A Randomized Phase II Trial for High-Risk Multiple Myeloma That is Refractory or in First Relapse With Daratumumab, Teclistamab (DT) Versus Daratumumab, Pomalidomide, Dexamethasone (DPd) or Daratumumab, Carfilzomib, Dexamethasone (DKd)

Official Summary

This phase II trial compares the effect of the combination of daratumumab-hyaluronidase (daratumumab) and teclistamab to the usual treatment of daratumumab, pomalidomide, dexamethasone or daratumumab, carfilzomib and dexamethasone in treating patients with multiple myeloma that has not responded to previous treatment (refractory) or that has come back after a period of improvement (relapsed). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Teclistamab is a bispecific antibody that can bind to two different antigens at the same time. Teclistamab binds to B-cell maturation antigen, a protein found on some B-cells and myeloma cells, and CD3 on T-cells (a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Pomalidomide is in a class of medications called immunomodulatory agents. It works by helping the immune system kill cancer cells and by helping the bone marrow to produce normal blood cells. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Carfilzomib, a type of proteasome inhibitor, blocks the action of enzymes called proteasomes, which may help keep cancer cells from growing and may kill them. Giving daratumumab and teclistamab may be more effective than the usual treatment of daratumumab, pomalidomide, dexamethasone or daratumumab, carfilzomib and dexamethasone in reducing myeloma cells to undetectable levels in patients with relapsed or refractory multiple myeloma.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 80 participants

Study Arms

• Arm A Treatment I (DPd) (ACTIVE_COMPARATOR)
  Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6, then on day 1 of subsequent cycles. Patients also receive pomalidomide PO on days 1-21 of each cycle, dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, bone marrow biopsy, and FDG PET/CT thr
• Arm A Treatment II Option 1 (DKd) (ACTIVE_COMPARATOR)
  Patients receive daratumumab-hyaluronidase SC over 3-5 minutes carfilzomib IV on days 1, 2, 8, 9, 15, and 16 of each cycle, and dexamethasone PO or IV on days 1, 2, 8, 9, 15, and 16 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, bone marrow biopsy, and FDG PET/CT throughout the study.
• Arm A Treatment II Option 2 (DKd) (ACTIVE_COMPARATOR)
  Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6 and on day 1 of subsequent cycles, carfilzomib IV on days 1, 8, and 15 of each cycle, and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, bone marrow biopsy, and FDG PET/CT throughout the s
• Arm B (daratumumab, teclistamab) (EXPERIMENTAL)
  Patients receive daratumumab-hyaluronidase SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3-6 and on day 1 of subsequent cycles. Patients also receive teclistamab SC on day 2, 4, 8, 15 and 22 of cycle 1, on days 1, 8, 15, and 22 of cycle 2, on days 1 and 15 of cycles 3-6 and then on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sampl

Interventions

• PROCEDURE: Biospecimen Collection — Undergo urine and blood sample collection
• PROCEDURE: Bone Marrow Biopsy — Undergo bone marrow biopsy
• DRUG: Carfilzomib — Given IV
• PROCEDURE: Computed Tomography — Undergo FDG PET/CT
• DRUG: Daratumumab and Recombinant Human Hyaluronidase — Given SC

Primary Outcomes

• Minimal residual disease (MRD) negativity (After 6 cycles of treatment (cycle length = 28 days), assessed at 6 months)

Secondary Outcomes

• Incidence of adverse events (AEs) (Up to 6 cycles (cycle length = 28 days) and overall assessed up to 10 years)
• Incidence of grade 3 or higher hematologic and/or non-hematologic AEs (Up to 6 cycles (cycle length = 28 days) and overall assessed up to 10 years)
• Progression-free survival (PFS) (From randomization until the earlier of progression or death due to any cause, assessed up to 10 years)
• Overall survival (OS) (From randomization to death due to any cause, assessed up to 10 years)
• Response rates (After 6 cycles of treatment (cycle length = 28 days) and overall, assessed up to 10 years)

Eligibility Criteria

Inclusion Criteria:

* Patient must be ≥ 18 years of age
* Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 (PS 3 allowed if secondary to pain)
* Patient must have an identifiable dominant sequence (clonotype) established based on Adaptive Biotechnologies clonoSEQ® assay
* Patient must have received only one prior line of therapy

  * One prior line of systemic therapy is defined as 1 or more cycles of single agent or combination therapy, as well as a series of treatment regimens administered in a sequential manner (e.g., lenalidomide, bortezomib and dexamethasone induction therapy for 4 cycles followed by autologous stem cell transplantation and then lenalidomide +/- proteasome inhibitor or anti-CD38 monoclonal antibody (mAb) maintenance therapy would be considered 1 line of prior therapy)
  * NOTE: Autologous stem cell transplant is allowed provided the stem cell infusion was \> 90 days prior to randomization. Allogeneic stem cell transplantation (SCT) patients are ineligible
* Patient must be diagnosed with relapsed or refractory (RR) multiple myeloma, as defined by disease progression, either an increase in serum or urine M protein of any level, or other evidence of progression biochemical or clinical as specified in the IMWG progression criteria (including disease which becomes non-responsive or progressive on therapy or within 60 days of the last treatment in patients who had achieved a partial response or better on prior therapy)
* Patient must be daratumumab-hyaluronidase (or isatuximab) naïve or daratumumab-hyaluronidase (or isatuximab) sensitive and \> 180 days from their last dose of daratumumab-hyaluronidase (or isatuximab) at the time of randomization
* Patient must have high-risk multiple myeloma (HR-MM) as defined by one of the following either at diagnosis or at refractory status or at first relapse:

  * Evidence of deletion 17p by fluorescence in situ hybridization (FISH) testing on bone marrow
  * Evidence of t(4;14) by FISH testing on bone marrow
  * Evidence of t(14;16) by FISH testing on bone marrow
  * Evidence of t(14;20) by FISH testing on bone marrow
  * Evidence of chromosome 1 abnormalities either gain/amp 1q or deletion 1p by FISH testing on bone marrow OR
  * Evidence of non-hyperdiploid karyotype OR
  * Revised International Staging System (R-ISS) stage III beta2 microglobulin ≥ 5.5 mg/L and serum lactate dehydrogenase (LDH) \> institutional upper limit of normal (ULN) OR
  * Patient in first relapse and ≤ 24 months from the start of induction for both allogeneic stem cell transplantation (ASCT) eligible or ASCT ineligible patients (regardless of FISH, cytogenetic or RISS stage)
* Patient must have measurable disease as defined by having one or more of the following, obtained within 28 days prior to randomization:

  * Serum M protein ≥ 0.5 g/dL (≥ 5 g/L)
  * Urine M protein ≥ 200 mg/24 hours
  * Serum free light chain (FLC) assay: Involved free light chain level ≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is abnormal (\< 0.26 or \> 1.65)
  * Exception: patients without measurable disease in the serum or urine, but with bone or soft tissue plasmacytoma(s) ≥ 2 cm or who have bone marrow plasma cells ≥ 30% are eligible on study
* Patient must have serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum FLC assays along with bone marrow biopsy or aspirate performed within 28 days prior to randomization

  * NOTE: UPEP (on a 24 hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is ≥ 200 mg/24 hr. If both serum and urine M-components are measurable, both must be followed in order to confirm response
  * NOTE: The serum free light chain test is required to be done at each cycle
* Patient must not have any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure), or known sensitivity to mammalian-derived products
* Patients who have received prior systemic therapy for myeloma, including experimental therapy and steroids must have recovered from clinically significant adverse events prior to randomization
* Patient may not be on steroids (prednisone \> 40mg/day or equivalent) at the time of randomization
* Patient may have received prior palliative and/or localized radiation, provided that it is completed by the time of randomization
* Absolute neutrophil count (ANC) ≥ 1,000/uL (=\< 28 days prior to protocol randomization)
* Untransfused platelet count ≥ 50,000/uL (for patients with ≥ 50% plasma cells in the marrow) and untransfused platelet count \> 75,000/uL (for patients with \< 50% plasma cells in the marrow) (=\< 28 days prior to protocol randomization)
* Untransfused hemoglobin ≥ 8.0 g/dL (=\< 28 days prior to protocol randomization)
* Total bilirubin ≤ 1.5 x institutional ULN (upper limit

Study Officials

• Muhamed Baljevic — PRINCIPAL_INVESTIGATOR
  ECOG-ACRIN Cancer Research Group

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