A Phase 2 Adaptive Study of Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma

Plain English Summary

Subcutaneous Daratumumab, Once Weekly Carfilzomib, and Dexamethasone (DKd) in Patients With High-Risk Smoldering Multiple Myeloma is a Phase 2 clinical trial sponsored by National Cancer Institute (NCI) studying Multiple Myeloma. This trial tests a combination of three drugs (daratumumab, carfilzomib, and dexamethasone) to see if it can prevent or slow the progression of high-risk smoldering multiple myeloma. It is for adults aged 18 and older who have been diagnosed with high-risk smoldering multiple myeloma. Participation involves receiving the drugs via injection, IV, or pills over several months, followed by frequent study visits for tests and monitoring. There are no direct alternatives for this specific combination therapy in the smoldering phase; standard care may involve watchful waiting or treatment if the disease progresses. The trial aims to enroll 14 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have been diagnosed with high-risk smoldering multiple myeloma. You cannot join if you have already received treatment for smoldering multiple myeloma (with some exceptions), are taking other investigational drugs, or have certain medical conditions like anemia, kidney failure, or hypercalcemia. You must have adequate organ and bone marrow function, including specific blood counts. Women who can become pregnant and men who can father children must agree to use effective contraception during and after the study. This trial is studying Multiple Myeloma, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the rate of complete remission where no minimal residual disease is detected after treatment, meaning the therapy aims to eliminate all detectable signs of the cancer. The specific primary outcome measures are: Response Rate (12 cycles). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need to intervene in high-risk smoldering multiple myeloma, a condition that often progresses to active cancer, by testing a novel drug combination to potentially preve Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Multiple Myeloma, where improved treatment options are needed.

Investor Insight

This trial targets a pre-cancerous stage of a significant blood cancer, representing a potential shift towards early intervention in multiple myeloma, which could expand the market for these drugs if Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of each drug in the combination, how the treatment will be administered, and what to expect during study visits. Participation involves regular clinic visits for drug administration, blood tests, imaging scans, and questionnaires, with long-term follow-up planned for life. Be prepared for potential side effects and discuss any new or worsening symptoms with the study team immediately. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 14 participants

Interventions

• 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 Outcomes

• Response Rate (12 cycles)

Secondary Outcomes

• Overall Response Rate (every 6-8 weeks)
• Duration of Response (every 6-8 weeks)
• Biochemical and Symptomatic progression free survival (PFS) (every 6-8 weeks)
• Durability of MRD negative complete response (CR) (through 3 years post-treatment)
• Toxicity evaluation of DKd (through 30 days post treatment)

Full Eligibility 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 or 2.62 mmol/L
  * 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
* 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 2018, high-risk defined with two of the following:

  * Bone marrow plasmacytosis \>=20%,
  * Serum monoclonal protein \>=2 g/dL
  * Serum free light chain ratio of \>=20
* 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 ( (Bullet)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, individuals of child-bearing potential (IOCBP) and individuals who can father children 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. Individuals who can father children must use adequate contraception during treatment and for 3 months after stopping daratumumab and/or carfilzomib.
    * Negative serum or urine pregnancy test at screening for IOCBP.
    * 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 regi

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Multiple Myeloma
• Smoldering Multiple Myeloma
• Plasma Cell Dyscrasias
• Monoclonal Gammopathy
• Waldenstrom Macroglobulinemia
• Amyloidosis
• Monoclonal Gammopathy of Undetermined Significance (MGUS)
• Lymphoma
• Leukemia
• Bone Marrow Disorders

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