Yelak Biru: Phase 3 trials supporting FDA approvals in myeloma

Yelak Biru, President and Chief Executive Officer at International Myeloma Foundation, shared a post on X:

“Phase 3 Trials Supporting FDA Approvals in Myeloma:

Here is a list of key Phase 3 clinical trials whose results were pivotal in supporting US FDA approval for new myeloma drugs or significant new indications for existing drugs.

This list focuses on the Phase 3 trial(s) directly cited or strongly associated with a specific FDA approval action (new drug, new combination, new patient population like NDMM, or formulation change).

MM-009 and MM-010 (NCT00064387 and NCT00074159): Supported approval of Lenalidomide + Dexamethasone (initial approval in RRMM)

• Comparison: Lenalidomide + Dexamethasone vs Dexamethasone alone

MM-020 (FIRST) (NCT00689936): Supported approval of Lenalidomide + Low-Dose Dexamethasone (Rd) in transplant-ineligible NDMM

• Comparison: Continuous Rd vs MPT (Melphalan + Prednisone + Thalidomide) (Note: Also compared vs Rd for 18 cycles)

CALGB 100104 (NCT00114101) and IFM 2005-02 (NCT00430365): Supported approval of Lenalidomide maintenance therapy post-ASCT

• Comparison: Lenalidomide maintenance vs Placebo/No maintenance

APEX (NCT00048237): Supported approval of Bortezomib (full approval in RRMM, confirming prior accelerated approval based on Phase 2 SUMMIT trial)

• Comparison: Bortezomib vs Dexamethasone

VISTA (NCT00111319): Supported approval of Bortezomib + Melphalan + Prednisone (VMP) in transplant-ineligible NDMM

• Comparison: VMP vs MP (Melphalan + Prednisone)

MMY-3021 (NCT00722566): Supported approval of Subcutaneous (SC) formulation of Bortezomib

• Comparison: Subcutaneous Bortezomib vs Intravenous Bortezomib (non-inferiority)

E1A00 (ECOG E1A00): Supported approval of : Thalidomide + Dexamethasone in NDMM

• Comparison: Thalidomide + Dexamethasone vs Dexamethasone alone

MM-003 (NCT01311687): Supported approval of Pomalidomide + Low-Dose Dexamethasone in RRMM (after lenalidomide and bortezomib failure; provided confirmatory data supporting initial accelerated approval based on Phase 2 MM-002 data)

• Comparison: Pomalidomide + Low-Dose Dexamethasone vs High-Dose Dexamethasone

POLLUX (NCT02076009): Supported approval of Daratumumab in combination with lenalidomide and dexamethasone (Rd) for relapsed/refractory multiple myeloma (RRMM).

• Comparison: Dara-Rd vs Rd

CASTOR (NCT02136134): Supported approval of Daratumumab in combination with bortezomib and dexamethasone (Vd) for RRMM.

• Comparison: Dara-Vd vs Vd

MAIA (NCT02252172): Supported approval of Daratumumab in combination with lenalidomide and dexamethasone (Rd) for newly diagnosed multiple myeloma (NDMM) patients ineligible for autologous stem cell transplant (ASCT).

• Comparison: Dara-Rd vs Rd

CANDOR (NCT03158688): Supported approval of Daratumumab in combination with carfilzomib and dexamethasone (Kd) for RRMM.

• Comparison: Dara-Kd vs Kd

APOLLO (NCT03180736): Supported approval of Daratumumab (subcutaneous formulation – Darzalex Faspro) in combination with pomalidomide and dexamethasone (Pd) for RRMM.

• Comparison: Dara(SC)-Pd vs Pd

COLUMBA (NCT03277105): A non-inferiority trial that was key for the approval of the subcutaneous formulation of Daratumumab (Darzalex Faspro), demonstrating comparable pharmacokinetics and safety to the intravenous formulation.

• Comparison: Daratumumab SC vs Daratumumab IV

ICARIA-MM (NCT02990338): Supported approval of Isatuximab in combination with pomalidomide and dexamethasone (Pd) for RRMM.

• Comparison: Isa-Pd vs Pd

IKEMA (NCT03275285): Supported approval of Isatuximab in combination with carfilzomib and dexamethasone (Kd) for RRMM.

• Comparison: Isa-Kd vs Kd

ELOQUENT-2 (NCT01239797): Supported approval of Elotuzumab in combination with lenalidomide and dexamethasone (Rd) for RRMM.

• Comparison: Elo-Rd vs Rd

ELOQUENT-3 (NCT02654132): Supported approval of Elotuzumab in combination with pomalidomide and dexamethasone (Pd) for RRMM.

• Comparison: Elo-Pd vs Pd

ASPIRE (NCT01080391): Supported approval of Carfilzomib in combination with lenalidomide and dexamethasone (Rd) for RRMM.

• Comparison: KRd vs Rd

ENDEAVOR (NCT01568866): Supported approval of Carfilzomib in combination with dexamethasone (Kd), demonstrating superiority over bortezomib and dexamethasone (Vd) in RRMM.

• Comparison: Kd vs Vd

TOURMALINE-MM1 (NCT01564537): Supported approval of Ixazomib (oral proteasome inhibitor) in combination with lenalidomide and dexamethasone (Rd) for RRMM.

• Comparison: Ixa-Rd vs Placebo-Rd

TOURMALINE-MM3 (NCT02181413): Supported approval of Ixazomib as maintenance therapy after autologous stem cell transplant (ASCT).

• Comparison: Ixazomib vs Placebo maintenance

PANORAMA-1 (NCT01023308): Supported approval of Panobinostat (HDAC inhibitor) in combination with bortezomib and dexamethasone (Vd) for RRMM patients who received at least two prior regimens including bortezomib and an immunomodulatory agent.

• Comparison: Panobinostat-Vd vs Placebo-Vd

BOSTON (NCT03110562): Supported approval of Selinexor (XPO1 inhibitor) in combination with bortezomib and dexamethasone (Vd) for RRMM patients who received at least one prior therapy. (Note: Initial Selinexor approval for penta-refractory myeloma was based on Phase 2 STORM trial).

• Comparison: Selinexor-Vd vs Vd

KarMMa-3 (NCT03651128): Pivotal for the full approval and expanded indication (use in earlier lines, after 2 prior lines of therapy) of Idecabtagene vicleucel (Abecma), a BCMA-directed CAR-T therapy. (Initial accelerated approval was based on Phase 2 KarMMa study).

• Comparison: Ide-cel vs Standard Combination Regimens

CARTITUDE-4 (NCT04181827): Pivotal for the full approval and expanded indication (use in earlier lines, after 1 prior line of therapy) of Ciltacabtagene autoleucel (Carvykti), a BCMA-directed CAR-T therapy. (Initial accelerated approval was based on Phase 1b/2 CARTITUDE-1 study).

• Comparison: Cilta-cel vs Standard of Care (PVd or DPd)

Phase 3 (and key Phase 2 for some initial approvals) Trials Supporting FDA Approvals in Myeloma (Grouped by approved drugs or combinations):

For Daratumumab (Darzalex / Darzalex Faspro):

• POLLUX (NCT02076009): Dara-Rd vs Rd (RRMM)
• CASTOR (NCT02136134): Dara-Vd vs Vd (RRMM)
• MAIA (NCT02252172): Dara-Rd vs Rd (Transplant-ineligible NDMM)
• CANDOR (NCT03158688): Dara-Kd vs Kd (RRMM)
• APOLLO (NCT03180736): Dara(SC)-Pd vs Pd (RRMM)
• COLUMBA (NCT03277105): Dara SC vs Dara IV (Supporting SC formulation approval)

For Isatuximab (Sarclisa):

• ICARIA-MM (NCT02990338): Isa-Pd vs Pd (RRMM)
• IKEMA (NCT03275285): Isa-Kd vs Kd (RRMM)

For Elotuzumab (Empliciti):

• ELOQUENT-2 (NCT01239797): Elo-Rd vs Rd (RRMM)
• ELOQUENT-3 (NCT02654132): Elo-Pd vs Pd (RRMM)

For Carfilzomib (Kyprolis):

• ASPIRE (NCT01080391): KRd vs Rd (RRMM)
• ENDEAVOR (NCT01568866): Kd vs Vd (RRMM)

For Ixazomib (Ninlaro):

• TOURMALINE-MM1 (NCT01564537): Ixa-Rd vs Placebo-Rd (RRMM)
• TOURMALINE-MM3 (NCT02181413): Ixazomib vs Placebo maintenance (Post-ASCT maintenance)

For Panobinostat (Farydak):

• PANORAMA-1 (NCT01023308): Panobinostat-Vd vs Placebo-Vd (RRMM, specific prior therapies required)

For Selinexor (Xpovio):

• BOSTON (NCT03110562): Selinexor-Vd vs Vd (RRMM, >=1 prior therapy). (Note: Initial penta-refractory approval based on Phase 2 STORM trial).

For Idecabtagene Vicleucel (Abecma):

• KarMMa-3 (NCT03651128): Ide-cel vs Standard Regimens (Full approval/earlier line expansion for RRMM). (Note: Initial accelerated approval based on Phase 2 KarMMa trial).

For Ciltacabtagene Autoleucel (Carvykti):

• CARTITUDE-4 (NCT04181827): Cilta-cel vs Standard Regimens (Full approval/earlier line expansion for RRMM). (Note: Initial accelerated approval based on Phase 1b/2 CARTITUDE-1 trial).

For Bortezomib (Velcade):

• APEX (NCT00048237): Bortezomib vs Dexamethasone. (Confirmatory data for full approval in RRMM). (Note: Initial accelerated approval based on Phase 2 SUMMIT trial).
• VISTA (NCT00111319): Bortezomib + Melphalan + Prednisone (VMP) vs Melphalan + Prednisone (MP) (transplant-ineligible NDMM)
• MMY-3021 (NCT00722566): subcutaneous vs intravenous Bortezomib

For Pomalidomide (Pomalyst):

• MM-003 (NCT01311687): Pomalidomide + Low-Dose Dexamethasone vs High-Dose Dexamethasone (RRMM patients previously treated with lenalidomide and bortezomib) (Note: Initial accelerated approval relied on Phase 2 MM-002 data)

For Thalidomide (Thalomid):

• E1A00 (ECOG E1A00) Thalidomide + Dexamethasone vs Dexamethasone alone (NDMM)

For Lenalidomide (Revlimid):

• MM-009 and MM-010 (NCT00064387 and NCT00074159): Lenalidomide + Dexamethasone vs Dexamethasone alone. (RRMM)
• MM-020 (FIRST) (NCT00689936): continuous Lenalidomide + Low-Dose Dexamethasone (Rd) vs Rd for 18 cycles vs MPT. (Rd in transplant-ineligible NDMM)
• CALGB 100104 and IFM 2005-02 (NCT00114101 and NCT00430365): Lenalidomide maintenance vs placebo/no maintenance post-ASCT. (maintenance therapy).”

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