Management of Multiple Myeloma: From Newly Diagnosed to Relapsed/Refractory Disease
July 28, 2025
The treatment paradigm for newly diagnosed multiple myeloma (NDMM) is shaped by two key considerations: cytogenetic risk stratification and eligibility for autologous stem cell transplant (ASCT). High-risk multiple myeloma (HRMM) is defined by the presence of del(17p) and/or TP53 mutations, one of these high-risk translocations such as t(4;14), t(14;16), or t(14;20) co-occurring with 1q gain and/or del(1p32), monoallelic del(1p32) with 1q+, biallelic del(1p32), and elevated β2-microglobulin (β2M >5.5 mg/dL) with normal renal function (creatinine <1.2 mg/dL). Patients are then evaluated for transplant eligibility, typically based on age, performance status, and comorbidities.
Tailoring Treatment Based on Transplant Eligibility
For transplant-eligible patients, quadruplet regimens combining a proteasome inhibitor (PI), immunomodulatory drug(IMiD), dexamethasone, and an anti-CD38 monoclonal antibody are emerging as the new standard of care (SoC), surpassing traditional triplet regimens in terms of depth and durability of response.
The ADVANCE trial demonstrated that the addition of daratumumab to KRd (carfilzomib, lenalidomide, dexamethasone) significantly improved minimal residual disease (MRD)negativity (59% vs 36%) and progression-free survival (PFS) at 32.7 months (86% vs 79%) with a comparable safety profile. Similarly, the PERSEUS trial showed improved outcomes with D-VRd (daratumumab, bortezomib, lenalidomide, dexamethasone) compared with VRd: 4-year PFS was 84.3% versus 67.7%, complete response (CR) or better was 87.9% versus 70.1%, and MRD negativity was achieved in 75.2% versus 47.5%. These data position D-KRd and D-VRd as leading frontline options for transplant-eligible patients, especially those with HRMM.
For transplant-ineligible or deferred transplant patients, quadruplet therapy has also demonstrated superiority.
In the CEPHEUS trial, D-VRd outperformed VRd, achieving higher MRD negativity (61% vs 39%) and reducing the risk of progression or death by 43% (PFS 68.1% vs 49.5%).
The IMROZ trial evaluated isatuximab-VRd and found a ~40% reduction in progression or death risk compared with VRd, improved CR rates (74.7% vs 64.1%), and enhanced MRD negativity (55.5% vs 40.9%). In the MAIA trial, D-Rd (daratumumab, lenalidomide, dexamethasone) extended median PFS to 62 months versus 34 months with Rd alone, with improved OS and MRD negativity (32% vs 11%), albeit with a modest increase in toxicity.
MRD-Guided Transplant Strategy: MIDAS Trial
Given the increased ability to achieve MRD negativity, the MIDAS trial questioned the necessity of ASCT in MRD-negative patients following Isa-KRd (isatuximab plus KRd) induction. The study concluded that MRD-negative patients derived no additional benefit from transplant, suggesting MRD-guided treatment deferral may be a future strategy pending survival data.
Novel Therapies in Relapsed/Refractory Multiple Myeloma
Treatment decisions at relapse should be guided by duration of response, refractoriness to previous therapies or drug classes, cumulative toxicities, comorbidities, and performance status.
CAR T-Cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated transformative efficacy in relapsed/refractory multiple myeloma (RRMM). The CARTITUDE-1 trial, a phase 1b/2 study of ciltacabtagene autoleucel (cilta-cel) in patients with three or more prior lines of therapy (PI, IMiD, anti-CD38), reported a median OS of 5 years and a 5-year PFS of ~33%, following a single infusion. CARTITUDE-4 expanded cilta-cel’s use to earlier lines after lenalidomide failure, demonstrating superiority over standard regimens. In KarMMa-3, idecabtagene vicleucel extended median PFS to 13.3 months versus 4.4 months with standard regimens (HR, 0.49), with deeper responses (overall response rate [ORR], 71% vs 42%; CR/sCR, 39% vs 5%).
Bispecific Antibodies
Bispecific antibodies bind to CD3 on T cells and tumor antigens, such as BCMA or GPRC5D, redirecting T cells to kill myeloma cells. Teclistamab (anti-BCMA) was the first FDA-approved bispecific based on data from MajesTEC-1 in RRMM, showing an ORR ~62% in heavily pretreated patients, with durable responses and manageable cytokine release syndrome (CRS). Elranatamab is another anti-BCMA bispecific antibody evaluated in the MagnetisMM-3 trial demonstrating high response rates of ~61% ORR, median PFS of 17.2 months, and median OS of 24.6 months. Talquetamab is a novel bispecific targeting GPRC5D and CD3 that showed ORR ~70% in pretreated patients with RRMM and ORR ~67% after prior BCMA-directed therapy. Distinct toxicities, such as dysgeusia and skin/nail changes, not overlapping with BCMA-based therapies, makes it a strong sequential option.
Current guidance recommends administering CAR-T cell therapy prior to bispecific antibody treatment. Bispecifics are generally considered after 4 prior lines of treatment including CAR Tl, elotuzumab-based regimens, and selinexor.
Emerging Trispecific Antibodies
Emerging T-cell redirecting therapies like JNJ-5322, a next-generation trispecific antibody targeting BCMA and GPRC5D through T-cell engagement, have demonstrated encouraging activity. In a phase 1 open-label dose-escalation and expansion study of heavily pretreated patients with RRMM—including those with prior exposure to BCMA- or GPRC5D-targeted therapies—the recommended phase 2 dose (RP2D) was established as 100 milligrams (mg) subcutaneously every 4 weeks, preceded by a 5 mg step-up dose. Among BCMA/GPRC5D-naïve patients treated at RP2D, the ORR was 100%, with 70.4% achieving CR or better and 96.3% attaining very good partial response or better. The 1-year PFS in this cohort was approximately 95%. CRS occurred in 59% of patients (mostly grade 1–2) and was mitigated by prophylactic tocilizumab; no immune effector cell-associated neurotoxicity syndrome events were reported at RP2D.
An early phase study (NCT05862012) evaluated ISB 2001, a trispecific antibody, in patients with RRMM who were heavily pretreated. Sustained deep responses, including MRD negativity and stringent CR, were seen from 50 μg/kg, with an ORR of 75%. Dose escalation study is ongoing.
Take-Home Points
NDMM SoC: Transitioning to frontline quadruplets (e.g., D-KRd or D-VRd) delivering deeper responses and higher MRD negativity. MRD status may allow for deferred transplant in select patients. OS data is still needed.
RRMM SoC: CAR T-cell therapy (cilta-cel) and BCMA-targeted bispecifics offer powerful, durable remissions; subcutaneous isatuximab combinations provide more convenient regimens. Trispecific antibodies are being evaluated in clinical trials. Current sequencing strategies favor CAR T-cell therapy prior to bispecifics.