Second Line Treatment in Patients with Multiple Myeloma Progressing after Bortezomib, Lenalidomide, Dexamethasone Induction, Autologous Transplant and Lenalidomide Maintenance
Authors: Pasvolsky Oren , Milton Denái R. , Tanner Mark R. , Bashir Qaiser , Srour Samer A. , Saini Neeraj Y. , Lin Paul , Siddiqui Umer R. , Khan Hina N. , Ramdial Jeremy , Nieto Yago , Tang Guilin , Lakhani Kiran , Aljawai Yosra M. , Kebriaei Partow , Lee Hans C. , Patel Krina K. , Thomas Sheeba K. , Orlowski Robert Z. , Shpall Elizabeth J. , Champlin Richard E. , Qazilbash Muzaffar H. 
Published: December 2024

Background: For patients with newly-diagnosed multiple myeloma (MM), induction therapy with bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous hematopoietic stem cell transplantation (autoHCT) and single-agent lenalidomide (Len) maintenance is one of the most commonly-used standard of care therapy sequences for transplant-eligible MM patients. There are scarce data on outcomes after second line (2L) treatment following the first progression in this setting.
Methods: This retrospective single-center study included adult MM patients with first progression after receiving VRD induction, upfront autoHCT between 2005-2021, and single-agent Len maintenance. Primary outcome was second progression-free survival (PFS2), computed from the date of start of 2L regimen to the date of second disease progression or death (if died without second disease progression) or the last follow-up date. Secondary outcomes included overall survival (OS) and response rates. First progression-free survival (PFS1) was computed from the date of autoHCT to date of first disease progression. High-risk cytogenetics were defined as del17p, t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization.
Results: A total of 146 patients were included in the study, with a median age of 60 years (range 32-80). Twenty seven percent (n=39) of the cohort had high-risk cytogenetic abnormalities, and the majority of patients had either revised international staging system (R-ISS) stage I (n=42,29%) or stage II (n=53, 36%) disease. Single-agent melphalan was used for conditioning for most patients (n=129, 88%). After induction and prior to transplant, 85 (58%) patients achieved ≥ very good partial response (VGPR), whereas 57 (39%) patients had a partial response (PR) and four (3%) patients had stable disease (SD).
Median PFS1 was 27.5 months (95% CI 24.3-32.9). At first post-transplant progression, 31% (n=45) received an immunomodulatory agent (IMiD)+ proteosome inhibitor (PI) - containing triplet as a 2L regimen, 24% (n=35) received a daratumumab (Dara)-based regimen (33/35 triplet regimen with IMID/PI and dexamethasone) and 21% (n=30) received IMiD/PI - containing doublet. Patients who received Dara-based 2L regimens had higher rates of ≥ VGPR (63%) at best response, compared to those who received other regimens: IMiD+PI - containing triplet (35%), IMiD/PI - containing doublet (34%) (p=0.001).
After a median follow-up of 35.8 months (range 0.6-139.2) from the first progression, median PFS2 and OS of the entire cohort were 12.4 months (95% CI 10.2-16.9) and 52.6 months (95% CI 45.0-86.3), respectively. For patients who received Dara-based 2L regimens, the median PFS2 was 59.9 months (95% CI 12.4 - not reached), and for those who received IMID+PI doublet or triplet 2L regimens the median PFS2 was 12.3 months (95% CI 5.5-34.3) and 11.5 (95% CI 6.7-19.3), respectively (p=0.001). The type of 2L regimen did not significantly impact OS.
In multivariable analysis, use of Dara-containing 2L regimens was associated with better PFS2 (HR [95% CI] 0.35 [0.20-0.61]; p&lt;0.001), whereas having clinical (vs. biochemical) first progression was associated with worse PFS2 (HR [95% CI] 1.58 [1.06-2.37]; p=0.026).
Progression after ≥ 12 months from autoHCT (vs. &lt;12 months) was associated with better OS in multivariable analysis (HR [95% CI] 0.23 [0.11-0.46]; p&lt;0.001). Use of busulfan+melphalan -based conditioning (HR [95% CI] 4.06 [1.87-8.81]; p&lt;0.001) and having clinical (vs. biochemical) first progression (HR [95% CI] 1.99 [1.22-3.25]; p=0.006) were associated with worse OS.
Conclusions: In a real-world cohort of patients who received VRD induction, upfront autoHCT followed by single-agent Len maintenance, and then had first progression, median PFS2 was approximately 12 months and median OS was &lt; 4.5 years. Patients receiving a Dara-based 2L regimens had a better PFS2 that lasted almost 5 years.