Autologous transplant in myeloma: IFM 2009 and DETERMINATION

A 54-year-old nurse was diagnosed with multiple myeloma after months of back pain and anemia. She completed four cycles of induction treatment with lenalidomide, bortezomib and dexamethasone and reached a very good partial response. Now the team proposes collecting stem cells from the blood and giving high-dose chemotherapy with an autologous transplant. She asks why go through this if she is already responding, and whether the transplant will cure her. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is early autologous transplant in multiple myeloma based on the IFM 2009 and DETERMINATION studies, and the question Dr. Alexei proposed for the series: who is a candidate for transplant and how to discuss its early use, toxicities and maintenance? The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you will recognize the challenge: deciding when a more intensive treatment is worth it.

Key points

• The IFM 2009 and DETERMINATION studies compared the same induction treatment with or without high-dose melphalan and early autologous transplant.
• In both, early transplant prolonged progression-free survival.
• In neither was an overall survival benefit demonstrated.
• Transplant increased acute toxicity, mainly neutropenia, infections and gastrointestinal effects.
• Maintenance with lenalidomide after transplant prolonged time to progression and, in CALGB 100104, also survival.
• Autologous transplant does not routinely establish cure in myeloma, and the conversation must make this clear.

Why this is a reasoning scenario

Multiple myeloma is a cancer of the plasma cells in the bone marrow. The Global Burden of Disease study estimated that about 138 thousand people received this diagnosis worldwide in 2016, and noted that stem cell transplant is routine in high-income countries but lacking in parts of Africa and the Middle East (Cowan et al., 2018). Access, therefore, also enters the decision.

Autologous transplant has been part of the standard treatment for eligible patients for more than 30 years, according to a review on the topic (Al Hamed et al., 2019). With the arrival of very effective induction combinations, a legitimate question arose: if induction alone already produces deep responses, is it still worth doing the transplant early, or can it wait for relapse? The post on clinical decision-making helps think through this type of choice.

Different outcomes, different conversations

The studies that answer this question show a benefit in one outcome, time without progression, and no demonstrated benefit in another, overall survival. This pattern requires careful reasoning and an honest conversation with the patient. The post on diagnostic uncertainty works through how to decide when the evidence does not point to a single answer.

What autologous transplant is in myeloma

In autologous transplant, the patient is their own donor. After induction, stem cells are mobilized into the blood with growth factors, sometimes with chemotherapy or plerixafor, collected by apheresis and frozen. Then the patient receives high-dose melphalan, which destroys myeloma cells and also the normal marrow. The frozen cells are then returned through a vein to rebuild the marrow.

The transplant, in this case, is a way to allow a dose of chemotherapy that the marrow could not tolerate on its own. There is no graft-versus-tumor effect, as in allogeneic transplant. The post on differential diagnosis recalls the importance of naming each intervention correctly before discussing its effects.

The steps, in order

• Induction with a combination of drugs, usually for a few months.
• Mobilization and collection of stem cells from the blood by apheresis.
• Freezing and storage of the cells.
• High-dose melphalan, followed by infusion of the cells a few days later.
• Bone marrow recovery, with support and infection prevention.
• Consolidation and maintenance, according to the protocol.

In DETERMINATION, patients in the transplant group resumed the consolidation regimen after recovery, around day 60 after the procedure (Richardson et al., 2022). Explaining this sequence helps the patient understand why the whole process takes months, and not just the days of hospitalization.

Cell collection

Some induction combinations can make collection harder. In the CASSIOPEIA study, for example, plerixafor was used in about 22 of every 100 mobilized patients in the daratumumab group, versus about 8 of every 100 in the group without daratumumab (Hulin et al., 2021). Planning the collection is part of the strategy, even when the transplant will not be done right away.

Who is a candidate

The answer to the first part of Dr. Alexei's question starts with the study criteria. DETERMINATION included adults aged 18 to 65 with newly diagnosed symptomatic myeloma and performance status 0 to 2, and excluded those with inadequate hematologic, hepatic, renal or cardiac function, as well as primary amyloidosis or central nervous system involvement (Richardson et al., 2022). IFM 2009 included patients up to 65 years old with creatinine clearance of at least 50 mL per minute and normal cardiac and pulmonary function (Attal et al., 2017).

In practice, eligibility is assessed case by case, and not only by age. A review on autologous transplant notes that renal failure alone does not contraindicate the procedure, but it increases toxicity and usually leads to lower melphalan doses (Al Hamed et al., 2019). Older patients in good physical condition may also be candidates, although with less randomized data.

What to assess before indicating

• Biological age, performance status and frailty, in addition to chronological age.
• Cardiac and pulmonary function.
• Renal function, which influences the melphalan dose.
• Hepatic function and bone marrow reserve.
• Active infections and comorbidities.
• Support network, access to a transplant center and patient preference.

Frailty and age

Because myeloma mainly affects older people, frailty assessment has gained ground. A systematic review of 43 clinical trials in myeloma found wide variation in the proportion of patients considered frail, from about 17 to 74 of every 100 participants, and recorded that frail patients generally had worse outcomes than patients in good condition (Mian et al., 2023). Tools such as the frailty index of the international myeloma working group help separate chronological age from functional reserve.

The melphalan dose

Both studies used melphalan 200 mg per square meter (Richardson et al., 2022). The dose of 140 mg per square meter is widely used in older patients or those with reduced renal function. An analysis of the European registry with almost 2000 transplants compared the two doses and concluded that remission status at the time of transplant may favor one dose or the other, with no clear interaction with age or renal function (Auner et al., 2018).

IFM 2009 and DETERMINATION

The two studies had a similar design. All patients received lenalidomide, bortezomib and dexamethasone, and were then randomized to continue with that regimen alone or to receive high-dose melphalan with autologous transplant, followed by more cycles of the regimen. The big difference was in lenalidomide maintenance: for one year in IFM 2009 and until progression in DETERMINATION.

In IFM 2009, with 700 patients, median progression-free survival was 50 months with transplant and 36 months without it, with a hazard ratio of 0.65 (Attal et al., 2017). Transplant also increased complete response and minimal residual disease negativity. In DETERMINATION, with 722 patients and a median follow-up of 76 months, the median was 67.5 months with transplant and 46.2 months without it (Richardson et al., 2022).

Result	IFM 2009	DETERMINATION
Lenalidomide maintenance	1 year	Until progression
Median progression-free survival, with transplant	50 months	67.5 months
Median progression-free survival, without transplant	36 months	46.2 months
Overall survival	Similar, about 81 and 82 out of every 100 at 4 years	Similar, about 81 and 79 out of every 100 at 5 years
Serious treatment-related events	More with transplant	About 94 versus 78 out of every 100

Sources for the table numbers: Attal and colleagues, 2017 and Richardson and colleagues, 2022.

Deeper response

Beyond time without progression, transplant increased the depth of response. In IFM 2009, complete response was about 59 out of every 100 with transplant and 48 out of every 100 without it, and minimal residual disease negativity was about 79 versus 65 out of every 100 among those assessed (Attal and colleagues, 2017). The benefit in progression-free survival appeared in all subgroups analyzed, including those defined by international staging and by cytogenetic risk.

In DETERMINATION, by contrast, the proportion of patients with partial response or better and with complete response or better was similar between the groups (Richardson and colleagues, 2022). This difference between the studies is a reminder that depth of response and duration of control are not the same thing, and that continuous maintenance can change the picture.

The overall survival question

This is the point that calls for the most care. In IFM 2009, four-year survival was about 81 out of every 100 with transplant and 82 out of every 100 without it (Attal and colleagues, 2017). In DETERMINATION, five-year survival was about 81 and 79 out of every 100, with a hazard ratio for death of 1.10 and a wide confidence interval (Richardson and colleagues, 2022). There was no demonstrated overall survival gain in either study.

One possible explanation is that many patients in the no-transplant group received the transplant later, at relapse. In DETERMINATION, 78 of the 279 patients in the no-transplant group who left the study treatment had a transplant later (Richardson and colleagues, 2022). The studies therefore compare the timing of transplant more than whether or not to perform the procedure.

What early relapse means

Early relapse after transplant is a sign of poor prognosis. A study by the French group with 2474 patients defined early relapse as relapse occurring up to 18 months after the start of treatment, the equivalent of about 12 months after transplant, and found this situation in 343 patients, with worse survival regardless of cytogenetic risk (Corre and colleagues, 2020). It is one more reason not to promise results to the patient.

The toxicities

The answer to the second part of Dr. Alexei's question includes the toxicities. In IFM 2009, grade 3 or 4 neutropenia occurred in about 92 out of every 100 patients with transplant, versus 47 out of every 100 without it, and gastrointestinal events and infections were also more frequent (Attal and colleagues, 2017). In DETERMINATION, grade 3 or higher treatment-related events occurred in about 94 out of every 100 with transplant, versus 78 out of every 100 without it (Richardson and colleagues, 2022).

One finding from DETERMINATION deserves attention. Acute myeloid leukemia or myelodysplastic syndrome occurred in 10 patients in the transplant group and in none in the no-transplant group, although the incidence of invasive second cancers in general was similar (Richardson and colleagues, 2022).

What the melphalan label says

The US label for injectable melphalan describes nausea, vomiting, diarrhea, stomatitis, colitis and gastrointestinal bleeding at high doses, above 100 mg per square meter, and identifies bone marrow suppression as the main toxic effect (melphalan label). That is why transplant is performed in centers with the structure for transfusion support, antibiotics and isolation when needed.

Toxicities to explain

• A drop in blood cells for a few weeks, with risk of infection and bleeding.
• Oral mucositis, nausea and diarrhea.
• Fever during neutropenia, which requires prompt treatment.
• Prolonged fatigue during recovery.
• Small long-term risk of leukemia or myelodysplasia.
• Need for revaccination after transplant.

On vaccination, international guidelines for stem cell transplant recipients recommend revaccination between 6 and 24 months after the transplant, depending on immune recovery (Tomblyn et al., 2009). The same guidelines recommend that family members and close contacts keep their vaccination up to date.

Maintenance after the transplant

Maintenance is an inseparable part of the strategy. In the CALGB 100104 study, 460 patients who responded to the transplant were randomly assigned to lenalidomide or placebo (Holstein et al., 2017). With a median follow-up of 91 months, time to progression was 57.3 months with lenalidomide and 28.9 months with placebo, and median overall survival was 113.8 versus 84.1 months.

The price was more neutropenia and more second cancers. Grade 3 or 4 neutropenia occurred in about 50 of every 100 patients on lenalidomide, versus 16 of every 100 on placebo (Holstein et al., 2017). The US label indicates lenalidomide 10 mg once daily, continuously on days 1 to 28 of 28-day cycles, as maintenance after transplant, and carries boxed warnings for embryo-fetal toxicity, hematologic toxicity and venous and arterial thromboembolism (Revlimid label).

For how long

DETERMINATION continued lenalidomide until progression, and IFM 2009 for one year (Richardson et al., 2022). The difference in duration helps explain why the median progression-free survival was so different between the studies. The ideal duration of maintenance remains under discussion and should be decided with the patient, weighing disease control, adverse effects and quality of life.

How to hold the conversation

The nurse in the scene asked two questions: why do the transplant if she is already responding, and whether it will cure her. The honest answer to the first is that early transplant, in the studies, lengthened the time without progression but did not show an increase in overall survival compared with saving the transplant for later. The answer to the second is that autologous transplant does not routinely establish a cure in myeloma, even when the response is deep.

With these two pieces of information, the decision comes to depend on values. Some people prefer to face the toxicity now to have more time without disease and without new lines of treatment. Others prefer to postpone, knowing that the transplant can be done at relapse, as long as the cells have been collected and health allows. Both paths are reasonable, and the choice must be recorded as a shared decision.

When postponing makes sense

Postponing the transplant can be reasonable for someone with a deep response, standard cytogenetic risk, a strong preference to avoid toxicity now and guaranteed access to the procedure in the future. In this strategy, collecting and freezing the cells soon after induction prevents mobilization from becoming harder with future treatments. For those with high-risk disease, the decision to postpone requires more caution, because early relapse has a poor prognosis.

In any scenario, it is worth agreeing with the patient when the decision will be reviewed. A response that deepens, a new adverse effect during induction or a change in personal life can alter the choice, and the team must make clear that postponing does not mean giving up on the transplant.

Common reasoning errors

• Telling the patient that the transplant cures myeloma.
• Stating that early transplant prolongs life, when the demonstrated gain was in time without progression.
• Excluding the patient based only on chronological age.
• Postponing the transplant without collecting and storing the cells.
• Forgetting to discuss maintenance and its risks before starting.

Adapting the plan to biological risk

The decision about transplant and maintenance does not depend only on age and kidney function. It also depends on the biology of the myeloma, and the definition of high risk has changed. In 2025, the International Myeloma Society and the International Myeloma Working Group published a consensus genomic staging for newly diagnosed myeloma. Maclachlan and colleagues summarize the high-risk criteria (Maclachlan and colleagues, 2026):

• del(17p) present in more than 20 out of every 100 tumor cells, or a TP53 mutation;
• IgH translocation, such as t(4;14), t(14;16) or t(14;20), together with gain of 1q or del(1p32);
• monoallelic del(1p32) together with gain of 1q, or biallelic del(1p32);
• beta-2-microglobulin of 5.5 mg/L or more with normal creatinine, below 1.2 mg/dL.

Two changes stand out. Isolated t(4;14) and isolated gain of 1q are no longer enough: what defines high risk is the combination. And the TP53 mutation, which requires sequencing, enters for the first time in a score designed for clinical use. In practice, most centers still assess myeloma by FISH, not by sequencing, and so the TP53 data is often not available.

The same authors applied the new criterion to 503 patients treated with daratumumab-based quadruple induction. The high-risk group had shorter progression-free survival and overall survival, even among those who reached MRD negativity after transplant. The rate of early MRD negativity, on the other hand, was similar between high risk and standard risk. Their conclusion is that future decisions guided by MRD should also consider genomic risk.

In the review by Aljumaa and colleagues, the implications appear at each phase of treatment (Aljumaa and colleagues, 2026). At induction, the high-risk patient should receive a quadruple regimen, which gives deeper and more durable responses than triple or double regimens. Autologous transplant remains indicated for all eligible patients, and all the more so in high risk. At maintenance, the trend is to use continuous therapy with two different drug classes, such as a proteasome inhibitor, an immunomodulator or an anti-CD38 antibody. The authors also recall the category of myeloma with double or triple hit, defined by the accumulation of two or more high-risk abnormalities, such as del(17p), t(4;14), gain of 1q and TP53 mutation, with a higher risk of early and extramedullary relapse.

For the case in this post, that means ordering FISH with del(17p), t(4;14), t(14;16), t(14;20), 1q and 1p before closing the plan, and, if possible, TP53 sequencing. The result does not change eligibility for transplant, but it changes the intensity of induction, the maintenance and the conversation about prognosis.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Transplant in myeloma is a good exercise because the study outcomes do not all point in the same direction. The post about heuristics in clinical reasoning helps you notice when a gain in one outcome is mistaken for a gain in another, and the post about pretest probability helps you read absolute numbers.

Three exercises with cases

Change the age. Say how you would assess a 71-year-old patient who is active and has no major comorbidities.

Change the kidney. Say what changes if the creatinine clearance is 35 mL per minute.

Change the preference. Say how you would record the decision of a patient who prefers to postpone the transplant.

The limits on using the game are described on the NEXO economy page. If you research the teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information under curation and under creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Does autologous transplant cure myeloma?

Cure should not be promised. Transplant lengthens the time without progression, but it does not routinely establish a cure.

Does early transplant increase survival?

In the IFM 2009 and DETERMINATION studies, there was no demonstrated gain in overall survival (Richardson and colleagues, 2022).

Can I have the transplant later?

Yes, in many cases, as long as the cells are collected and stored and health allows. In the studies, some patients without an initial transplant had the procedure later.

Is maintenance mandatory?

Maintenance with lenalidomide prolonged time to progression and, in CALGB 100104, also survival (Holstein et al., 2017). The decision takes tolerance and preference into account.

What is the maintenance dose?

The US label indicates lenalidomide 10 mg daily on days 1 to 28 of 28-day cycles, with adjustment for renal function (Revlimid label).

Does negative minimal residual disease change the decision?

In IFM 2009, transplantation increased the proportion of patients with negative minimal residual disease, but using this test to decide whether transplantation can be skipped is still a topic of study, and the decision should follow the service protocol.

Final checklist

• I assessed eligibility by functional status, organs and frailty, and not by age alone.
• I explained that early transplantation prolongs time without progression.
• I explained that no demonstrated overall survival gain was shown.
• I made it clear that transplantation does not routinely establish cure.
• I described the acute toxicities and long-term risks.
• I planned cell collection and storage, even if transplantation is postponed.
• I discussed maintenance, its duration and its risks.
• I recorded the decision as shared.

Want to practice your reasoning with progressive clues? Play the case of the day.

References

1. Al Hamed R, Bazarbachi AH, Malard F, et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019. PMID 30962422.
2. Aljumaa M, Hamam Refai H, Chawla Y, et al. Defining High-Risk Disease Biology in Multiple Myeloma: A Narrative Review. Blood Lymphat Cancer. 2026. PMID 42078091.
3. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017. PMID 28379796.
4. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018. PMID 29217776.
5. Celgene Corporation. REVLIMID (lenalidomide) capsules, for oral use. Prescribing information. DailyMed. 2026. DailyMed.
6. Corre J, Montes L, Martin E, et al. Early relapse after autologous transplant for myeloma is associated with poor survival regardless of cytogenetic risk. Haematologica. 2020. PMID 33054068.
7. Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018. PMID 29800065.
8. Holstein SA, Jung SH, Richardson PG, et al. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017. PMID 28826616.
9. Hulin C, Offner F, Moreau P, et al. Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib/thalidomide/dexamethasone in the phase 3 CASSIOPEIA study. Haematologica. 2021. PMID 33657786.
10. Maclachlan KH, Tan CR, Shekarkhand T, et al. IMS-IMWG 2025 consensus genomic staging predicts outcomes with daratumumab-based quadruplet regimens for NDMM. Blood Adv. 2026. PMID 41701976.
11. Mian H, McCurdy A, Giri S, et al. The prevalence and outcomes of frail older adults in clinical trials in multiple myeloma: A systematic review. Blood Cancer J. 2023. PMID 36599867.
12. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022. PMID 35660812.
13. Sagent Pharmaceuticals. Melphalan hydrochloride for injection. Prescribing information. DailyMed. 2024. DailyMed.
14. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009. PMID 19747629.