Total Marrow Irradiation for Multiple Myeloma

(TMI-ASCT Trial)

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ottawa Hospital Research Institute

Must be taking: Intense corticosteroids

Disqualifiers: Non-secretory myeloma, Life expectancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to treat multiple myeloma, a type of blood cancer, using Total Marrow Irradiation (TMI). Researchers aim to determine if higher doses of radiation targeting the bone marrow can improve cancer control without increasing side effects compared to the usual treatment. The study seeks to identify the highest safe dose of TMI when combined with a stem cell transplant. Individuals whose multiple myeloma has returned or not responded to treatment and who have a specific protein in their blood or urine may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What prior data suggests that Total Marrow Irradiation is safe for treating multiple myeloma?

Research has shown that Total Marrow Irradiation (TMI) is generally safe for people with multiple myeloma. One study found that combining TMI with melphalan, a chemotherapy drug, proved both safe and effective. Another study reported that patients whose multiple myeloma had returned tolerated TMI well.

Some long-term side effects, such as dry mouth, affected about 37% of patients, but these were manageable. Overall, various studies have safely used TMI, with low rates of serious problems related to the transplant process. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple myeloma?

Most treatments for multiple myeloma, such as chemotherapy and standard radiation, work by targeting rapidly dividing cells throughout the body, which can lead to significant side effects. Total Marrow Irradiation (TMI) is unique because it specifically targets the bone marrow, where multiple myeloma cells proliferate, potentially sparing healthy tissues and reducing side effects. Researchers are excited about TMI because it can be combined with autologous stem cell transplants to enhance the effectiveness of the treatment, possibly leading to better outcomes for patients with this challenging condition.

What evidence suggests that Total Marrow Irradiation might be an effective treatment for multiple myeloma?

Research has shown that total marrow irradiation (TMI), the treatment under study in this trial, could be a promising approach for multiple myeloma. Studies have found that combining TMI with high-dose chemotherapy is safe and effective for patients with this condition. For those with relapsed multiple myeloma, TMI allows for higher doses of radiation, which patients tolerate well and which leads to good results. Specifically, some patients experienced long-term survival, with a significant number not seeing their cancer worsen. These findings suggest that TMI might be a helpful option for managing multiple myeloma. ^{1 2 5 6 7}

Who Is on the Research Team?

Harold L Atkins, MD

Principal Investigator

Ottawa Hospital Research Institute

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with relapsed or refractory multiple myeloma, who have measurable monoclonal gammopathy. They must have enough cryopreserved stem cells for transplantation and be in good enough health to undergo the procedure. Pregnant women, those with non-secretory myeloma or other plasma cell disorders, previous radiation treatments, severe concurrent illnesses, or a history of non-compliance are excluded.

Inclusion Criteria

My heart, kidneys, liver, and lungs are healthy enough for a stem cell transplant.

My multiple myeloma has not responded to initial treatment or has come back.

I am between 19 and 59 years old.

Exclusion Criteria

I have a plasma cell disorder that is not multiple myeloma.

Subjects with a history of non-compliance in other studies.

I haven't had intense corticosteroid treatment for my multiple myeloma.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive Total Marrow Irradiation (TMI) as part of the dose escalation study to determine the maximum tolerated dose

4-6 weeks

Autologous Stem Cell Transplantation

Participants undergo autologous stem cell transplantation following TMI

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Total Marrow Irradiation

Trial Overview The study tests if Total Marrow Irradiation (TMI) can deliver higher doses to bone marrow malignancies compared to traditional methods without increasing toxicity. It's a dose escalation study aiming to find the maximum tolerated dose of TMI before autologous hematopoietic stem cell transplantation in patients with multiple myeloma.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 1 Intervention

Treatment with TMI and autologous Stem Cell transplant

Total Marrow Irradiation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Total Marrow Irradiation for:

• High-risk acute leukemia
• Myelodysplastic syndrome

Approved in European Union as Total Body Irradiation for:

• Acute leukemia
• Myelodysplastic syndrome
• Lymphoma

Approved in Canada as Total Marrow Irradiation for:

• High-risk acute leukemia
• Myelodysplastic syndrome

Who Is Running the Clinical Trial?

Ottawa Hospital Research Institute

Lead Sponsor

Trials

585

Recruited

3,283,000+

Published Research Related to This Trial

Targeted marrow irradiation (TMI) maintains effective coverage of the clinical target volume (CTV) for patients undergoing bone marrow transplantation, similar to total body irradiation (TBI), but with improved dose distribution.

TMI significantly spares critical organs such as the lungs, brain, kidneys, and liver, reducing their radiation exposure by up to 55%, which may allow for higher doses to the target area or more frequent treatments without increasing tissue complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ sparing of linac-based targeted marrow irradiation over total body irradiation. Warrell, GR., Colussi, VC., Swanson, WL., et al.[2023]

Using helical tomotherapy for total body irradiation (TBI) allows for significant sparing of normal organs while effectively targeting bone marrow and lymphatics, with a median dose reduction of 51% to organs at risk compared to traditional TBI methods.

This technique not only enables dose escalation but also potentially reduces the severity and frequency of late effects associated with radiation, such as pneumonitis and second tumors, by minimizing exposure to healthy tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-guided total marrow and total lymphatic irradiation using helical tomotherapy. Schultheiss, TE., Wong, J., Liu, A., et al.[2022]

In a study of 326 patients with acute leukemia undergoing bone marrow transplantation (BMT) after total-body irradiation (TBI), the technique of TBI (single dose vs. fractionated) did not significantly affect survival rates or the incidence of complications.

However, the incidence of cataracts was significantly influenced by the instantaneous dose rate of TBI, with higher rates observed in patients receiving higher dose rates, highlighting the importance of dose management in minimizing long-term side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total-body irradiation before bone marrow transplantation for acute leukemia in first or second complete remission. Results and prognostic factors in 326 consecutive patients. Belkacémi, Y., Pène, F., Touboul, E., et al.[2023]

Total marrow irradiation (TMI) significantly reduces radiation exposure to critical organs such as the liver, kidneys, and lungs compared to total body irradiation (TBI), achieving up to a 59% reduction in kidney dose while maintaining the necessary dose to the targeted skeletal area.

TMI not only protects organs at risk more effectively but also decreases the treatment time by an average of 217 seconds, making it a potentially safer and more efficient alternative to TBI for patients undergoing hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total marrow irradiation versus total body irradiation using intensity-modulated helical tomotherapy. Köksal, M., Kersting, L., Schoroth, F., et al.[2023]

Using 24 MV photons for total-body irradiation (TBI) in bone marrow transplantation helps achieve a more uniform radiation dose distribution, which reduces the risk of organ injury to the lungs, liver, and kidneys in patients with high-risk leukemias.

The study found that while TBI increased bone marrow dose due to interactions with bone, the overall treatment regimen effectively minimized end-organ toxicities, making it a safer option for patients undergoing transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications. Bradley, J., Reft, C., Goldman, S., et al.[2019]

Total Marrow Irradiation (TMI) and Total Marrow and Lymphoid Irradiation (TMLI) are promising alternatives to traditional Total Body Irradiation (TBI) in hematopoietic cell transplantation, allowing for higher doses of targeted radiotherapy while minimizing damage to surrounding organs.

These techniques have been shown to be safely administered with low rates of transplant-related mortality, making them suitable for high-risk patients, including those with multiple myeloma and elderly or frail individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies. Kerbauy, MN., Arcuri, LJ., Favareto, SL., et al.[2023]

In a study involving 15 patients with relapsed acute leukemia, the combination of total body irradiation (TBI) followed by total marrow irradiation (TMI) was found to be clinically feasible, with all patients achieving complete remission after stem cell transplant.

TMI significantly reduced radiation exposure to surrounding organs by 30% to 65%, while maintaining effective targeting of bone marrow, suggesting it may enhance treatment efficacy with a lower risk of severe side effects compared to conventional TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helical tomotherapy targeting total bone marrow after total body irradiation for patients with relapsed acute leukemia undergoing an allogeneic stem cell transplant. Corvò, R., Zeverino, M., Vagge, S., et al.[2012]

JP4-039, a novel radiation mitigator, was administered to mice after exposure to high doses of total-body irradiation (9.0 and 9.15 Gy) and demonstrated safety with no adverse effects on liver or kidney function, nor on survival rates.

The treatment with JP4-039 led to significant recovery of bone marrow cellularity and hematopoietic function by day 30, indicating its potential efficacy in promoting recovery after radiation exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiobiologic effects of GS-nitroxide (JP4-039) on the hematopoietic syndrome. Goff, JP., Epperly, MW., Dixon, T., et al.[2021]

In a pilot study involving 10 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), intensity-modulated radiation therapy total body irradiation (IMRT-TBI) was found to be well tolerated, with all patients experiencing early adverse events but no severe complications (grade III-IV acute graft-versus-host disease).

All patients achieved neutrophil engraftment and remained alive and disease-free at the final follow-up, suggesting that IMRT-TBI is a safe option for myeloablative conditioning in allo-HSCT, warranting further investigation for long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of total body irradiation using intensity-modulated radiation therapy by helical tomotherapy in allogeneic hematopoietic stem cell transplantation: a prospective pilot study. Konishi, T., Ogawa, H., Najima, Y., et al.[2021]

In a phase 1 trial involving 13 patients with multiple myeloma, total marrow irradiation (TMI) combined with melphalan showed a low rate of acute toxicity, with only one dose-limiting toxicity observed at the 12 Gy dose level, indicating a good safety profile for this treatment approach.

After a median follow-up of 55 months, 70% of patients were alive, with 38.5% achieving a very good partial response and 30.8% achieving complete response, suggesting that TMI is effective in improving outcomes for patients at first relapse in multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Study of the Combination of Escalated Total Marrow Irradiation Using Helical Tomotherapy and Fixed High-Dose Melphalan (140 mg/m²) Followed by Autologous Stem Cell Transplantation at First Relapse in Multiple Myeloma. Cailleteau, A., Maingon, P., Choquet, S., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11868127/

Total marrow irradiation as part of autologous stem cell ... Our preliminary results suggest that melphalan 120–140 mg/m 2 plus TMI 12 Gy/6f as a conditioning regimen is safe and efficient for patients with MM.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36174802/

Phase 1 Study of the Combination of Escalated Total ... Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301622033946

Phase 1 Study of the Combination of Escalated Total ... Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the ...

4. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/12913/492002/Long-Term-Adverse-Events-of-Total-Marrow

Long-Term Adverse Events of Total Marrow Irradiation (TMI ... In our long-term HSCT survivors receiving TMI-based conditioning, we observed xerostomia in 9 cases (37%, 3 of which had eating impairment), ...

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1003908/full

Total marrow irradiation (TMI): Addressing an unmet need ... Overall survival (OS) at 10 years were 38.8% with a progression-free survival (PFS) plateau of 20.4%. The first patient with stage I disease remains in ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00800059

Study Details | NCT00800059 | Total Marrow Irradiation & ... Further,the investigators hypothesize that this will result in an improvement in disease response and disease control for patients with multiple myeloma. This ...

7. withpower.com withpower.com/trial/phase-2-multiple-myeloma-10-2008-67b26

Total Marrow Irradiation for Multiple Myeloma Total marrow irradiation (TMI) has been shown to be safely administered in various studies, with low rates of transplant-related mortality and manageable early ...