Combining elranatamab with carfilzomib and dexamethasone shows promising results in relapsed or refractory multiple myeloma
For patients with relapsed or refractory multiple myeloma (RRMM)—a blood cancer that has returned or stopped responding to treatment—each new line of therapy represents both hope and uncertainty. While modern treatments have improved outcomes, triple-class refractory disease (resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies) remains a formidable challenge, with many patients exhausting effective options.
Enter a promising new strategy: combining established myeloma drugs with innovative immunotherapy. Recent research presented at the 66th American Society of Hematology Annual Meeting reveals a compelling approach—pairing the bispecific antibody elranatamab with the proteasome inhibitor carfilzomib and dexamethasone. This combination leverages complementary mechanisms to activate the immune system against cancer cells, offering new hope for patients with limited treatment options.
Triple-class refractory myeloma patients often exhaust effective treatment options
Combining immunotherapy with established drugs creates synergistic effects
Early trial data shows 100% initial response rate with manageable side effects
Understanding how these medications work together to combat myeloma cells
A bispecific antibody that physically connects T-cells to myeloma cells by simultaneously binding to CD3 on T-cells and BCMA on myeloma cells. This connection activates the immune system to destroy the cancer.
A proteasome inhibitor that blocks the protein-disposal machinery in cells, causing toxic buildup that preferentially kills myeloma cells. Emerging evidence suggests it may also prime tumor cells for immune-mediated destruction.
A corticosteroid that reduces inflammation and manages treatment side effects, while also having direct anti-myeloma activity.
Preclinical research indicated that these agents might work better together than alone. As Dr. Michael Tomasson, a principal investigator, explained: "The idea is that the immune priming of the tumor cells by carfilzomib makes the myeloma cells even more sensitive to elranatamab" 7 . This potential synergy formed the scientific basis for the MagnetisMM-20 trial.
The MagnetisMM-20 study (NCT05675449) is a Phase 1b, open-label, non-randomized clinical trial designed to evaluate the safety and effectiveness of this combination therapy in specific patient populations 4 .
The initial findings from part 1 of the trial focused on 12 patients with specific characteristics 2 3 :
Step-up doses of subcutaneous elranatamab (12 mg on day 1, 32 mg on day 4) to gradually activate the immune system and minimize reactions
Either 44 mg or 76 mg of elranatamab, establishing the initial dose level for comparison
Weekly elranatamab combined with carfilzomib (70 mg/m² intravenously on days 1, 8, and 15 of each 4-week cycle) and dexamethasone (40 mg weekly)
Patients who responded for ≥6 months could switch to biweekly elranatamab dosing to improve long-term tolerability 3
The preliminary results from the first 12 patients exceeded expectations, demonstrating substantial clinical benefits 2 3 :
| Outcome Measure | Results | Significance |
|---|---|---|
| Objective Response Rate (ORR) | 100% (unconfirmed) | All patients experienced tumor reduction |
| Confirmed ORR | 83.3% (10/12 patients) | Majority achieved confirmed responses |
| Median Time to Response | 1.41-1.5 months | Relatively rapid onset of action |
| Median Duration of Response | Not reached | Responses appeared long-lasting |
| Ongoing Treatment | 41.7-91.7% | Majority continued benefiting from therapy |
Perhaps most notably, these strong responses were observed across different patient subtypes, including those with high-risk cytogenetics and advanced disease stages who typically have poorer outcomes 7 .
The combination demonstrated manageable side effects, with no dose-limiting toxicities reported in the first 10 evaluable patients 3 . The most common adverse events were predictable and generally manageable:
| Adverse Event | Any Grade (%) | Grade 3/4 (%) | Management Strategies |
|---|---|---|---|
| Fatigue | 83.3% | 8.3-16.7% | Dose modification, supportive care |
| CRS | 75.0% | 0% | Priming doses, premedication |
| Neutropenia | 58.3-75.0% | 33.3-75.0% | Monitoring, growth factors |
| Thrombocytopenia | 58.3-75.0% | 25.0-41.7% | Transfusion support |
| Injection site reaction | 50.0% | 0% | Topical treatments, rotation |
| Infections | 75.0-91.7% | 16.7% | Prophylactic antibiotics, IVIG |
The MagnetisMM-20 trial represents more than just another clinical study—it exemplifies the evolution of cancer treatment toward rational combination therapies that leverage complementary mechanisms of action.
When considered alongside the MagnetisMM-3 trial, which established elranatamab as a single agent with a 61.0% response rate in heavily pretreated patients , the MagnetisMM-20 combination achieving 100% initial response rate suggests genuine synergistic potential.
An updated indirect comparison study further contextualizes these results, showing that elranatamab significantly improved progression-free survival, overall survival, and duration of response compared to real-world physician's choice therapies 6 .
As the MagnetisMM-20 trial continues to enroll patients, the early results offer compelling evidence for this combination approach. The 100% initial response rate, manageable safety profile, and deep, durable responses observed—even in patients with high-risk features—suggest that strategically combining immunotherapies with established agents may redefine treatment for relapsed/refractory multiple myeloma.
Dr. Tomasson summarized the promise well: "Single agent elranatamab in low-stage patients, or combo therapy in high-stage patients has the promise for deep and long-lasting remissions after failure of quadruplet therapy" 7 .
For the myeloma community, these findings represent more than statistical success—they offer tangible hope that through continued scientific innovation, even the most challenging cases may find new paths to remission.