Of 313 patients screened for the LocoMMotion study, 248 patients were enrolled between August 2, 2019, and October 26, 2020 (all-treated analysis set). As previously reported, 225 (90.7%) patients were from Europe and 23 (9.3%) were from the United States. At the end of study in October 2022, median study follow-up was 26.4 months (range, 0.1–35.0), and 205 (82.7%) patients had completed the study, including 158 (63.7%) patients who died. Forty-three (17.3%) patients had discontinued, including 13 who were lost to follow-up (Fig. 1). Patient and disease baseline characteristics have been previously described [12]. Median age was 68 years (range, 41–89), 87 (40.1%) had creatinine clearance ≤60 mL/min, 81 (40.5%) had lactate dehydrogenase levels >245 U/L, and 135 patients (54.4%) were male. At baseline, patients had received a median of 4 prior LOT (range, 2–13), 25.0% had received 4 prior LOT, and 49.2% had received ≥5 prior LOT. One hundred eighty-two (73.4%) patients were triple-class refractory, 229 (92.3%) were refractory to the last LOT, and 160 (64.5%) had prior stem cell transplantation. Median time to triple-class exposure was 4.7 years (range, 0–20.4).

aEnrolled patients are those who signed informed consent and were formally enrolled into the study. bTreated patients are those who were enrolled into the study and received at least 1 real-world clinical practice treatment. cPatients who completed the study are those who either died or remained on study at the end of the study (24 months), whichever occurred first.

Ninety-one unique RWCP treatment regimens were used by patients in the index LOT, including a range of combinations of glucocorticoids (91.5%), PIs (54.4%), IMiDs (48.8%), and anti-CD38 monoclonal antibodies (9.7%) (Table 1). Six (2.4%) patients received stem cell transplantation (all autologous), and 7 patients (2.8%) received BCMA-targeted therapy. In total, 162 (65.3%) patients received a combination of ≥3 drugs. The most commonly received index regimens were carfilzomib-dexamethasone (Kd, 14.1%), pomalidomide-cyclophosphamide-dexamethasone (PCd, 14.1%), and pomalidomide-dexamethasone (Pd, 11.7%); most other regimens were used by fewer than 5 patients (15 regimens were used by only 2 patients and 46 were used by only 1 patient each). Patients received a median of 4 (range, 1–37) cycles of index treatment; median duration of treatment was 4.0 months (range, 0.1–33.6). Two hundred twenty-one patients (89.1%) discontinued index treatment, most commonly due to PD (54.8%), death (8.5%), and physician decision (8.5%). Twenty-seven patients completed the study.

One hundred fifty-two patients (61.3%) received at least 1 subsequent LOT after the index LOT (Supplementary Table S2). One hundred thirty-four unique regimens were used; 19 regimens were used by only 2 patients and 89 by only 1 patient. Overall, the most commonly used first subsequent LOTs were belantamab mafodotin (10.5% of those who received subsequent LOT) and PCd (6.6%; Table 2). A range of doublet and triplet therapies were also used during subsequent LOT, including daratumumab-carfilzomib-dexamethasone, isatuximab-carfilzomib-dexamethasone, Kd, Pd, and isatuximab-pomalidomide-dexamethasone. Compared to index LOT, more patients received BCMA-targeted therapy as subsequent LOT (2.8% during index vs 39.5% of those who received subsequent LOT). Overall, patients spent a median 4.5 months (range, 0.03–29.70) on subsequent LOT. Seventy-eight patients (31.5% of enrolled patients) had only 1 subsequent LOT, and 74 (29.8%) had ≥2 subsequent LOT (Fig. 2).

LOT line of therapy. aIncludes 36 (14.5%) patients who remained on index LOT.

ORR with index treatment, assessed by RRC, for patients treated with RWCP therapies was 31.9% (95% CI, 26.1–38.0), median duration of treatment was 4.0 months (range, 0.1–33.6), and median DOR was 7.4 months (95% CI, 4.9–11.1). Overall best response for patients was generally unchanged from the previous data cut at 16.1 months median study follow-up [8]. No patients achieved stringent complete response, 1 patient (0.4%) achieved CR, 32 (12.9%) achieved VGPR, 46 (18.5%) achieved PR, 14 (5.6%) had minimal response, 78 (31.5%) had stable disease, and 43 (17.3%) had PD. Thirty-four patients (13.7%) were not evaluable by RRC (mainly due to death, AEs, or rapid disease progression requiring a switch to another treatment, occurring before confirmation of response). Among the 34 RRC-unevaluable patients, investigators assessed 3 as responders and 31 as not evaluable, PD, stable disease, or minimal response.

In RRC-evaluable responders (n = 79), median time to first response was 1.9 months (range, 0.7–25.8), and median time to best response was 2.4 months (range, 0.7–25.8). ORR results as assessed by investigators (34.7% [95% CI, 28.8–41.0%]) were similar (85.9% concordant). Median PFS by RRC was 4.6 months and median OS was 13.8 months (Fig. 3). Twelve- and 24-month PFS rates were 21.0% (95% CI, 15.3–27.3) and 10.5% (95% CI, 6.1–16.3); 12- and 24-month OS rates were 53.4% (95% CI, 46.7–59.6) and 33.7% (95% CI, 27.3–40.2), respectively.

Kaplan–Meier plots showing (A) progression-free survival and B overall survival based on RRC assessment at median study follow-up 26.4 months in all patients. OS overall survival, PFS progression-free survival, RRC response review committee, VGPR very good partial response.

Prespecified subgroup analysis showed that ORR was minimally impacted by high-risk disease characteristics at baseline, including ≥4 prior LOT (29.9%), International Staging System (ISS) stage III at study entry (29.5%), extramedullary plasmacytomas (29.2%), penta-drug refractory MM (23.3%), and penta-drug exposed MM (28.6%) (Fig. 4). ORRs were lower in patients who had a low level of thrombocytes (<75 × 109/L) at baseline (14.8% vs 37.6% in those with thrombocyte levels ≥75 × 109/L) and those who had triple-class refractory MM (26.9% vs 45.5% in patients who did not have triple-class refractory MM) than in patients without these risk factors. Missing data prevented interpretation of data for subgroups by cytogenetic risk and percentage of bone marrow plasma cells. Several risk factors also impacted PFS outcomes, including extramedullary plasmacytomas (median 2.7 months with plasmacytomas vs 5.1 months without plasmacytomas), triple-class refractoriness (4.1 vs 8.2 months in patients who did not have triple-class refractory MM), penta-refractoriness (3.4 vs 5.5 months in patients who did not have penta-drug refractory MM), low thrombocyte levels (3.1 vs 5.6 months in patients with ≥75 × 109/L thrombocytes), and lactate dehydrogenase (LDH) > 245 U/L (3.4 vs 5.6 months in patients with LDH ≤ 245 U/L) (Supplementary Fig. S1). OS outcomes were worse in patients who had baseline ECOG PS ≥ 1 (median 11.1 months vs 24.1 months in those with ECOG PS 0), ISS stages II or III (stage II: 9.7 months and stage III: 12.4 months vs stage I: 24.0 months), LDH > 245 U/L (7.4 vs 17.0 months in patients with LDH ≤ 245 U/L), low thrombocyte levels (5.8 vs 18.1 months in patients with ≥75 × 109/L thrombocytes), and those who had penta-drug refractory MM (8.2 vs 15.3 months in patients who did not have penta-drug refractory MM).

ECOG Eastern Cooperative Oncology Group, GFR glomerular filtration rate, ISS International Staging System, LDH lactate dehydrogenase, PS performance status, RRC response review committee. aTriple-class exposed/refractory is defined as exposed/refractory to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. bPenta-drug exposed/refractory is defined as exposed/refractory to at least 2 PIs, 2 IMiDs, and 1 anti-CD38 antibody (includes triple-class exposed/refractory).

Outcomes were worse for patients who did not (n = 215) versus those who did achieve (n = 33) ≥ VGPR. Median PFS was 3.9 months in patients who did not achieve ≥VGPR versus 15.2 months in patients who did achieve ≥VGPR, and median OS was 10.9 months versus not estimable. Patients who achieved ≥VGPR showed significantly longer median DOR versus those who achieved PR (13.1 months vs 4.7 months).

Estimated median time from start of index LOT to next treatment was 5.2 months (95% CI, 4.4–6.0). Median duration of treatment with first subsequent LOT was 2.8 months (range, <1–29.7). Median PFS2 by investigator assessment was 10.8 months (95% CI, 8.4–13.0).

During index LOT, 86.7% of patients experienced an AE; grade 3/4 TEAEs occurred in 144 (58.1%) patients (Table 3). The most common TEAEs were hematologic, occurring in 50% of patients, and included thrombocytopenia (any grade 26.2%, grade 3/4 19.4%), anemia (any grade 25.8%, grade 3/4 10.9%), and neutropenia (any grade 20.2%, grade 3/4 17.3%) (Supplementary Table S3). The most common non-hematologic TEAEs (all grades; reported in ≥15% patients) were general disorders and administration site conditions (40.7%), gastrointestinal disorders (33.5%), and infections and infestations (33.1%). No grade 3/4 non-hematological TEAEs occurred in ≥15% of patients. SPMs were reported in 13 (5.2%) patients; 5 were reported during index LOT and 8 were reported after index LOT. Cases of SPMs included squamous cell carcinoma (n = 4), basal cell carcinoma (n = 2), secondary acute myeloid leukemia (n = 2), cancer of the lung/bronchus (n = 2), and 1 case each of high grade suspected cholangio cellular carcinoma, plasma cell leukemia, and an SPM described as multiple destructive fluorodeoxyglucose (FDG)-positive lesions throughout the skeleton and skull. Of note, the case of plasma cell leukemia and of SPM with multiple destructive FDG-positive lesions may have been MM; however, they were reported as SPM by the investigators. Only 1 SPM case (plasma cell leukemia) was reported as fatal.

Overall, 158 (63.7%) patients died during the study. Most deaths were due to PD (67.7%), 15.8% were due to AEs, and 16.5% were due to other causes (Fig. 5). Sixty deaths occurred during or after index LOT (but before subsequent LOT) and 98 occurred after the start of subsequent LOT. During index LOT, 21 (8.5%) patients died from TEAEs, most commonly infection (13 patients, 5.2%), and 1 patient had a grade 5 TEAE that did not resolve before the patient died from PD.

AE adverse event, PD progressive disease, LOT line of therapy. aThese patients did not receive subsequent LOT.