Evolving Treatment Strategies in Relapsed/Refractory Multiple Myeloma

During a Training Academy hosted by CancerNetwork®, a panel of experts gathered to discuss patient identification, emerging clinical data, and case-based sequencing considerations for BCMA-directed bispecific antibodies in early-relapse multiple myeloma.

The panel was moderated by Binod Dhakal, MD, a professor of medicine at the Medical College of Wisconsin, and a hematologist at the Clinical Cancer Center at Froedtert Hospital in Milwaukee, Wisconsin. He was joined by Carol Ann Huff, MD, an associate professor of oncology and medicine at Johns Hopkins University School of Medicine, and medical director for the Johns Hopkins Kimmel Cancer Center, and Prerna Mewawalla, MD, an associate professor of medicine at Drexel University College of Medicine and director of the Stem Cell Transplant and Cellular Therapy Program at Allegheny Health Network.

Here are their key takeaways:

Defining Exposure vs Refractoriness at Second Line

• With 70% to 80% of patients exposed to anti-CD38 treatment by second line, distinguishing exposure from true refractoriness is central to treatment selection.
  • Exposure reflects treatment history; refractoriness reflects disease behavior.
  • A practical definition: a patient currently on daratumumab (Darzalex), or within 60 days of their last dose, is considered refractory; beyond 60 days, they are considered exposed but not refractory.
  • Patients who are anti-CD38 exposed but not refractory remain candidates for a daratumumab-containing regimen in the next line; those who are refractory generally should not receive another daratumumab backbone.
• Shorter remission durations and high-risk features favor a more aggressive second-line approach; longer remissions with lenalidomide (Revlimid) maintenance alone, without anti-CD38 refractoriness, open up anti-CD38 combination options.
• Patients relapsing within roughly 2.5 to 3 years of stem cell transplant should be prioritized for cellular therapy when eligible, based on trial data showing superiority of BCMA-based approaches over standard-of-care regimens in 1 to 3 prior lines of therapy.

Choosing Between CAR T-Cell Therapy and Bispecific Antibodies

• Selection is not one-size-fits-all; the panel emphasized shared decision-making that weighs several factors together rather than any single rule.
  • Disease aggressiveness and pace of progression: rapidly progressing disease or extramedullary disease may not allow time for CAR T-cell manufacturing, favoring a bispecific.
  • Patient fitness and eligibility: age alone should not exclude CAR T candidacy, but comorbidities and frailty matter.
  • Access and logistics: patients unwilling or unable to travel and remain near a treatment center for CAR T manufacturing and infusion often prefer a bispecific.
  • Toxicity profile: CAR T carries a higher risk of higher-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome than bispecifics, which some patients weigh heavily.
• Retrospective data suggest CAR T-cell therapy followed by a BCMA-directed bispecific yields better outcomes than the reverse sequence, since prior bispecific exposure may blunt subsequent CAR T efficacy.
• For patients who are candidates for CAR T but require bridging therapy, the panel emphasized collecting T cells before introducing a bispecific whenever possible, even if that means giving only a single bridging cycle first.

Patient Case 1: Standard-Risk Disease With an Early, Aggressive Relapse

A 60-year-old patient with standard-risk cytogenetics received daratumumab-based quadruplet induction, autologous stem cell transplant, and lenalidomide maintenance, then relapsed 30 months post-transplant. Anti-CD38 refractory status was unclear, and the patient was CAR T eligible.

• The panel would first confirm the maintenance regimen and time since last daratumumab exposure; based on the timeline described, this patient was more likely anti-CD38 exposed than refractory.
• Despite standard-risk cytogenetics, a 30-month remission after quadruplet induction and transplant was considered a short duration bordering on functional high-risk disease, favoring CAR T-cell therapy as the preferred next line in a fit, 60-year-old patient.
• Teclistamab (Tecvayli) plus daratumumab was considered a reasonable alternative with similarly high expected response rates, and would be favored if the patient were older or otherwise not a strong CAR T candidate.
• If this patient was rapidly progressing, with a doubling M-spike, circulating plasma cells, or high light chains, the panel would forgo attempting to collect T cells and proceed directly to teclistamab plus daratumumab rather than risk an incomplete bridging strategy.

Patient Case 2: An Older Patient With Comorbidities

A 74-year-old man with multiple comorbidities, including cardiovascular disease and mild renal impairment, received daratumumab-based frontline therapy and relapsed 18 to 24 months later. He was lenalidomide-refractory and anti-CD38 exposed, and was not considered an ideal CAR T candidate.

• The panel noted that age alone does not automatically exclude CAR T candidacy; overall fitness matters more than chronological age.
• Because this patient was not anti-CD38 refractory, teclistamab plus daratumumab remained a preferred bispecific-based option.
• Expanding outpatient step-up dosing capability, including to infusion sites farther from the main academic center, was identified as key to making bispecific therapy accessible to patients like this one who live outside a major metropolitan area.
• Extending bispecific access to community sites not formally affiliated with an academic center remains a gap; the panel suggested partnering with community practices, including performing step-up dosing centrally before transitioning maintenance dosing to a local site.