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Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT04933539
Recruitment Status : Not yet recruiting
First Posted : June 21, 2021
Last Update Posted : October 15, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Multiple myeloma (MM) is a tumor in which malignant plasma cells accumulate in the bone marrow. It can cause organ damage and is not curable. Researchers want to see if a combination drug treatment can help.

Objective:

To try to prevent or slow down developing MM and its associated organ damage by treating it while still in the smoldering phase with a mix of drugs known as DKd.

Eligibility:

People ages 18 and older with smoldering MM that is at high risk of converting to symptomatic MM.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Bone survey (x-rays of their bones)

Spinal magnetic resonance imaging

Bone marrow biopsy (a needle is used to remove bone marrow from their hipbone)

Electrocardiogram (to check heart function)

Lung function tests

Treatment will be given in 28-day cycles. Participants will get daratumumab by injection under the skin. They will get carfilzomib intravenously (IV) through a tube inserted in a vein. They will get dexamethasone as oral tablets or as an IV. They will get all 3 drugs for 8 or 12 cycles. Then they will get daratumumab alone for up to 24 cycles. They may have stem cells collected.

Participants will have frequent study visits. At these visits, they will repeat some screening tests. They will complete questionnaires. They will have imaging scans. For these scans, they may receive an oral or IV contrast.

Participants will have a follow-up visit 30 days after treatment ends. Then they will have visits every 3-12 months. They will be followed on this study for life.

...


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Dexamethasone Drug: Carfilzomib Biological: Daratumumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 59 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Adaptive Study of Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma
Estimated Study Start Date : October 20, 2021
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : October 31, 2027


Arm Intervention/treatment
Experimental: Arm 1
Daratumumab SC (Cycles 1-2: Days 1, 8, 15, 22; Cycles 3-6: Days 1, 15; Cycles =7: Days 1 of the 28-day cycle); Carfilzomib IV (Days 1, 8, 15 of the 28-day cycle); Dexamethasone PO/IV (Days 1, 8, 15, 22 of the 28-day cycle)
Drug: Dexamethasone
Dexamethasone PO/IV (for Cycles 1-4: Dexamethasone 40 mg IV/PO on days 1, 8, 15, 22; for Cycles =5: Dexamethasone 20 mg IV/PO on days 1, 8, 15, 22); for up to 12 cycles

Drug: Carfilzomib
Carfilzomib IV (for Cycles 1-2: 20 mg/m2 IV on day 1, 56 mg/m2 IV on days 8, 15; Cycles =2: 56/m2 IV on days 1, 8, 15); for up to 12 cycles

Biological: Daratumumab
Daratumumab SC 1800 mg (Cycles 1-2: Days 1, 8, 15, 22; Cycles 3-6: Days 1, 15; Cycles =7: Days 1 of the 28-day cycle); up to 36 cycles total




Primary Outcome Measures :
  1. Response Rate [ Time Frame: 12 cycles ]
    To assess the remission rate of DKd in participants with high-risk (HR) SMM by determining the minimal residual disease (MRD) negative complete response (CR) by flow cytometry (10-5 sensitivity) rate after 12 cycles of therapy


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: every 6-8 weeks ]
    The fraction of participants who experience a PR, VGPR, CR or sCR after DKd determined by dividing the number of responders by the total evaluable patients.

  2. Duration of Response [ Time Frame: every 6-8 weeks ]
    Time from PR or better until the time of PD. Kaplan-Meier will be utilized

  3. Biochemical and Symptomatic progression free survival (PFS) [ Time Frame: every 6-8 weeks ]
    Using Kaplan-Meier method, considering those who biochemically progress or die and those who clinically progress or die, and censoring those who do not

  4. Durability of MRD negative complete response (CR) [ Time Frame: through 3 years post-treatment ]
    Sustained negative CR rate 1, 2, 3 years.

  5. Toxicity evaluation of DKd [ Time Frame: through 30 days post treatment ]
    Descriptive statistics to determine safety of receiving KRd with daratumumab maintenance

  6. Overall survival (OS) [ Time Frame: ongoing ]
    Determined using the Kaplan-Meier method



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically or cytologically confirmed smoldering multiple myeloma (SMM) based on the International Myeloma Working Group Criteria:

    • Serum M-protein >=3 g/dl and/or bone marrow plasma cells >=10 % and <60%
    • Absence of anemia: hemoglobin >10 g/dl
    • Absence of renal failure: serum creatinine <2.0 mg/dL
    • Absence of hypercalcemia: Ca <10.5 mg/dl
    • Absence of lytic bone lesion on X-ray, CT, or PET/CT and not more than 1 lesion on spinal MRI (NOTE: At the discretion of the investigator, PET/CT may replace MRI in patients who have a contraindication to MRI.)
    • Involved/un-involved light chain ratio must be < 100 (unless involved light chain is <=10 mg/dL)
  • Measurable disease within the past 4 weeks defined by any one of the following:

    • Serum monoclonal protein >= 0.5 g/dl
    • Urine monoclonal protein >200 mg/24 hour
    • Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda serum free light chain ratio (reference 0.26-1.65)
    • Because the primary endpoint is MRD (-) remission rate, per the discretion of the Principal Investigator, patients without measurable disease in the serum (e.g., Mspike <0.5 g/dL) may also be enrolled. This is in line with the most recent IMWG MM response criteria.
  • Age >=18 years.
  • ECOG performance status <=2 (Karnofsky >=60%).
  • Patients must have adequate organ and marrow function as defined below:

    • absolute neutrophil count (ANC) >=1.0 K/uL

NOTE: At the discretion of the investigator, patients with an ANC of 0.5 K/uL -1.0 K/uL may also be enrolled if clinically appropriate (e.g., patients with a baseline neutropenia that is chronic and that does not cause complications).

  • platelets >=75 K/uL
  • hemoglobin > =8 g/dL, for anemia not due to MM (transfusions are permissible)
  • total bilirubin = <1.5 X institutional upper limit of normal
  • AST(SGOT)/ALT(SGPT) =<3.0 X institutional upper limit of normal
  • creatinine within normal institutional limits, OR
  • If creatinine is outside of the normal limits, then creatinine Clearance (CrCl) or Egfr (estimated glomerular filtration Rate) >=40 ml/min calculated by Cockcroft-Gault method, modification of diet in renal disease (MDRD), or the chronic kidney disease (CKD)-epidemiology collaboration (EPI) (institutional standard) equations.

    -In addition to having SMM, patients must also be classified as high-risk SMM per at least one of three criteria below:

  • Criteria 1: Mayo Clinic, high-risk defined as:

    • Bone marrow plasmacytosis >=10%,
    • Serum monoclonal protein >=3 g/dL, AND
    • Serum free light chain ratio of >=8 or <=0.125
  • Criteria 2: Spanish PETHEMA, high-risk defined as:

    • Immunoparesis (depression of one of the uninvolved immunoglobulin isotypes in the total serum immunoglobulin assay, AND
    • >=95% aberrant plasma cells on bone marrow aspirate flow cytometry
  • Criteria 3: Rajkumar, Landgren, Mateos may also be used to define high risk disease, namely clonal bone marrow plasma cells >=10% AND any one or more of the following:

    • Serum M protein >=30g/L,
    • IgA SMM,
    • Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes,
    • Serum involved/uninvolved FLC ratio >=8 (but <100),
    • Progressive increase in M protein level (evolving type of SMM; increase in serum M protein by >=25% on 2 successive evaluations within a 6-month period),
    • Clonal BMPCs 50%-60%,
    • Abnormal PC immunophenotype (>=95% of BMPCs are clonal) and reduction of >=1 uninvolved immunoglobulin isotypes,
    • t(4;14) or del(17p) or 1q gain,
    • Increased circulating PCs,
    • MRI with diffuse abnormalities or 1 focal lesion, AND/OR PET-CT with focal lesion with increased uptake without underlying osteolytic bone destruction

      • The effects of carfilzomib and daratumumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 3 months after daratumumab and/or 6 months after the last dose of carfilzomib, whichever is longer. Males with female partners of reproductive potential must use adequate contraception during treatment and for 3 months after stopping daratumumab and/or carfilzomib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
      • Negative serum or urine pregnancy test at screening for WOCBP.
      • Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients who are receiving any other investigational agents.
  • Prior therapy for SMM. At the discretion of the investigator, exceptions might be made depending on prior treatments received and response to those treatments, provided that by the start of protocol therapy, there will be a 4-week washout period. Exceptions will not be made for patients who have received the current DKd with daratumumab maintenance regimen nor any other regimen consisting of daratumumab and a proteasome inhibitor (e.g., bortezomib, ixazomib). Treatment with corticosteroids for other indications is permitted.
  • Contraindication to any concomitant medication, including support/prophylaxis for infusion reaction, antiviral, antibacterial, anticoagulation or tumor lysis given prior to therapy.
  • Patient has either of the following:

    --Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. NOTE: FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.

    ---Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. NOTE: Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.

  • Seropositive for human immunodeficiency virus (HIV). HIV-infected patients on effective anti-retroviral therapy with undetectable viral load for at least the 3 months prior to enrollment are eligible for this trial.
  • Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen (HbcsAg) or hepatitis B core antibody (HbcAb) positive will need to have a negative HBV PCR result before enrollment. Those with a positive PCR for hepatitis B are excluded.
  • Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
  • Peripheral neuropathy of any cause that is Grade 2 or higher
  • History of inflammatory bowel disease
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or daratumumab or other agents used in study.
  • Current uncontrolled hypertension (chronic systolic blood pressures >160 mm Hg) or diabetes (chronic clinical signs/symptoms of hyperglycemia and/or an A1c value >9%).
  • Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia.
  • No studies of carfilzomib or daratumumab have been conducted on breast feeding women and it is not known if it is excreted in milk. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with carfilzomib/daratumumab.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, venous thromboembolic disease, hemorrhage, pulmonary fibrosis, pneumonitis, or psychiatric illness/social situations that would limit compliance with study requirements.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04933539


Contacts
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Contact: NCI Medical Oncology Referral Office (240) 760-6050 ncimo_referrals@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark J Roschewski, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04933539    
Other Study ID Numbers: 210024
21-C-0024
First Posted: June 21, 2021    Key Record Dates
Last Update Posted: October 15, 2021
Last Verified: September 7, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
anti-CD38 monoclonal antibody
Proteasome Inhibitor
Anti-Myeloma Activity
Immunomodulatory Agents
Combination Therapy
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Smoldering Multiple Myeloma
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Precancerous Conditions
Hypergammaglobulinemia
Dexamethasone
Daratumumab
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents