Myeloma Physicians Consider Approaches to Subcutaneous Therapy

Patients with newly diagnosed transplant-ineligible or transplant-deferred (TI/D) multiple myeloma are, almost by definition, the patients least able to absorb a demanding treatment schedule. They tend to be older, are more likely to carry comorbidities, and are more likely to depend on someone else to get them to and from the infusion chair. As CD38-directed monoclonal antibodies have become fixtures of frontline quadruplet regimens, the practical question facing community oncologists has shifted from whether to add an anti-CD38 agent to how that agent should be delivered, and increasingly, whether a new on-body delivery device changes that calculus at all.

In a virtual Case-Based Roundtable event for oncologists across North Carolina, Sikander Ailawadhi, MD, a professor with the Division of Hematology-Oncology at Mayo Clinic in Jacksonville, Florida, reviewed the evidence supporting CD38-based quadruplet therapy in TI/D newly diagnosed multiple myeloma (NDMM) and moderated a discussion built around a patient whose candidacy for aggressive therapy was complicated as much by logistics as by biology. Ailawadhi noted that frailty, transportation burden, and route of administration should enter the treatment conversation nearly as early as disease genetics do.

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CASE SUMMARY

Initial presentation:

• The patient is a 72-year-old man.
• Presents with fatigue, worsening back pain, unintentional weight loss
• Difficulty with daily activities; daughter says he’s “slowing down”
• Comorbidities: mild chronic kidney disease, hypertension, osteoarthritis (limited mobility)
• ECOG performance status: 2
• Laboratory findings: anemia and elevated total protein
• Suspicion for malignancy
• Referred to hematology

Workup confirms multiple myeloma:

• Serum free light chains, lactate dehydrogenase, and beta-2-microglobulin: elevated
• Complete blood count: anemia present, otherwise unremarkable
• Bone marrow biopsy: 50% to 60% clonal plasma cells
• PET-CT scan: positive uptake

Clinical profile

• International Myeloma Working Group status: frail​
• Transplant ineligible NDMM ​

Social & Functional Context​

• Lives 45 to 60 minutes from treatment center ​
• Relies on daughter for transit and some support ​
• Prolonged clinic visits are physically taxing ​
• Occasional missed/rescheduled appointments due to transit and low energy ​

EVENT RECAP

During the event, the patient’s frailty and difficulty traveling were points of discussion; several participants flagged the latter as more clinically limiting than the frailty score itself. “The thing that concerned me about this case even more than the frailty was the tenuousness of the patient’s ability to get to the treatment center in the first place,” said Haley Simpson, MD, of UNC, noting that a 2-hour round trip resting on one caregiver’s availability deserved its own line of questioning at the visit.

The gaps between guideline-preferred intensity and real-world deliverability run through the current evidence base. Quadruplet therapy combining an anti-CD38 antibody with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) is a preferred, category 1 option for TI/D NDMM under NCCN guidelines, provided the patient is not frail.¹

The phase 3 CEPHEUS trial (NCT03652064) helped establish the standard using subcutaneous (SC) daratumumab (Darzalex) plus VRd (D-VRd) against VRd alone; at a median follow-up of nearly 5 years, D-VRd produced a minimal residual disease (MRD) negativity rate of 60.9% vs 39.4% with VRd and a complete response (CR) rate or better of 81.2% vs 61.6%, respectively, translating into a clear progression-free survival (PFS) advantage (HR, 0.57; 95% CI, 0.41-0.79).²

The phase 3 IMROZ trial (NCT03319667) tested a parallel approach with intravenous isatuximab (Sarclisa) plus VRd (Isa-VRd), reporting CR rates of 75% vs 64% and MRD negativity rates of 58.1% vs 43.6% over VRd alone, again favoring the quadruplet.⁴ Both regimens carried more grade 3 or higher neutropenia and infection than the triplet comparator, a toxicity signal Ailawadhi tied to why truly frail patients remain difficult to carry through 4 drugs.

When asked which CD38-based regimen they select most often for TI/D NDMM, the substantial majority chose SC D-VRd. Barry Paul, MD, of Atrium Health Levine Cancer Institute, put the calculus plainly: SC daratumumab cuts an infusion that can run hours down to about 5 minutes with fewer infusion reactions, and “there’s really no reason, in my opinion, to continue to use intravenous [IV] daratumumab unless...insurance dictates it.” Ailawadhi agreed that IV daratumumab has become vestigial in his own practice, whereas Maurizio Bendandi, MD, of the W.G. Hefner Salisbury Department of Veterans Affairs Medical Center in North Carolina, noted that as long as patients are not concurrently receiving another IV therapy, he has never heard a patient request IV over SC administration.

The newer question is whether an on-body injector (OBI) for subcutaneous isatuximab, approved across all 3 of the drug’s indications weeks before this event, adds meaningful value on top of a manual subcutaneous push.⁴ The device loads the drug at bedside, adheres to the skin, and delivers it over roughly 13 minutes without a clinician holding a syringe. In the phase 2 IZALCO trial (NCT05704049), which crossed patients between manual subcutaneous isatuximab and OBI delivery with carfilzomib (Kyprolis)-dexamethasone, efficacy was similar regardless of delivery method, but patients and health care providers alike preferred the OBI, and injection-site and infusion reactions were numerically lower with the device than with the manual push.⁵ The phase 3 IRAKLIA trial (NCT05405166) then established noninferiority of OBI-delivered isatuximab against IV isatuximab on both efficacy and pharmacokinetics, with fewer infusion reactions and better patient-reported experience favoring the OBI.⁶

In the TI/D NDMM population most relevant to this case, the phase 2 ISASOCUT trial (NCT05889221) paired subcutaneous isatuximab OBI with VRd and reported a CR rate of 24%, MRD negativity of 35.1% at the 10⁻⁵ threshold, and device completion above 99%, with a mean patient age of 73 years, closely mirroring the case patient’s profile.⁷

Paul argued that although the OBI could be “a big gamechanger” if it can eventually be administered outside a clinical setting, currently it requires a healthcare provider to activate and observe as opposed to a true self-injection. He suggested that it can be complex and more time-consuming than a manual SC injection, since a nurse still has to load the device, apply it, and remain present for up to 20 minutes. Heather White, MD, of Physicians East, was similarly skeptical, noting that from the patient’s perspective little changes: “They still have to come in. They still have to get a needle. They still have to sit in the chair.”

Vinay Gudena, MD, of Cone Health, offered a different rationale, suggesting the device’s real value may be standardizing an injection that otherwise varies with nurse technique, patient anatomy, and time of day. Paul acknowledged that nurses would prefer to avoid slow pushes and find the OBI more convenient.

Ailawadhi pointed out that another advantage of the OBI was the reported reduction in injection-related reactions vs manual injection (1.9% vs 25% in IRAKLIA), which he attributed to the needle size for the OBI. Simpson concurred that fewer infusion or injection site–related reactions would be a benefit of the OBI. Meanwhile, Paul observed that the comparator to the isatuximab OBI that would help most with real-world treatment selection would actually be SC daratumumab, as the isatuximab OBI could be chosen instead of daratumumab. Ailawadhi noted that the isatuximab OBI would have a numerical reduction in injection-site reactions in such a comparison but cautioned against a direct cross-trial comparison and didn’t think a direct trial would be run.

Several participants said their decisions would also be influenced by cost and reimbursement. White observed that she has been unable to get insurance to pay for self-administered injectors for lifestyle-related medications unless a patient lives far away, and she hopes for no similar issues with the isatuximab OBI.

Polling results from the live event reflected the sentiment on subcutaneous therapies:

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DISCLOSURES: Ailawadhi previously reported consultancy for Sanofi, Bristol Myers Squibb, BeOne, Janssen, Regeneron, Cellectar, Pfizer, GSK, Ascentage, Kite/Arcellex, and institutional research funding from Sanofi, GSK, BMS, Genentech, Janssen, Cellectar, Abbvie, Ascentage, and Astra Zeneca.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple Myeloma, version 5.2026. Accessed August 11, 2026. https://tinyurl.com/4zkfub8e

2. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7

3. Facon T, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712

4. Ocio EM, Parmar G, Mateos MV, et al. Review of the first on-body injector (OBI) for the subcutaneous delivery of an oncology drug: isatuximab in multiple myeloma. Expert Opin Drug Deliv. 2026;23(7):1289-1303. doi:10.1080/17425247.2026.2659263

5. Parmar G, Capra M, Seguro F, et al. Efficacy and safety of isatuximab subcutaneous plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma: results of the Phase 2 study IZALCO. Blood Cancer J. 2025;16(1):16. Published 2025 Dec 27. doi:10.1038/s41408-025-01436-0

6. Ailawadhi S, Špička I, Spencer A, et al. Isatuximab subcutaneous by on-body injector versus isatuximab intravenous plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: phase III IRAKLIA study. J Clin Oncol. 2025;43(22):2527-2537. doi:10.1200/JCO-25-00744

7. Bobin A, Zhang R, Morisse M, et al. Multicenter phase 2 study of subcutaneous isatuximab plus bortezomib , lenalidomide and dexamethasone (Isa Sc-VRd) in transplant ineligible newly diagnosed multiple myeloma: Final analysis of the isasocut study (IFM 2022-05). Blood. 2026;146(suppl 1):2275. doi: 10.1182/blood-2025-2275