Multiple Myeloma Treatment in 2026: From Chemotherapy to CAR-T

Research-informed explainer — last updated April 12, 2026

Multiple myeloma was once a disease where most patients survived fewer than three years; today, median survival for newly diagnosed patients exceeds ten years in many centers, a transformation driven by a succession of novel drug classes introduced over the past 25 years. The treatment landscape has evolved from steroids and alkylating agents to a layered approach combining proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and — most recently — BCMA-targeted CAR-T cells and bispecific antibodies.

This article draws on the research of five specialist physicians whose published work documented and enabled this evolution. Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, authored the preclinical work that launched the proteasome inhibitor era and led trials of daratumumab-based combinations that now define first-line care. Edward Stadtmauer, MD, Director of Hematologic Malignancies Clinical and Translational Research at the University of Pennsylvania's Abramson Cancer Center, led the APEX trial comparing bortezomib to dexamethasone and the landmark lenalidomide maintenance trial after transplant. David Dingli, MD, Professor of Medicine in the Division of Hematology at Mayo Clinic, documented the population-level survival improvements in myeloma in two widely cited studies spanning 2007 to 2013. Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, led the pivotal bb2121 (ide-cel) BCMA CAR-T trial. Ajay Nooka, MD, MPH, at Emory's Winship Cancer Institute, published the daratumumab-bortezomib-dexamethasone triplet trial and more recent teclistamab bispecific antibody data.

How the modern treatment era began: proteasome inhibitors

The foundational insight was that myeloma cells — which are plasma cells producing abnormal proteins at high volume — are unusually dependent on the proteasome, the cellular machinery that degrades misfolded proteins. Disrupting the proteasome causes toxic protein accumulation specifically in these cells. Dr. Richardson's 2001 preclinical paper in Cancer Research (1,529 citations) demonstrated that bortezomib (PS-341) inhibited myeloma cell growth, induced apoptosis, and overcame resistance to conventional chemotherapy in laboratory models. That work directly led to clinical development.

The APEX trial, co-led by Dr. Stadtmauer and published in the New England Journal of Medicine in 2005 (2,489 citations), enrolled 669 patients with relapsed myeloma and showed that bortezomib produced a response rate of 38% versus 18% for high-dose dexamethasone, with a significant survival advantage. Bortezomib became standard of care, and the proteasome inhibitor class eventually expanded to include carfilzomib and ixazomib.

Immunomodulatory drugs: thalidomide, lenalidomide, pomalidomide

Thalidomide — infamously withdrawn in the 1960s for teratogenicity — was repurposed as an antimyeloma agent in the late 1990s. Its analogue lenalidomide offered improved efficacy and tolerability. The 2007 trial published by Dr. Stadtmauer's group in the New England Journal of Medicine (1,235 citations) established lenalidomide plus dexamethasone as an effective regimen for relapsed myeloma. A subsequent randomized trial that Dr. Stadtmauer contributed to, published in 2012 in the New England Journal of Medicine (1,139 citations), demonstrated that lenalidomide maintenance after autologous stem cell transplant significantly prolonged progression-free survival — evidence that shifted practice toward indefinite maintenance therapy.

Daratumumab: the anti-CD38 antibody that changed first-line care

Daratumumab targets CD38, a protein abundantly expressed on myeloma cells. It was first approved as monotherapy for heavily pretreated patients, then rapidly incorporated into combination regimens. Dr. Richardson contributed to the MAIA trial (1,421 citations) comparing daratumumab plus lenalidomide-dexamethasone to lenalidomide-dexamethasone alone in newly diagnosed patients ineligible for transplant — daratumumab-containing therapy produced a significantly longer progression-free survival. Dr. Nooka's group published on the CASTOR trial (1,500 citations) establishing daratumumab plus bortezomib-dexamethasone as an effective relapsed regimen.

Dr. Raje contributed to the trial establishing daratumumab plus lenalidomide-dexamethasone for untreated myeloma (970 citations), and together these studies cemented daratumumab-based quadruplet regimens as the standard first-line approach for most newly diagnosed patients.

Documenting the survival benefit

Dr. Dingli and colleagues at Mayo Clinic quantified what these successive drug approvals meant for patients. A 2007 paper in Blood (2,238 citations) analyzing 387 patients who relapsed after stem cell transplantation found that those relapsing after 2000 had a median overall survival of 23.9 months versus 11.8 months for those relapsing before 2000 — a doubling of post-relapse survival coinciding exactly with the introduction of novel agents. A 2013 follow-up paper in Leukemia (1,381 citations) confirmed continued improvement, particularly in early mortality and outcomes for older patients.

BCMA-targeted therapies: CAR-T and bispecific antibodies

B-cell maturation antigen (BCMA) is expressed on virtually all myeloma cells but not on most normal tissues, making it an ideal target for precision therapies. Dr. Raje contributed to the bb2121 (idecabtagene vicleucel, ide-cel) trial published in the New England Journal of Medicine in 2019 (1,690 citations). In 128 heavily pretreated patients with a median of six prior lines of therapy, the overall response rate was 73% and the complete response rate was 33% — remarkable results in a population where median prior regimens had included proteasome inhibitors, IMiDs, and daratumumab.

The 2023 KarMMa-3 trial published in the New England Journal of Medicine (647 citations), to which Dr. Nooka contributed, randomized patients with relapsed myeloma to ide-cel versus standard regimens. Ide-cel produced a median progression-free survival of 13.8 months versus 4.4 months — the clearest demonstration yet that CAR-T outperforms conventional regimens in relapsed disease.

Dr. Nooka also contributed to the teclistamab trial (1,022 citations, 2022), which evaluated a bispecific T-cell engager antibody targeting BCMA and CD3. In 165 patients with heavily pretreated myeloma, the overall response rate was 63%, including 39% complete responses — without the manufacturing delay and logistics of CAR-T, since bispecific antibodies are off-the-shelf.

Questions to ask your doctor

• Am I a candidate for autologous stem cell transplant as part of my initial treatment?
• Should my first-line regimen include a daratumumab-based quadruplet, and which one fits my disease risk and health status?
• If I relapse after standard therapy, at what point would I be evaluated for BCMA-targeted CAR-T or a bispecific antibody?
• What genetic or cytogenetic features of my myeloma affect my prognosis and treatment selection (17p deletion, t(4;14), t(14;16))?
• How long should I continue lenalidomide maintenance after transplant, and what monitoring is required?
• Are there clinical trials currently enrolling for patients at my disease stage?

The bottom line

Multiple myeloma treatment has undergone a generational transformation, with median survival more than tripling over 25 years. The modern first-line standard — typically a four-drug regimen including a proteasome inhibitor, an IMiD, daratumumab, and dexamethasone — reflects decades of iterative clinical trial work. For patients who relapse, BCMA-targeted CAR-T cell therapy and bispecific antibodies now offer response rates that previously seemed unachievable. Working with a myeloma specialist at a center experienced in all available modalities is the most reliable path to optimal sequencing.