Buadi, Francis K.

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

Abstract Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6–0.9) years for secondary EMM and 3.6 (95%CI: 2.4–5.6) years for de novo EMM. The median progression‐free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4–3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7–18 months) for de novo EMM. Patients with secondary EMM treated with CAR‐T therapy ( n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months‐not reached; NR). Patients with EMM treated with bispecific antibodies ( n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months‐NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t (4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6–5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1–2], p = .001).

AbstractIn this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

e20032 Background: The introduction of anti-CD38 antibodies (daratumumab) in the treatment landscape of multiple myeloma (MM) has increased the progression-free survival (PFS) in recent years. Still, the ideal combination (Dara-IMiD vs. Dara-PI) of these drugs in patients with relapsed MM is unclear. Methods: We reviewed MM patients treated with daratumumab as second-line therapy at our institution from 2016 to 2022 to assess the outcomes with the different combination therapies. We used the Kaplan-Meier method to estimate PFS from the first relapse. Results: We identified 329 patients with a median age of 63.6 years (range: 27.1 – 90.4). Most of the patients received triplet induction therapy (95%) and upfront transplant (67%) as primary therapy. At the time of Dara initiation, 41% were refractory to IMiDs, 22% to PIs, 18% to both, and 18% to neither drug. Patients treated with Dara-IMiD had significantly better PFS than Dara-PI (28.7 months vs. 18.5 months, p < 0.01, respectively). In a subgroup analysis based on the FISH results, high-risk patients had similar PFS outcomes (24.3 vs. 10.2 months, p = NS, respectively), while standard-risk patients benefited significantly from the Dara-IMiD regimen (48.3 vs. 19.2 months, p < 0.01, respectively). Among patients treated with Dara-IMiD, those already refractory to IMiDs from the first line had significantly shorter PFS than those without IMiD resistance (14.9 vs. 43.3 months, p < 0.01, respectively). In addition, the lenalidomide-based combination resulted in significantly better PFS compared to pomalidomide in our cohort (40.5 vs. 19.2 months, p < 0.01, respectively). However, no difference was found in the IMiD refractory population (12.3 vs. 15.1 months, respectively). Finally, no significant differences were seen between Dara-IMiD and Dara-PI in patients only refractory to IMiDs (16.1 vs. 12.8 months, p = NS, respectively). Conclusions: While further studies are required to adjudicate the best combination, we conclude that Dara-IMiD might be more effective in patients with relapsed MM, especially for patients not refractory to IMiD at first line. [Table: see text]

e20011 Background: Drug refractoriness is an important factor determining choice of next therapy and prognosis in multiple myeloma (MM). It is debatable whether refractoriness to a drug varies among patients (pts) with MM progressing on different administration schedules of the drug. Outcomes of MM pts refractory to different doses of lenalidomide have been previously described, but similar data about proteasome inhibitors (PIs) are limited. In this study, we assessed the impact of refractoriness to different schedules of bortezomib (V) on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts at our center diagnosed between January 2004 and December 2018, who progressed on/ after receiving first line therapy with V containing regimens. At first relapse, we divided pts into 3 groups- MM progressing on or within 60 days of receiving (1) 1-1.3 mg/m2 V once weekly or more frequently (Standard Dose Refractory), (2) 1-1.3 mg/m2 V once every 2 weeks or less frequently (Low Dose Refractory), and (3) MM progressing at least 60 days after stopping V (Not Refractory). In addition to V, we classified pts as being refractory to cyclophosphamide and immunomodulatory drugs (IMiDs) at first relapse. We classified salvage regimens into daratumumab (Dara), PI, IMiD, PI+IMiD, and VDTPACE like regimens. We then assessed progression free survival (PFS) and overall survival (OS) for next line therapy, and for next V containing therapy using Kaplan Meier and Cox models. Results: A total of 302 pts were included. Median age at diagnosis was 62 years and 60% pts were male. Overall, 23%, 31%, and 27% were International Staging System (ISS) stage I, II, and III respectively; 40% had high risk FISH as per mSMART. Of the 302 pts, 134 (44%) pts received another V containing regimen after the first line therapy at any time during the disease course. Using a multivariable Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, duration of first line therapy, and treatment received at relapse, the Not Refractory Group had a better PFS for both 2nd line therapy and the next V containing line of therapy, while no significant differences were seen between the Standard Dose Refractory and Low Dose Refractory groups. OS differences followed the same trend but were not statistically significant (Table). Conclusions: On multivariable analysis, the PFS did not differ among standard dose vs low dose refractory pts, and both were significantly inferior to pts not refractory to V. These data suggest that refractoriness to V might not be a dose dependent phenomenon. [Table: see text]