In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose limiting. Per 3+3 phase I design, an additional 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll 3 additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved ≥partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.

Myleoma (MM) is characterised by frequent disease relapse with the need to introduce further lines of therapy (LoTs). How often all these theoretical options (Dimopoulos et al, 2021) are actually used in "Real World (RW) settings is considered controversial. In recent studies MM patients were found to have attriction rates (ARs) of up to 57% from LoT-1 to LoT-2. (Yong et al, 2016; Fonseca et al, 2020). We aim to assess ARs inside the Austrian Multiple Myeloma Registry and verify treatment patterns in the RW. Methods:Patients with an index diagnosis made between JAN 2009 and AUG 2021 were eligible. Baseline data and treatment patterns were collected. Attrition was defined as being either deceased, progressive without receiving a further LoT, or being lost to follow up for 5 years or more. Results: 571 pts. (n) were identified, of whom 57.1% were men. Median age at FD was 72 years (SD 12.7 y) with a median follow-up of 50.8 months (SD 44.1 m). 507 patients (88.1%) received the first LOT. In 1st LoT 43.2 % (n 219) received stem cell transplantation (SCT), 39.4% (n 200) received maintenance therapy (55.9 % of transplanted patients). The most common treatment in both transplanted and non-transplanted patients was VRD with 20.5 %. AR was nearly constant across LoT 1 to 4 pending between 19.9-27 %. Summarized ARs across all LoTs without SCT was 36% (n 98) compared to 27.7% in the SCT cohort (n 65). A further LoT was instituted in 37.7-48.6 % of pts. in LoT 1-4. Treatment duration (DoT) decreased with a mean of 12.4months in LoT-1 (SD 15.8) to 4 months (SD 15.4) in LoT-5. The exception is LoT-2 with a DoT of 18.4 months (SD 22.1). The latter may be explained by the short observation window with many patients in the 1st line not yet completed. The depth of remission decreases with each subsequent LoT, as PD is present in 10.5% of patients after 1st LoT compared to 29.7% of patients in LoT-5. The risk of attrition decreases by 32.1% in SCT pts. (CI95% 0.679: 0.47-0.99; p=0.045), and follow-up time becomes significantly longer at 53.8 months versus 47.2 months (p=0.007). Patients defined as being victims of attrition were significantly older at 75 years (SD 10.52months, p=0.003). Both factors influence each other, since patients with SCT were significantly younger (64 years, p=0.003). Frontline regimens with a PI and DEX alone increased the risk of falling into AR by 80% (95%CI 1.802:1.09-2.99; p=0.022) compared to triplet and quadruplet inductions. This might mirror the difference between fixed duration vs continuous therapies. Maintenance (nearly uniformly with LEN) in frontline regimens reduces the risk of attrition by 51.5% (95%CI 0,485:0.33-0.73; p<0.001). Conclusions: Overall, our analyses demonstrated ARs significantly lower that than previously reported (Yong et al, 2016; Fonseca et al, 2020). This indicates that issues like drug access and reimbursement might also play major roles with respect to long term results in MM. Our results confirm a negative impact of doublet 1st treatments vs. more intensive ones. The ...