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JAK Inhibitors for Myeloma?
It’s great to learn about another class of therapy for the treatment of multiple myeloma. JAK inhibitors for myeloma, according to Dr. James Berenson, may be yet another therapy option.
Because myeloma is an incurable blood cancer, patients go into and out of remission undergoing one class of myeloma therapy after another.
To be clear, more research has to be done before JAK inhibitors become a regular therapy for MM survivors. However, what struck me as I listed to the interview linked below, was Dr. Berenson’s focus on JAK inhibitors as a MM treatment as well as his focus on JAK inhibitors as a well-tolerated therapy.
Both quantity and quality of life.
What are the different classes of chemotherapy regimens for the treatment of multiple myeloma?
1. Proteasome Inhibitors
- Mechanism: Inhibit proteasomes, leading to the accumulation of damaged proteins and inducing apoptosis in myeloma cells.
- Examples:
- Bortezomib (Velcade)
- Carfilzomib (Kyprolis)
- Ixazomib (Ninlaro)
- Usage: Often part of combination regimens such as VRd (bortezomib, lenalidomide, dexamethasone).
2. Immunomodulatory Drugs (IMiDs)
- Mechanism: Enhance immune response, inhibit angiogenesis, and directly target myeloma cells.
- Examples:
- Thalidomide
- Lenalidomide (Revlimid)
- Pomalidomide (Pomalyst)
- Usage: Frequently used in both newly diagnosed and relapsed/refractory myeloma.
3. Alkylating Agents
- Mechanism: Cause DNA damage by adding alkyl groups, disrupting cancer cell replication.
- Examples:
- Melphalan
- Cyclophosphamide
- Usage: Often used in combination regimens or high-dose melphalan for autologous stem cell transplantation.
4. Corticosteroids
- Mechanism: Reduce inflammation and directly induce apoptosis in myeloma cells.
- Examples:
- Dexamethasone
- Prednisone
- Usage: Typically combined with other agents to enhance efficacy.
5. Monoclonal Antibodies
- Mechanism: Target specific surface proteins on myeloma cells to trigger immune-mediated destruction.
- Examples:
- Daratumumab (targets CD38)
- Isatuximab (targets CD38)
- Elotuzumab (targets SLAMF7)
- Usage: Often part of combination regimens in relapsed or refractory settings.
6. Histone Deacetylase (HDAC) Inhibitors
- Mechanism: Modify gene expression by inhibiting histone deacetylases, leading to cancer cell death.
- Example:
- Panobinostat (Farydak)
- Usage: Combined with bortezomib and dexamethasone for refractory cases.
7. Anthracyclines
- Mechanism: Interfere with DNA replication and repair through intercalation and free radical production.
- Examples:
- Doxorubicin (Adriamycin)
- Usage: Historically used but less common in modern regimens.
8. B-cell Maturation Antigen (BCMA)-Targeted Therapies
- Mechanism: Target BCMA, a protein highly expressed on myeloma cells.
- Examples:
- Belantamab mafodotin (antibody-drug conjugate)
- CAR-T cell therapies (e.g., idecabtagene vicleucel, ciltacabtagene autoleucel)
- Usage: Typically reserved for relapsed/refractory myeloma.
When I was first diagnosed with MM in early 1994, SOC induction therapy was vincristine, adriamycin and dexamethasone aka VAD. Approximately 50% of MM patients responded to this induction. More tan 95% of NDMM patients respond to today’s SOC induction regimen of VRDd.
Certainly more work has to be done on the subject of JAK inhibitors for myeloma before a therapy will be available for you in your onc.’s office. But it Dr. Berenson is doing clinical trials for it and because the FDA has already approved this therapy, use of JAK inhibitors can’t be too far away.
Email me at David.PeopleBeatingCancer@gmail.com with questions you may have.
Good luck,
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Exploring the Potential Role of JAK Inhibitors in Multiple Myeloma
“Berenson, founder, medical and scientific director, and president and chief executive officer of the Institute for Myeloma and Bone Cancer Research and private practitioner in West Hollywood, California, described the factors associated with the overexpression of JAK in the bone marrow, which may constitute a prime survival factor for multiple myeloma. This overexpression may affect the checkpoint inhibitor proteins in the body, resulting in resistance to standard anti-myeloma therapies such as immunomodulatory drugs.
Additionally, he mentioned a patient case that had involved a scenario in which JAK-mutated multiple myeloma progressed following prior treatment with lenalidomide (Revlimid). According to Berenson, the disease’s resistance to lenalidomide was primarily associated with proteins driven by JAK; subsequent treatment involving JAK inhibition proved successful in restoring the efficacy of lenalidomide.
Based on a rationale to target JAK overactivity in the bone marrow and results from this patient case, Berenson and colleagues have focused on researching ruxolitinib as a therapeutic candidate for potentially improving outcomes in multiple myeloma via JAK inhibition.
Findings from a phase 1 trial (NCT03110822), for example, have demonstrated that the efficacy and tolerability of ruxolitinib plus methylprednisolone can be extended with lenalidomide in those with multiple myeloma. Additionally, other ongoing trials aim to combine ruxolitinib with agents such as selinexor (Xpovio).
“The question is, where will ruxolitinib sit in the sequencing of treatment of [patients with] multiple myeloma? Where will selinexor be?” Berenson stated. “At this point, there’s certainly been low use of these drugs, especially ruxolitinib in multiple myeloma. We hope, with a more positive signal, these drugs will move further up in the algorithm of how you treat multiple myeloma.”
A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone
Results: Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP.
The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were
- 1 very good partial response,
- 8 partial responses,
- 1 minor response,
- 12 stable disease,
- and 7 progressive disease.
The median progression-free survival was 3.5 months (range 0.5-36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen.
After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were
- 2 very good partial responses,
- 4 partial responses,
- 2 minor responses,
- 8 stable disease,
- and 4 progressive disease.
The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months).
Conclusions: For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment.”