Multiple myeloma has changed enough over the past decade that many of its clinical boundaries are becoming less rigid. Diagnosis no longer always waits for organ damage. Cytogenetic risk is read through combinations of abnormalities, not isolated markers. Treatments once reserved for heavily pretreated disease are moving into earlier lines. And even the way treatment success is measured is changing.
Minimal residual disease can detect responses far deeper than conventional complete remission, and in 2026, MRD-negative complete response entered regulatory decision-making, supporting the FDA’s accelerated approval of an iberdomide-based regimen in relapsed multiple myeloma.
These advances have also made treatment decisions more complex. Multiple myeloma can follow very different courses, developing through precursor states and ranging from indolent disease to aggressive presentations such as plasma cell leukemia and extramedullary disease. Management therefore begins before a regimen is selected.
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Before Active Multiple Myeloma
Multiple myeloma accounts for approximately 10% of hematologic malignancies and primarily affects older adults, with a median age at diagnosis of 65 years. More than 36,000 new cases are diagnosed annually in the US, with higher incidence in men.
Almost all multiple myeloma develops from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic precursor state found in ~5% of people older than 50 years. MGUS progresses to multiple myeloma or a related malignancy at an average rate of about 1% per year. More than half of people diagnosed with MGUS are estimated to have already carried it for over a decade.
Some patients pass through a clinically recognizable intermediate stage, smoldering multiple myeloma (SMM), whose behavior is considerably more variable. The average risk of progression is approximately 10% per year during the first 5 years after diagnosis, falling to around 3% annually over the next 5 years and 1.5% per year thereafter.
Disease burden is only part of that risk, cytogenetic abnormalities identify precursor disease with greater potential for progression. The boundary between these states is increasingly based on risk of impending injury.
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Diagnosing Multiple Myeloma Before Organ Damage Occurs
The diagnosis of multiple myeloma requires at least 10% clonal plasma cells in the bone marrow, or a biopsy-proven plasmacytoma, together with at least one myeloma-defining event.
The classic myeloma-defining events remain the CRAB manifestations: hypercalcemia, renal impairment, anemia, and osteolytic bone disease attributable to the plasma-cell disorder. Current International Myeloma Working Group criteria also recognize 3 biomarkers capable of defining active MM before CRAB-related damage occurs:
- clonal bone marrow plasma cells ≥60%
- an involved-to-uninvolved serum free light-chain ratio ≥100, with an involved free light-chain concentration ≥100 mg/L and the required monoclonal protein criteria
- more than one focal lesion on MRI, each at least 5 mm
This distinction matters most when separating active myeloma from SMM, where patients may carry a substantial monoclonal protein burden or 10%-60% clonal bone marrow plasma cells but no myeloma-defining event or amyloidosis. The main consideration is whether the disease has reached the point where treatment is indicated.
The Modern Myeloma Workup
When multiple myeloma is suspected, serum protein electrophoresis, serum immunofixation, and serum free light-chain testing remain central to detecting and characterizing the monoclonal protein. Mass spectrometry is emerging as a more sensitive and specific alternative. A negative monoclonal protein evaluation doesn’t fully exclude myeloma, about 2% of patients have true non-secretory disease.
Bone marrow assessment serves a second purpose beyond confirming plasma-cell infiltration. At diagnosis, FISH or appropriate sequencing should screen for t(11;14), t(4;14), t(14;16), t(6;14), t(14;20), trisomies, del(17p), del(1p), and gain(1q), establishing the molecular context needed for prognosis and, increasingly, treatment planning.
Low-dose whole-body CT and PET/CT are more sensitive for defining osteolytic disease, while MRI is particularly useful when SMM is suspected, since focal marrow lesions can appear before overt cortical destruction. MRI also remains important for suspected cord compression, extramedullary disease, or detailed assessment of a symptomatic region.
One distinctive feature of myeloma bone disease is worth remembering: unlike many solid tumors that metastasize to bone, myeloma osteolytic lesions characteristically show little or no new bone formation, a major source of ongoing morbidity.
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Risk Stratification: Moving Beyond a Single Label
Contemporary studies suggest median survival exceeding 10 years in transplant-eligible patients, with 4-year survival above 90%. In patients older than 65, median survival is ~7-8 years, with 5-year survival exceeding 70%. Even these figures may lag current outcomes, since much of the survival data predates the widespread use of highly active immunotherapies. Still, an average survival number is increasingly unhelpful for an individual patient.
Prognosis reflects several interacting dimensions: patient characteristics, tumor burden, cytogenetic features, and depth of response to therapy. Modern risk stratification tries to separate how much disease is present from how aggressive it’s likely to be.
The current International Myeloma Society/International Myeloma Working Group definition identifies several cytogenetic patterns associated with high-risk disease: del(17p) and/or TP53 mutation, biallelic del(1p), gain(1q) combined with del(1p), and high-risk IgH translocations such as t(4;14), t(14;16), or t(14;20) when accompanied by gain(1q) or del(1p).
The emphasis on combinations matters, an abnormality that historically carried a poor prognosis in isolation may not carry the same weight alongside others. This is one reason broad categories like “standard risk” and “high risk” are becoming less satisfactory as treatment improves.
The Mayo mSMART framework adds clinically aggressive features such as plasma cell leukemia, extramedullary disease, and a high S-phase fraction, and recognizes “double-hit” disease when multiple high-risk features coexist.
There’s an important paradox here: some patients classified as high risk can achieve outcomes approaching those of standard-risk patients when treated appropriately. Prognosis, in other words, is partly treatment-dependent.
Response Is Becoming Part of Risk Assessment
MRD testing has become increasingly important, since two patients can both meet criteria for complete response while harboring very different amounts of disease detectable by highly sensitive assays.
It may eventually help guide treatment intensity and duration, and identify patients with prolonged treatment-free MRD negativity who may be functionally cured. Those questions remain unsettled, randomized evidence is still needed.
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Newly Diagnosed Multiple Myeloma: Quadruplets at the Front
Frontline therapy for newly diagnosed myeloma now rests on two variables set before treatment starts: transplant eligibility and disease risk. Anti-CD38-based quadruplets are increasingly used in both groups, with frailty playing a greater role in determining treatment intensity than age or transplant status alone.
PERSEUS established this for daratumumab. Dara-VRd produced higher overall response (97% vs. 94%) than VRd alone, but the more telling result was 4-year PFS: 84% vs. 68%. Overall survival at this follow-up was similar between arms, around 90%.
The benefit of the quadruplet isn’t response rate, it’s depth and durability. That’s why quadruplet therapy is now standard for transplant-eligible patients, with the aim of suppressing the initial clone as deeply as possible, before and after transplant.
IMROZ shows the same pattern with isatuximab. Isa-VRd improved 5-year PFS from 45% (VRd) to 63% of patients. Five-year OS was 72% vs. 66%, though this difference wasn’t statistically significant at this analysis. The choice between Dara-VRd and Isa-VRd comes down to access, administration, and local practice, since both are considered appropriate options.
Not Every Four-Drug Regimen Is Automatically Better
The BENEFIT trial is useful because it prevents the discussion from becoming “more drugs must always be better.” In older patients, Isa-VRd produced somewhat higher response depth than Isa-Rd, but estimated 2-year PFS was 85% vs. 80%, not a statistically significant difference at this analysis.
Many patients labeled transplant-ineligible in European trials because they’re 65-70 years old would still be considered transplant candidates in the US. Fit older adults may tolerate and benefit from quadruplet therapy, frail patients may gain more from a less intensive regimen they can actually sustain.
The recommendation is: Dara-VRd or Isa-VRd for non-frail patients regardless of whether transplant is immediately planned, with DRd or Isa-Rd reserved as important options for frailer patients.
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Does Everyone Still Need Early Transplant?
In IFM 2009, early ASCT improved median progression-free survival from 36 to 50 months. Yet at 8 years, overall survival was 60% with delayed transplant and 62% with early transplant.
The US DETERMINATION trial reached the same broad conclusion under prolonged lenalidomide maintenance. Median progression-free survival increased from 46 months without immediate transplant to 68 months with early ASCT, but 5-year overall survival was virtually identical: 79% vs. 81%.
Early ASCT provides a longer first remission. What the trials haven’t demonstrated is that every standard-risk patient lives longer by receiving it immediately. Effective salvage therapy now means some patients can preserve stem cells after induction and defer ASCT until relapse without clearly compromising overall survival.
High-risk disease is different, 3-4 cycles of Dara-VRd or Isa-VRd followed by ASCT and maintenance may be preferred. The BMT-CTN 0702 trial helped narrow what should happen after transplant: additional VRd consolidation didn’t provide a significant benefit over proceeding straight to maintenance, and tandem transplant hasn’t demonstrated a convincing survival advantage in the modern US treatment setting.
Maintenance Therapy: What and How Long?
Lenalidomide has the longest evidence base, with randomized-trial meta-analysis showing improvements in both progression-free and overall survival compared with placebo or observation. High-risk disease may also justify proteasome inhibitor-based maintenance, particularly bortezomib plus lenalidomide, while anti-CD38 antibodies are also entering this setting.
Duration is less settled. In the phase III ENDURANCE trial, indefinite lenalidomide maintenance didn’t improve overall survival over a fixed 2-year course in standard-risk patients who hadn’t undergone upfront ASCT, and was associated with greater toxicity.
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Relapsed Multiple Myeloma: Immunotherapy Moves Earlier
Nearly all myeloma patients relapse, and each successive remission tends to be shorter than the last. Choosing therapy at relapse comes down to TRAP: timing of relapse, response to prior therapy, aggressiveness of disease, and performance status, layered against prior treatment exposure and refractoriness.
CAR-T and bispecific antibodies are now core options at first and second relapse, alongside established triplets. When a triplet is used, at least two of its drugs should be ones the patient isn’t refractory to.
Many lenalidomide-based trials enrolled lenalidomide-naive patients, but today most relapses happen on lenalidomide maintenance, making pomalidomide-based regimens the better choice in that setting. ASCT still has a place at relapse too, for eligible patients who never underwent transplant, or as a second transplant if the first remission lasted at least 36 months with maintenance.
CAR-T in Early Relapse
In KarMMa-3, idecabtagene vicleucel produced a response rate of 71% compared with 42% with standard regimens, and median PFS increased from 4.4 to 13.3 months. The phase III CARTITUDE-4 trial produced even deeper responses with ciltacabtagene autoleucel. Together, these trials changed the positioning of CAR-T, initially developed for heavily pretreated disease, into an early-relapse option.
CAR-T also offers something pharmacologically different from continuous therapy: a single treatment may allow patients to remain off myeloma therapy for prolonged periods. The trade-off is logistics, cell collection, manufacturing, lymphodepletion, and treatment take time, making CAR-T difficult when immediate disease control is needed.
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Bispecific Antibodies Are Challenging Standard Relapse Regimens
The phase III bispecific trials make clear why these agents are moving earlier. In MajesTEC-3, teclistamab plus daratumumab was compared with standard daratumumab-based regimens. At 3 years, PFS was 83.4% vs. 29.7%, and OS was 83.3% vs. 65.0%.
For patients already exposed or refractory to daratumumab, MajesTEC-9 is particularly relevant. Teclistamab monotherapy improved outcomes compared with PVd or Kd, achieving an 84.5% response rate, with 18-month progression-free and overall survival of 69.8% and 79.2%, respectively.
BCMA-directed bispecific therapy is no longer competing only with other experimental immunotherapies, it’s outperforming established relapse regimens in randomized trials.
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MonumenTAL-3 Expands the Target Beyond BCMA
The MonumenTAL-3 trial is equally important because it validates a different target. Talquetamab directs T cells against GPRC5D. In the trial, talquetamab-daratumumab and talquetamab-daratumumab-pomalidomide were compared with DPd.
Both experimental arms produced statistically significant PFS and OS improvements versus DPd. As BCMA CAR-T cells, bispecifics, and antibody-drug conjugates move earlier, preserving a non-BCMA target becomes increasingly valuable for sequencing.
Talquetamab does bring a distinct toxicity profile, including dysgeusia, appetite loss, weight loss, nail abnormalities, and skin toxicity.
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Belantamab Returns Through Combination Therapy
Belantamab mafodotin illustrates how a drug’s fate can change with its schedule and combination partner. Single-agent belantamab was limited by both modest efficacy and keratopathy. In DREAMM-7, belantamab-bortezomib-dexamethasone achieved a median PFS of 37 months, compared with 13 months for daratumumab-bortezomib-dexamethasone.
In DREAMM-8, belantamab-pomalidomide-dexamethasone also improved PFS compared with bortezomib-pomalidomide-dexamethasone, with estimated 1-year PFS of 71% vs. 51%.
The main limitation remains ocular toxicity: keratopathy occurs in the majority of patients at conventional dosing and can interrupt treatment. DREAMM-9 suggests that schedule modification may help manage this toxicity. Longer Q9/12W and Q12W intervals were associated with fewer ophthalmic findings than more intensive schedules (69% vs. 90%), while responses remained high across cohorts.
Sequencing Is Increasingly Central
No randomized trial can yet provide a universal sequence for modern myeloma, because the treatment paradigm is changing faster than long-term studies can mature.
At first relapse, cilta-cel or Tec-Dara are preferred when the patient remains sensitive to anti-CD38 therapy. In anti-CD38-refractory disease, cilta-cel or a BCMA-directed bispecific becomes more attractive. Conventional triplets remain important when cellular therapy or bispecific antibodies are unavailable or unsuitable, but should ideally contain at least two drugs to which the disease isn’t refractory.
At later relapse, prior antigen exposure matters increasingly. A patient treated with BCMA-directed therapy earlier may benefit from a conventional triplet or a GPRC5D-directed approach, when a patient who received standard drug combinations earlier may move toward CAR-T, bispecific antibodies, or belantamab. The effectiveness of BCMA-directed CAR-T after BCMA bispecific exposure, and vice versa, isn’t yet defined.
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Other and Emerging Options
In heavily pretreated disease, options include alkylator-based regimens such as KCd, VDT-PACE for selected patients requiring intensive cytoreduction, and bendamustine-containing combinations.
Several newer immune-directed approaches are in development: etentamig, a BCMA-directed bispecific antibody, cevostamab, which targets FcRH5 and CD3, and ramantamig, a trispecific antibody targeting BCMA, GPRC5D, and CD3. Their eventual place will depend not only on response rates, but on how effectively they work after prior BCMA- or GPRC5D-directed therapy.
The CELMoDs iberdomide and mezigdomide provide another route beyond current immunotherapies. Iberdomide has now moved from an emerging agent to an approved therapy: in August 2026, the FDA granted accelerated approval to iberdomide plus daratumumab and dexamethasone for patients who’ve received at least one prior line containing a proteasome inhibitor and an immunomodulatory agent.
Supportive Care Is Part of Effective Treatment
Bone protection remains fundamental. Zoledronic acid or pamidronate is recommended, while denosumab is particularly useful in patients with significant renal dysfunction. Less frequent bisphosphonate dosing, every 3-4 months, may maintain protection while reducing toxicity.
Herpes zoster prophylaxis with acyclovir or valacyclovir is recommended for patients receiving proteasome inhibitors or anti-CD38 therapy, along with routine intravenous immunoglobulin for patients on bispecific antibodies.
The efficacy of modern immune therapies can’t be separated from their immune consequences. A treatment capable of producing deep remission but accompanied by severe recurrent infection may require altered dosing, prophylaxis, or even treatment interruption.
Smoldering Multiple Myeloma: Rethinking Observation
SMM is clinically heterogeneous. Early intervention was initially difficult to justify because older studies lacked precise risk selection and effective, tolerable therapies. That changed with randomized trials focused specifically on high-risk SMM.
Phase III AQUILA trial provided the strongest evidence for early treatment. In patients with high-risk SMM, daratumumab given for 3 years improved 5-year PFS from 40.8% with active monitoring to 63.1%, supporting its approval in this setting.
An ongoing ECOG randomized trial is testing whether daratumumab-lenalidomide-dexamethasone (DRd) is superior to lenalidomide-dexamethasone, while other studies are evaluating more intensive strategies with curative intent.
(A. Badros, et al., 2025, H. Avet-Loiseau, et al., 2025, B. Puliafito, et al., 2025, S. Lonial, et al., 2025, S. Zanwar, et al., 2026, S. Kumar, et al., 2026, S. V. Rajkumar, et al., 2026.)
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FAQ
What Is New in Multiple Myeloma Treatment in 2026?
Multiple myeloma treatment in 2026 is increasingly defined by immunotherapy moving earlier in the disease course. Anti-CD38 quadruplets have strengthened their role in newly diagnosed disease, while CAR-T cells and bispecific antibodies are being used at earlier relapse. New phase III data from MajesTEC-3, MajesTEC-9, and MonumenTAL-3 are also challenging established relapse regimens, while iberdomide has introduced CELMoDs into the approved treatment landscape.
What New Multiple Myeloma Drugs Were Approved in 2026?
One of the major additions in 2026 was iberdomide, a cereblon E3 ligase modulator (CELMoD). In August 2026, the FDA granted accelerated approval to iberdomide combined with daratumumab and dexamethasone for patients who had received at least one previous line containing a proteasome inhibitor and an immunomodulatory agent.
Does Multiple Myeloma Maintenance Therapy Need to Continue Indefinitely?
Not necessarily. The 2026 ENDURANCE analysis found that indefinite lenalidomide maintenance did not significantly improve overall survival compared with a fixed 2-year course in standard-risk patients who did not undergo upfront transplant, while longer treatment produced greater toxicity. The optimal duration after transplant and in high-risk disease remains less certain.
Are Bispecific Antibodies Moving Earlier in Multiple Myeloma?
Yes. Bispecific antibodies were initially developed for heavily pretreated MM, but randomized trials are rapidly moving them toward earlier relapse. MajesTEC-3 demonstrated a major progression-free survival advantage with teclistamab plus daratumumab, while MajesTEC-9 showed that teclistamab can also outperform established regimens in patients previously exposed to anti-CD38 therapy.
Can MRD Negativity Change How Multiple Myeloma Is Treated?
Potentially. MRD can distinguish patients with very deep responses even when both meet conventional criteria for complete remission. A major goal of ongoing studies is to determine whether sustained MRD negativity can eventually guide treatment duration, maintenance discontinuation, or treatment intensification. For now, MRD-guided treatment decisions remain an evolving area rather than a universal standard.
Could Smoldering Multiple Myeloma Be Treated Before Symptoms Develop?
For selected high-risk patients, this is already becoming possible. The AQUILA trial showed that daratumumab could delay progression in high-risk smoldering MM, changing the traditional assumption that all asymptomatic patients should remain under observation until active disease develops. The challenge now is identifying patients whose risk is high enough to justify early treatment without overtreating those whose disease may remain indolent for years.