Background: RRMM treatment (Tx) has been transformed by novel Txs including anti-CD38 monoclonal antibodies (mAbs) and 2^nd/3^rd generation immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), resulting in an increasing population of TCE pts (i.e., prior exposure to ≥1 each of an IMID, a PI, and an anti-CD38 mAb). Many such pts are exposed to ≥5 drugs in these classes (i.e., “penta-exposed” PE: ≥2 IMIDs, ≥2 PIs, and an anti-CD38 mAb). Some are refractory to ≥1 drug in each class (“triple-class refractory” TCR) and some are both PE and TCR (PE-TCR). Real-world outcomes data for the spectrum of these advanced RRMM pts are limited. Methods: A US commercial insurance claims dataset (IQVIA PharMetrics Plus®) spanning 2007-20 was used to examine outcomes in pts with RRMM (≥1 prior line of therapy [LOT]) who were TCE, TCR, PE, and PE-TCR. The 1^st LOT after becoming TCE or PE was defined as the “index LOT” (start date of index LOT = “index”). Subsets of TCE and PE pts who were also TCR at index were identified. To ensure complete documentation of treatment history, continuous enrollment for ≥6-mos before 1^st claim with MM diagnosis was required. Outcomes assessed included Txs received, time to next Tx (TTNT), % with 2^nd primary malignancy (SPM), healthcare resource use (HRU), and costs. Results: 500 TCE and 217 PE pts were identified including 228 TCR and 142 PE-TCR. Mean age across groups was 62-63 y; 39-42% were female, 39% (TCR) to 46% (PE) had prior autologous stem cell transplant; mean number of prior LOTs ranged from 3.3 (TCE and TCR) to 4.3 (PE); 5.7% (TCR) to 8.8% (PE) had extramedullary disease at index. The no. of new TCE pts increased by ̃6X from 25 in 2016 to 145 in 2020; similar increases were seen for TCR, PE, and PE-TCR. Mean post-index follow-up (mos) was 11.6 for TCE, 11.7 for TCR, 10.7 for PE, and 10.3 for PE-TCR. There was no standard Tx across cohorts; the most frequent index LOT regimens were pomalidomide (POM)+daratumumab (11% TCE), POM+carfilzomib (15% TCR), and POM+elotuzumab (7% PE and 9% PE-TCR). Kaplan-Meier median TTNT was short, ranging from 6.5 (TCR) to 11.0 mos. (TCE). TCE pts had high HRU with mean of 0.13 emergency department visit, 3.5 office/outpatient visits, 7.6 prescriptions, 0.21 hospitalizations, and 1.7 days in hospital per month. Mean monthly all-cause healthcare costs (2021 $US) for TCE pts were $31,127, including $18,033 (58%) for MM medications and $8,728 (28%) for other MM-related care. Monthly HRU and costs for TCR, PE, and PE-TCR pts were similar. In TCE pts with no SPM before index date (N = 291), 29 (10%) developed SPM post-index. Conclusions: Despite increasing numbers of TCE, TCR, PE, and PE-TCR pts, there is no apparent standard Tx. With current Tx, TTNT is short, HRU and costs are high, and risk of SPM is 10% (TCE). These data underscore the unmet need for new therapies in this growing population.