Background: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM patients (pts), treatment with Isa-Kd showed continued, significant improvement in progression-free survival (PFS) vs Kd (HR 0.58; 95.4% CI 0.42–0.79), with meaningful increase in depth of response (complete response or better [≥CR] 44.1% vs 28.5%; minimal residual disease negativity [MRD-] 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. In this subgroup analysis of IKEMA, we evaluated efficacy of Isa-Kd in pts with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n=179) or Kd (n=123). Assessment was prespecified (at 30% cut-off by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater PFS benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (HR 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21) (Table). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), ≥CR, MRD-, and MRD- ≥CR (Table). Conclusions: 1q21 abnormalities affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM. Clinical trial information: NCT03275285.