An interventional study of Total Bone Marrow Irradiation (TBMI) 8 Gy and Total Bone Marrow Irradiation (TBMI) 10 Gy in Multiple Myeloma in Relapse, sponsored by Institut Cancerologie de l'Ouest. Terminated at 8 sites in France. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-12-12.
Sponsored by Institut Cancerologie de l'Ouest · Not applicable, Interventional, and Other
In Multiple Myeloma, an adult hematological malignancy, mainly located in the Bone Marrow (BM), dramatic recent progresses have been observed, thanks to new agents (proteasome inhibitors and IMIDs). However, at time of first relapse, high-dose therapy followed by Stem Cell Rescue (SCR) is frequently mandatory as a consolidation in minimal residual disease, to healthy patients under 65 yo, combining Melphalan (MPH) and/or Total Body Irradiation. Modern irradiation modalities are now available by the use of HI-ART Tomotherapy system to realize a Total Bone Marrow Irradiation (TBMI), in order both to limit the dose administered to Organ at Risk (lungs, oral cavity) and to focus efficacy on BM. In this phase-1 study, the conditioning regimen before SCR will combine a fixed high-dose MPH (140 mg/m²) and a dose escalated TBMI, so as to define its Maximal Tolerated Dose (MTD) and the Dose Limiting Toxicities (DLT). An extended cohort will further in a phase-2 setting.
Experimental :
Total Bone Marrow Irradiation (TBMI) is delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. The escalated dose levels are determined according to a "3x3" modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy.
Drug : Melphalan is infused intravenously in 30 minutes on day -2 after IV anti-emetics.
Autologous Peripheral Stem Cell Rescue : are re-infused in the central line on day "0" after adequate premedication.
Despite the recent finding of new drugs (proteasome inhibitors and IMIDs), Multiple Myeloma still remain uncurable, especially after the first relapse, even in responding disease under conventional chemotherapy. In the healthy youngest patients (\<65 yo), when peripheral stem cells collection is available, a high-dose therapy is often proposed in consolidation of complete or very good partial remission: the conditioning regimen usually includes high dose alkylating agent (mostly Melphalan) and/or Total Body Irradiation. The new Tomotherapy HI-ART technology allows irradiating on a 1.6m length field all the bone marrow sites together with optimal respect of the Organ at Risk (lungs, oral cavity, heart, liver, kidneys…). The proposed phase-1 study will explore the safety and efficacy of escalated dose of Total Bone-Marrow Irradiation in combination with a fixed dose of Melphalan (140mg/m²), followed by autologous SCR. To determine the MTD is the main objective of the study, then the toxicity profile (DLTs) and the RP2D in an extended cohort at the MTD dose.
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This study's enrollment of 13 is below the median of 41 across 3,005 interventional studies indexed under Multiple Myeloma.
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Cohort 1: Total Bone Marrow Irradiation (TBMI): 8 Gy delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. Melphalan 140 mg/m² infused intravenously during 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : re-infused in the central line on day "0" after adequate premedication.
Radiation: Total Bone Marrow Irradiation (TBMI) 8 Gy
Cohort 2: Total Bone Marrow Irradiation (TBMI): 10 Gy delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. Melphalan 140 mg/m² infused intravenously during 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : re-infused in the central line on day "0" after adequate premedication.
Radiation: Total Bone Marrow Irradiation (TBMI) 10 Gy
Cohort 3: Total Bone Marrow Irradiation (TBMI): 12 Gy delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. Melphalan 140 mg/m² infused intravenously during 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : re-infused in the central line on day "0" after adequate premedication.
Radiation: Total Bone Marrow Irradiation (TBMI): 12 Gy
Cohort 4: Total Bone Marrow Irradiation (TBMI): 14 Gy delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. Melphalan 140 mg/m² infused intravenously during 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : re-infused in the central line on day "0" after adequate premedication.
Radiation: Total Bone Marrow Irradiation (TBMI): 14 Gy
Cohort 5: Total Bone Marrow Irradiation (TBMI): 16 Gy delivered by the Tomotherapy HI-ART machine, in 2 fractions per day during 4 consecutive days from d -6 to d -3. Melphalan 140 mg/m² infused intravenously during 30 minutes on day -2 after IV anti-emetics. Autologous Peripheral Stem Cell Rescue : re-infused in the central line on day "0" after adequate premedication.
Radiation: Total Bone Marrow Irradiation (TBMI): 16 Gy
Total Bone Marrow Irradiation (TBMI): 8 Gy
Total Bone Marrow Irradiation (TBMI): 10 Gy
Total Bone Marrow Irradiation (TBMI): 12 Gy
Total Bone Marrow Irradiation (TBMI): 14 Gy
Total Bone Marrow Irradiation (TBMI): 16 Gy
Maximal Tolerated Dose, Type of DLTs
Maximal Tolerated Dose Type of Dose-limiting Toxicities The escalated dose levels are determined according to a "3x3" modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy.
Time frame: 1 year
Safety Profile Recommended Dose for Phase-2 (RDP2)
Safety profile: acute, short and middle term toxicities Recommended Dose for Phase-2 (RDP2) and Extended Cohort for 14 patients at this dose
Time frame: 1 year
Efficacy Expressed as the Rate (%) of Complete Response and Very Good Partial Response
osteo-medullary PET fixations evaluation by FDG PET-Scan Disease-free survival at 1 year and Overall Survival
Time frame: 1 and 2 years
Study start date: April 9, 2013 Study completion date: October 6, 2020
| Milestone | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| Started | 3 | 3 | 6 | 1 | 0 |
| Completed | 3 | 3 | 6 | 1 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 |
Maximal Tolerated Dose Type of Dose-limiting Toxicities The escalated dose levels are determined according to a "3x3" modified Fibonacci method and five dose levels will be explored. The doses per fraction are: 1gy, 1.25gy, 1.5gy, 1.75gy and 2gy, and consequently the cumulative TBMI doses are: 8gy, 10gy, 12gy, 14gy and 16gy.
| Participants | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| DLT: Severe sepsis | 0 | 0 | 1 | 0 | — |
| Patients without DLT | 3 | 3 | 5 | 1 | — |
Safety profile: acute, short and middle term toxicities Recommended Dose for Phase-2 (RDP2) and Extended Cohort for 14 patients at this dose
| Participants | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| Recommended dose reached | 0 | 0 | 0 | 0 | 0 |
| Patients treated at lower dose levels | 3 | 3 | 6 | 1 | — |
| Extended Cohort performed | 0 | 0 | 0 | 0 | — |
osteo-medullary PET fixations evaluation by FDG PET-Scan Disease-free survival at 1 year and Overall Survival
| Participants | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| Patients with very good partial response | 1 | 1 | 3 | 0 | — |
| Patients with partial response | 2 | 0 | 2 | 0 | — |
| Patients with complete response | 0 | 2 | 1 | 1 | — |
Collected over The adverse events were collected from enrollment until 90 days post Autologous Peripheral Stem Cell (PSC) Rescue.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Total Bone Marrow Irradiation (TBMI): 8 Gy | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Total Bone Marrow Irradiation (TBMI): 10 Gy | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Total Bone Marrow Irradiation (TBMI): 12 Gy | 0/6 (0%) | 2/6 (33.3%) | 6/6 (100%) |
| Total Bone Marrow Irradiation (TBMI): 14 Gy | 0/1 (0%) | 0/1 (0%) | 1/1 (100%) |
| Total Bone Marrow Irradiation (TBMI): 16 Gy | — | — | — |
| Event | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| PyrexiaGeneral disorders | 1/3 | 0/3 | 0/6 | 0/1 | — |
| Interstitial lung diseaseRespiratory, thoracic and mediastinal disorders | 0/3 | 1/3 | 0/6 | 0/1 | — |
| DiarrhoeaGastrointestinal disorders | 0/3 | 0/3 | 1/6 | 0/1 | — |
| DyspnoeaCardiac disorders | 0/3 | 0/3 | 1/6 | 0/1 | — |
| Septic shockInfections and infestations | 0/3 | 0/3 | 1/6 | 0/1 | — |
| Device related sepsisInfections and infestations | 0/3 | 0/3 | 1/6 | 0/1 | — |
| Severe cognitive distressNervous system disorders | 0/3 | 0/3 | 1/6 | 0/1 | — |
| Event | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy |
|---|---|---|---|---|---|
| ThrombopeniaBlood and lymphatic system disorders | 2/3 | 3/3 | 6/6 | 1/1 | — |
| NeutropeniaBlood and lymphatic system disorders | 2/3 | 3/3 | 4/6 | 1/1 | — |
| AnemiaBlood and lymphatic system disorders | 1/3 | 0/3 | 1/6 | 1/1 | — |
| LymphopeniaBlood and lymphatic system disorders | 1/3 | 2/3 | 4/6 | 1/1 | — |
| MucositisGastrointestinal disorders | 2/3 | 1/3 | 2/6 | 0/1 | — |
| Febrile aplasiaGeneral disorders | 2/3 | 0/3 | 1/6 | 0/1 | — |
| LeucopeniaBlood and lymphatic system disorders | 1/3 | 2/3 | 2/6 | 0/1 | — |
| SepsisInfections and infestations | 1/3 | 0/3 | 0/6 | 0/1 | — |
| CystitisRenal and urinary disorders | 1/3 | 0/3 | 0/6 | 0/1 | — |
| DiarrheaGastrointestinal disorders | 1/3 | 0/3 | 1/6 | 0/1 | — |
The study was terminated prematurely, due to a lack of enrolments
| Age, Categorical(Participants) | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy | Total |
|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 3 | 3 | 6 | 1 | 0 | 13 |
| >=65 years | 0 | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy | Total |
|---|---|---|---|---|---|---|
| Female | 0 | 2 | 2 | 1 | 0 | 5 |
| Male | 3 | 1 | 4 | 0 | 0 | 8 |
| Race and Ethnicity Not Collected(Participants) | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy | Total |
|---|---|---|---|---|---|---|
| Count of participants | — | — | — | — | — | 0 |
| Region of Enrollment(Participants) | Total Bone Marrow Irradiation (TBMI): 8 Gy | Total Bone Marrow Irradiation (TBMI): 10 Gy | Total Bone Marrow Irradiation (TBMI): 12 Gy | Total Bone Marrow Irradiation (TBMI): 14 Gy | Total Bone Marrow Irradiation (TBMI): 16 Gy | Total |
|---|---|---|---|---|---|---|
| France | 3 | 3 | 6 | 1 | — | 13 |
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