPR) when compared to subjects on Rd. Notably, the rate of infusion-related reactions with this specific moAb was very low, with an overall rate of 10% in premedicated patients and only 1% of Grade 3 severity. Grades 4/5 infusion-related reactions were absent and only 1% of patients on elotuzumab discontinued for infusion-related reactions. Of particular interest is the observation in this trial, that response and PFS were independent of cytogenetic high-risk features, i.e., deletion of chromosome 17p and translocation t(4;14). This effect distinguishes elotuzumab from most, if not all, other drug-based approaches.

The investigators assume that incorporating the moAb into the KRd triple induction regimen should result in an even higher rate of deep (negative for MRD in conjunction with at least very good partial response [VGPR] as defined by the International Myeloma Working Group [IMWG]) with these responses occurring independently of cytogenetic risk. Due to potential interference of elotuzumab with serum immune fixation,the investigators chose VGPR rather than complete response (CR) to exclude false-positive immunofixation results. Furthermore the investigators hypothesize that combining elotuzumab with lenalidomide should prolong PFS further.

Details
Condition Newly Diagnosed Multiple Myeloma
Treatment Dexamethasone, Lenalidomide, Carfilzomib, Elotuzumab, Autologous Stem Cell Transplant
Clinical Study IdentifierNCT03948035
SponsorWuerzburg University Hospital
Last Modified on3 March 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 70 yrs?
Gender: Male or Female
Do you have Newly Diagnosed Multiple Myeloma?
Do you have any of these conditions: Do you have Newly Diagnosed Multiple Myeloma??
Do you have any of these conditions: Do you have Newly Diagnosed Multiple Myeloma??
Do you have any of these conditions: Do you have Newly Diagnosed Multiple Myeloma??
Eligible for autologous stem cell transplantation (ASCT)
Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma (only dexamethasone at a cumulative dose of 320 mg; plasmapheresis/dialysis without concomitant chemotherapy,local irradiation of bone lesions; and surgical intervention permitted as pretreatment)
Newly diagnosed multiple myeloma according to the IMWG updated criteria42: Clonal bone marrow plasma cells 10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically
Hypercalcaemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
Renal insufficiency: creatinine clearance < 40 mL per min or serum creatinine > 177 mol/L (> 2 mg/dL)
Anaemia: haemoglobin value of > 2 g/dL below the lower limit of normal, or a haemoglobin value < 10 g/dL
Bone lesions: one or more osteolytic lesions on skeletal radiography,computed tomography (CT), or PET-CT
Any one or more of the following markers of malignancy
Clonal bone marrow plasma cell percentage 60%
Involved: uninvolved serum free light chain ratio 100, provided the absolute level of the involved light chain is at least 100 mg/L
One or more focal lesions of at least 5mm or greater in size on MRI studies
Measurable disease parameters as follows
Serum monoclonal paraprotein (M-component) level 1 g/dL and/or urine M-protein level 200 mg/24 hours or
In case of IgA myeloma: Serum monoclonal paraprotein level 0.5 g/dL and/or urine M-protein level 200 mg/24 hours or
For patients with no detectable M-component: Serum FLC Assay: Involved FLC level 10 mg/dL ( 100 mg/L) provided serum FLC ratio is abnormal
ECOG Performance Status 2
Laboratory test results within these ranges
White blood cell count 2 x 109/L
Absolute neutrophil (ANC) count 1.0 x 109/L
Platelet count 75 x 109/L
Haemoglobin > 8 g/dL
Calculated creatinine clearance (according to MDRD) 30 mL/minute
Total bilirubin 1.5 x upper limit of normal (ULN)
AST and ALT 2.5 x ULN
Corrected serum calcium level < 3.5 mmol/L (< 14 mg/dL)
Patient's legal capacity to consent to study participation
Patients capable to understand the purposes and risks of the study, who are willing and able to participate in the study and from whom written and dated informed consent to participate in the study has been obtained
All females
must acknowledge to have understood the hazards lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of lenalidomide
must use adequate contraception and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence
must agree to have medically supervised pregnancy tests on a regular basis
must agree to abstain from breastfeeding while taking lenalidomide, carfilzomib and elotuzumab and for at least 28 days after the last dose of lenalidomide, carfilzomib, and elotuzumab
Male subjects must
practice complete abstinence or use a condom during sexual contact with a pregnant female or a female with child bearing potential while taking lenalidomide, carfilzomib, and elotuzumab
not donate semen or sperm
All subjects must
agree to abstain from donating blood while taking lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide
agree never to give lenalidomide to another person
agree to return all unused lenalidomide capsules to the investigator (with exception of prescribed lenalidomide capsules)
be aware that no more than a 28-day lenalidomide supply may be dispensed with each cycle of lenalidomide during induction and consolidation therapy and be prescribed during maintenance therapy

Exclusion Criteria

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy
monoclonal protein, and skin changes)
Waldenstrm's macroglobulinemia or IgM myeloma
Plasma cell leukemia (> 2.0 x 109/L circulating plasma cells by standard differential blood count)
Pregnant, breast-feeding females, FCBPs and males who are unwilling to comply with the lenalidomide Pregnancy Prevention Risk Management Plan
Patients with high cardiovascular risk, including but not limited to history of myocardial infarction or coronary stenting in the past 6 months; NYHA Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled arrhythmias
Prior cerebral vascular accident (CVA) with persistent neurological deficit
Active infection
Known HIV-seropositivity, active or chronic hepatitis A, B, C or D-infection (including patients who are tested anti-HBC positive and/or HBsAg positive)
Any other severe concomitant disease or disorder, including the presence of laboratory abnormalities, which places the subject at unacceptable risk or which could influence patient's ability to participate in the study and his/her safety during the study or interfere with interpretation of study results
Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrollment
Major surgery within 4 weeks prior to randomization
Any systemic anti-myeloma therapy within 4 weeks of randomization except a max. cumulative dose of 320 mg auf dexamethasone
Any prior or concurrent malignancy other than multiple myeloma
Exceptions include patients who have been disease-free for at least five years before study entry or patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer
Known hypersensitivity to carfilzomib, lenalidomide, and elotuzumab or to any of the excipients of carfilzomib, lenalidomide, and elotuzumab or to any other component of any study drug formulation
Participation in any other clinical trial or treatment with any experimental drug or other experimental therapy within 28 days before enrolment to the study or during study participation until the end of treatment visit
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