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SAR650984 shows promise in relapsed, refractory multiple myeloma
SAN FRANCISCO — More than 60% of pretreated patients with relapsed or refractory multiple myeloma responded to treatment with the novel monoclonal antibody SAR650984 plus lenalidomide and dexamethasone, according to study results presented at the ASH Annual Meeting and Exposition.
“There appears to be synergy between the anti-CD38 antibody SAR650984 and lenalidomide and dexamethasone, as the response rates observed are amongst the highest reported in heavily pre-treated patients with relapsed multiple myeloma,” study author Thomas G. Martin III, MD, clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program and associate director of the Myeloma Program at University of California, San Francisco, told HemOnc Today.
Martin and colleagues sought to determine whether the addition of SAR650984 (Sanofi) — a humanized lgG1 monoclonal antibody that targets a unique epitope on the human CD38 receptor — to lenalidomide (Revlimid, Celgene) and dexamethasone would improve outcomes in 31 patients with relapsed or refractory multiple myeloma.
Patients had been diagnosed for a median of 4 years (range, 1-12) and had received a median of seven prior regimens (range, 2-14). More than 94% of the population had received a prior immunomodulatory drug (lenalidomide, n=29; pomalidomide [Pomalyst, Celgene], n=9), 84% of whom had relapsed on or were refractory to at least one of these agents. More than 90% of the population had previously received bortezomib (Velcade, Millennium Pharmaceuticals) and 48% had received carfilzomib (Kyprolis, Onyx Pharmaceuticals).
Researchers treated cohorts of three to six patients with escalating doses of IV SAR650984 (3-mg/kg, 5-mg/kg or 10-mg/kg) every 2 weeks, together with 25 mg lenalidomide on days 1 through 21 and 40 mg dexamethasone on days 1, 8, 15 and 22 of the prescribed 28-day cycles. Eighteen additional patients received the highest 10-mg/kg dose after researchers determined its safety.
Median follow-up was 9 months. Patients were treated for a median of 26.4 weeks (range, 2-61).
The overall response rate for all treated patients (n=31) was 58% — which included two stringent complete responses, eight very good partial responses and 10 partial responses. The clinical benefit response rate was 65%.
The median time to first response was 4.2 weeks (range, 4-10.1) and the median time to best response was 8.5 weeks (range, 4-32.6). Patients’ responses endured for a median of 23.1 weeks (range, 0.1-54.7). The median PFS was 6.2 months for all patients and 5.8 months for patients who received three or more prior lines of therapy.
Researchers noted the 24 patients who received the 10-mg/kg dose demonstrated a 63% overall response rate and a 67% clinical benefit response rate.
Approximately half of patients who were refractory to prior immunomodulatory drugs responded to the SAR650984 regimen. Response rates included 44% of patients who were refractory to prior bortezomib and 40% of patients who were refractory to prior carfilzomib.
Six patients died, five of whom died due to disease progression. Three patients discontinued due to an adverse event.
The most common treatment-related adverse events were fatigue (45.1%), diarrhea (42%), nausea (38.7%), upper respiratory tract infection (35.7%) muscle spasms (32.3%), pyrexia (32.3%) and insomnia (32%). Twelve patients (38.7%) experienced an infusion-associated reaction, two of which were grade 3 and led to treatment discontinuation.
“I do think these anti-C38 antibodies are the next blockbuster class of agents; these are the next agents that are really going to show some benefit to myeloma patients,” Martin said during a press briefing. “The next 5 years are going to be really moving them from the refractory setting, to the less refractory setting, and then to the front-line setting.”
For more information:
Martin TG. Abstract #83. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.
Disclosure: Researchers report research funding and honoraria from and speakers’ bureau roles with Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Millennium, Novartis, Onyx and Sanofi.
Perspective
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Two studies presented at ASH — one by Moreau and colleagues (Abstract #176) and the other by Martin and colleagues (Abstract #83) — are both on targeted, anti-CD38 therapy for multiple myeloma. They target different epitopes on the CD38 receptor, so they are not the same antibodies. The most important thing is that these are targeting the patients who have high-risk disease who have been refractory to the other agents we’ve had standardly available. To be able to see responses in these very advanced patients is extremely compelling. Both of these trials have done them in combination. Daratumumab was in combination with backbones such as bortezomib (Velcade, Millennium Pharmaceuticals), thalidomide (Thalomid, Celgene) and dexamethasone; pomalidomide (Pomalyst, Celgene); or bortezomib, melphalan and prednisone. SAR650984 was in combination with lenalidomide (Revlimid, Celgene). This suggests the tolerability of combining them with other novel agents is important. Secondly, those novel agents may perhaps augment responses either by, in the case of the immunomodulatory agents, natural killer cell activity, or in the case of melphalan and prednisone, by direct cytotoxicity. We’ve been looking for antibodies for years for myeloma, and we now have two that have demonstrated tremendous clinical efficacy.
Given that these agents do target different epitopes, if a patient does not respond to one does not necessarily mean that they won’t respond to the other. This is going to be a very interesting question as times goes on. Right now, I don’t think we have enough to be able to pick out a patient who is going to respond to the SAR650984 compound vs. the daratumumab compound.
Something that always comes up when you talk about multiple myeloma is the role of transplantation in this setting, but these trials really weren’t designed to address that question. Really, these molecules might really be used to improve transplant. That way, you might use transplant as you’re debulking, and then you can target what myeloma remains in the body with these agents to get the patient down to a minimally residual disease-negative state.