A Phase 2 Study of Daratumumab in Combination with Dose-Attenuated Bortezomib, Lenalidomide, and Dexamethasone in Transplant Ineligible Older Adults with Newly Diagnosed Multiple Myeloma
Authors: Sanchez Larysa J , Moshier Erin , Lieberman-Cribbin Alex , Richter Joshua , Richard Shambavi , Rossi Adriana , Rodriguez Cesar , Thibaud Santiago , Cho Hearn Jay , Parekh Samir , Jagannath Sundar , Chari Ajai 
Published: December 2024

Background: Daratumumab (dara), an anti-CD38 mAb, is approved in combination with standard of care regimens for both SCT eligible and ineligible newly diagnosed multiple myeloma (NDMM) pts. The phase 3 MAIA study showed that dara + lenalidomide and dexamethasone (Dara-Rd) vs Rd significantly improved PFS in SCT ineligible NDMM pts. In the phase 3 IMROZ study, the addition of isatuximab, an anti-CD38 mAb, to bortezomib-Rd (VRd) in SCT ineligible NDMM pts also significantly reduced risk of progression or death vs VRd. These data support the use of front-line anti-CD38 mAb based combination regimens in SCT ineligible NDMM. Of note, dosing regimens in these trials included full dose R and dex and twice weekly V, which can be difficult to tolerate in older, frail adults. No data are available on the addition of dara to dose-attenuated VRd in SCT ineligible older adults with NDMM.
Methods: This is an ongoing single center, phase 2 study of dara + dose-attenuated VRd in SCT ineligible older adults (age ≥ 70) with NDMM by standard criteria (NCT04052880). Pts received an initial twelve 28-day cycles of dara-VRd as follows: dara 1800mg SC QW C1-2, Q2W C3-6, and Q4W thereafter, V 1.3mg/m2 SC D1, 8, 15, R 15mg PO D1-21 (for pts with CrCl 30-60 and 15-30 mL/min, R reduced to 10mg and 5mg, respectively), and dex 20mg QW. After 12 cycles of initial therapy, pts received maintenance with 28-day cycles of dara + R or dara + ixazomib only in pts with t(4;14). Therapy was continued until progression or unacceptable toxicity. Maintenance dara was discontinued after 2 years, however, if it was deemed that a pt would continue to derive clinical benefit from dara, pt could be taken off study to receive standard of care combination maintenance therapy with dara. The primary endpoint was ≥ VGPR rate. Key secondary endpoints were ≥ CR rate, MRD- (10-5 or 10-6 by flow/NGS) rate, PFS, OS, and predictive value of frailty assessments on outcomes. Adverse events (AEs) were graded with NCI CTCAE v5.0. Here we report an interim analysis after median follow-up of 43.5 mos.
Results: As of July 30, 2024, 15 pts have been enrolled. Median age was 77.3 y (70.4-87.3), 53.3% were male, 60% ECOG 1, 60% White, 57.1% r-ISS stage II, 28.5% had high risk FISH (defined by t4;14, t14;16, or del17p). 71.4% of pts had IMWG frailty score of ≥ 2 and 57.1% had a gait speed &lt;1 m/s, with 26.7% having a gait speed of &lt;0.8 m/s. Of 14 response evaluable pts, 85.7% (12/14) achieved ≥ VGPR, with 50% achieving ≥ CR. Median time to best response was 6.2 mos [2.3-14.7]. Of the 7 pts in ≥ CR, 4 achieved MRD-. Median time on study was 32.2 mos (1.1- 37.7), with median PFS and DOR not reached. The 24 mo PFS and DOR probability [95% CI] was 0.89 [0.71-1.00] and 0.86 [0.63-1.00], respectively. In 8 pts who completed 12 initial cycles, 2 years of maintenance, then continued on dara-based maintenance therapy off study, median PFS has not been reached, with 48 mo PFS probability 0.71 [0.43-1.00]. Median OS has not been reached (36 mo OS probability 0.91 [0.75-1.00]). The most common (occurring in ≥ 15% of pts) G3/4 TEAEs were lymphopenia (42.8%), neutropenia (28.5%). 14% had G3 infection (PNA and UTI). G1/2 infections occurred in 35.7% of pts. 35.7% developed G1 and 14.2% G2 peripheral neuropathy, 14% developed G2 DVT. 64% (9/14) pts had a dose reduction in 1 or more drugs due to AE, with 6 pts having a reduction in R, 5 in dex, and 1 in V. Two pts had a drug discontinuation due to AE (both R). No pts discontinued study due to AEs. There were no deaths. Among 10 pts with frailty score ≥ 2, 70% had dose reductions while among 3 pts with frailty score &lt;2, 0% had dose reductions (p=0.0699). The probability of CR within 12 mos of therapy was 13% vs 60% for pts with &lt;1m/s vs &gt;1m/s gait speed, respectively (log rank p-value=0.1293). The 12 mo CR rate in frail pts (score ≥2) was 25% vs. 67% in non-frail pts (score &lt;2). Overall, the time to achieving CR was significantly shorter in non-frail vs. frail pts (log rank p-value=0.0348).
Conclusions: In this frail, older adult transplant ineligible NDMM population, dara + dose-attenuated VRd was well-tolerated without compromise in efficacy. Although trends were noted, the predictive value of frailty assessments on outcomes was limited due to small sample size. Larger trials are warranted to further characterize the risk/benefit profiles of current treatment regimens and to define the predictive value of frailty assessments in this pt population.
Acknowledgments:This study was funded by Janssen Research & Development, LLC.