What is the next line of therapy for a patient with refractory multiple myeloma who has previously been treated with daratumumab (Darzalex)?

Treatment of Refractory Multiple Myeloma Post-Daratumumab

For patients with daratumumab-refractory multiple myeloma, prioritize CAR-T cell therapy (idecabtagene vicleucel or ciltacabtagene autoleucel) if triple-class refractory, or alternatively use isatuximab-based combinations (IsaPd or IsaKd), elotuzumab with pomalidomide-dexamethasone (EloPd), or selinexor-based triplets depending on prior exposures. 1

Primary Recommendation: CAR-T Cell Therapy for Triple-Class Refractory Disease

If your patient is refractory to daratumumab, a proteasome inhibitor (PI), and an immunomodulatory drug (IMiD), CAR-T therapy is the preferred next option rather than continuing with additional chemotherapy combinations. 1

• The FDA has approved idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) for patients with ≥4 prior therapies including lenalidomide, pomalidomide, and daratumumab. 1
• CAR-T demonstrates markedly superior efficacy with 71-97% response rates in heavily pretreated populations. 1
• The KarMMa trial showed 73% overall response rate with 33% complete response in patients with median 6 prior lines where 94% were anti-CD38 refractory. 1
• The CARTITUDE-1 trial demonstrated 96.9% overall response rate with 88% being triple-class refractory. 1

Alternative Options When CAR-T Is Not Immediately Available

For Patients Previously Exposed to Lenalidomide and a PI (Post-Daratumumab)

Isatuximab-based combinations are the strongest alternative, as isatuximab is a different anti-CD38 antibody that may retain activity after daratumumab failure. 2

• Isatuximab + pomalidomide + dexamethasone (IsaPd): Phase III trial showed median PFS of 11.5 months versus 6.5 months for pomalidomide-dexamethasone alone (HR 0.596; P = 0.001) in patients who failed ≥2 prior lines including lenalidomide and a PI. 2

• Isatuximab + carfilzomib + dexamethasone (IsaKd): In patients with 1-3 prior lines, median PFS was not reached for IsaKd versus 19.1 months for carfilzomib-dexamethasone (HR 0.53; P = 0.0007), with benefit maintained in lenalidomide-refractory patients (HR 0.60). 2

• Elotuzumab + pomalidomide + dexamethasone (EloPd): Phase II study showed median PFS of 10.3 months versus 4.7 months for pomalidomide-dexamethasone (HR 0.54; P = 0.008). 2

Selinexor-Based Triplet Regimens

Selinexor triplets are particularly effective in daratumumab-exposed patients and offer a PI- and IMiD-free alternative. 3, 4

• Selinexor + daratumumab + dexamethasone (SDd): In daratumumab-naïve RRMM patients, this combination achieved 73% overall response rate with median PFS of 12.5 months. 3
• Real-world data shows patients with prior anti-CD38 exposure in the immediate prior line had numerically higher survival outcomes (rwOS 20.9 months, dPFS 8.7 months) when treated with selinexor triplets. 4
• Selinexor + bortezomib + dexamethasone (SVd): Phase III trial showed median PFS of 13.9 versus 9.4 months compared to bortezomib-dexamethasone (HR 0.70, P = 0.0066). 2

For Triple-Class Refractory Patients Without CAR-T Access

When CAR-T is not available, selinexor-dexamethasone or belantamab mafodotin monotherapy are options, though with more modest efficacy. 2

• Selinexor + dexamethasone (Sd): In the STORM trial with 122 heavily pretreated patients (median 7 prior lines, all refractory to PIs, IMiDs, and daratumumab), overall response rate was 26% with median PFS 3.7 months and median OS 8.6 months. 2, 5

• Common adverse events include fatigue, nausea, and decreased appetite (typically grade 1-2), with thrombocytopenia in 73% (grade 3-4 in 58%). 2, 5

• Belantamab mafodotin: BCMA-targeting antibody-drug conjugate showed median PFS of 2.9-4.9 months in triple-class refractory patients, though it is being withdrawn from the market after failing to show superiority in the DREAMM-3 trial. 2

• Available through compassionate use for patients already receiving it. 2

Special Consideration: t(11;14) Patients

For patients with t(11;14) translocation who are lenalidomide-refractory and PI-sensitive, venetoclax + bortezomib + dexamethasone (VenVd) is an option. 2

• Phase III BELLINI trial showed significant PFS benefit among t(11;14) patients (HR 0.10; P = 0.003). 2
• Critical caveat: VenVd showed inferior OS in patients without t(11;14) and low BCL2 (HR 3.13; P = 0.019), so this should only be used in confirmed t(11;14) or high BCL2 expression. 2

Important Clinical Context

The prognosis for triple-class refractory patients is poor, with median OS of only 5.6 months, making aggressive therapy with CAR-T or clinical trial enrollment critical. 2

• For daratumumab-exposed or refractory patients, guideline recommendations are based on panel opinion as there is limited prospective evidence for approved second-line regimens in this specific population. 2
• Daratumumab retreatment has limited retrospective evidence of benefit, and isatuximab after daratumumab progression is an unlikely option based on cross-resistance concerns. 2

Treatment Algorithm Summary

1. Triple-class refractory (PI + IMiD + anti-CD38): CAR-T cell therapy (ide-cel or cilta-cel) is preferred 1
2. Daratumumab-refractory, lenalidomide-refractory: IsaPd or IsaKd 2
3. Daratumumab-refractory, not yet triple-class exposed: Selinexor-based triplets (SDd, SVd, or with carfilzomib) 3, 4
4. t(11;14) with lenalidomide-refractory, PI-sensitive: VenVd 2
5. Heavily pretreated without CAR-T access: Selinexor-dexamethasone or clinical trial 2, 5