UCSF Showcases Potentially Game-Changing Trials Across Multiple Myeloma Settings

Thomas G. Martin, MD

The University of California San Francisco (UCSF) has a number of ongoing clinical trials in both the newly diagnosed and relapsed/refractory settings of multiple myeloma that are open for patient enrollment and, if positive, could dramatically change practice, explained Thomas G. Martin, MD.

Martin, who is clinical professor of medicine, Adult Leukemia and Bone Marrow Transplantation Program, associate director, Myeloma Program, University of California San Francisco (UCSF), co-leader, Cancer Immunology & Immunotherapy Program, UCSF Helen Diller Family Comprehensive Cancer Center, talked through some of the exciting clinical trials open at UCSF, especially for those in the relapsed/refractory setting.

“The patients who have exhausted available options with a CD38-directed antibody, a proteasome inhibitor and immunomodulatory drug, are the unmet need,” Martin added. “We have some available agents; we have selinexor [Xpovio] and belantamab mafodotin [Blenrep], but those have side effects, and the response rates are essentially less than 40%. They are likely not to respond, and if they do respond, then sometimes the duration is certainly less than 1 year—most of the time less than 6 months. Therefore, these studies are necessary and have the potential of providing deep and durable responses in patients.”

Newly Diagnosed Multiple Myeloma

CARTITUDE-2:A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-cell Maturation Antigen (BCMA) in Participants With Multiple Myeloma (NCT04133636)

The multi-cohort, phase 2 CARTITUDE-2 trial is evaluating ciltacabtagene autoleucel (cilta-cel) in patients with multiple myeloma across various settings: following progressive disease after 1 to 3 prior lines of therapy (cohort A), early relapse after frontline therapy (cohort B), relapsed/refractory disease after a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and anti-BCMA therapy (cohort C), less than complete response after frontline autologous stem cell transplant (cohort D), newly diagnosed, high-risk disease (cohort E), newly diagnosed, standard-risk disease (cohort F).

“In the newly diagnosed space, we have [a cohort in the CARTITUDE-2] trial that's actually looking at the use of ciltacabtagene autoleucel as part of frontline therapy, and it's in patients with high-risk, newly diagnosed multiple myeloma,” said Martin. “[These are patients with] revised [International Staging System] stage III disease, they have to have an elevated beta-2 microglobulin, and then have either a high [lactate dehydrogenase] or an abnormal fluorescence in situ hybridization or karyotype. That puts them in the high-risk classification. Right now, that's actually the only newly diagnosed trial that we currently have open.”

Early Relapse Multiple Myeloma

Phase Ib Study of SAR650984 in Combination With Carfilzomib for Treatment of Relapsed or Refractory Multiple Myeloma (NCT02332850)

In this 2-arm, phase Ib trial, isatuximab (Sarclisa) is administered at a fixed dose while carfilzomib (Kyprolis) is given either at its standard dose of days 1, 2, 8, 9, 15, and 16, or a high-dose weekly administration, plus dexamethasone in 28-day cycles, in patients with relapsed/refractory multiple myeloma.

For those on the standard-dose carfilzomib arm, patients must have prior exposure to an immunomodulatory drug and proteasome inhibitor, and have had 2 prior regimens; on the weekly arm, patients must have had at least 1 but no more than 3 prior lines of anti-myeloma therapy.

“[The SARCAR trial is] using a CD38-directed antibody, isatuximab, together with weekly carfilzomib and dexamethasone, and it's based on the IKEMA trial and the phase 1 trial of isatuximab plus carfilzomib that we did here at UCSF,” Martin, who is principal investigator of this study, said.

“It's just trying to show that it's safe and efficacious to combine isatuximab with weekly carfilzomib. [We’re looking for] have similar data as what was recently presented with the IKEMA study [NCT03275285], with a [progression-free survival] that's looking like it's more than probably more than 28 months, and a very good safety signal with no additive or unexpected safety signals from using isatuximab together with carfilzomib and dexamethasone.”

A Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma (NCT04722146)

The bispecific T-cell engager teclistamab is being evaluated in different combination regimens as a method to identify optimal doses in this multi-arm, phase 1 trial. The various arms comprise regimens of teclistamab, daratumumab (Darzalex), and pomalidomide (Pomalyst); teclistamab, daratumumab, lenalidomide (Revlimid), and bortezomib (Velcade); teclistamab plus nirogacestat; teclistamab plus lenalidomide; and teclistamab plus daratumumab and lenalidomide.

“The other study that we have is that we have a combination of a bispecific T-cell engagers study from Janssen with teclistamab, and we have teclistamab plus daratumumab, pomalidomide and dexamethasone in early-relapse patients—a quadruplet in the early-relapse setting,” Martin said. “That is likely going to be a very potent combination. That study has ongoing enrollment at the current time. It is an important study for anybody who has failed their first-, second- or even third-line of therapy..”

Relapsed/Refractory Multiple Myeloma

TRIMM-2: A Study of Subcutaneous Daratumumab Regimens in Combination With Bispecific T Cell Redirection Antibodies for the Treatment of Participants With Multiple Myeloma (NCT04108195)

Investigators are currently enrolling patients on this phase 1 trial, which has both dose-escalation and dose-expansion phases, to identify recommended phase 2 doses (RP2Ds) for each treatment combination between subcutaneous daratumumab plus talquetamab, and teclistamab plus daratumumab, with or without pomalidomide, and to characterize the safety of each RP2D for selected treatment combinations.

“It's a phase 1 trial and it's combining the BCMA-targeted bispecific teclistamab with daratumumab, and there are cohorts with pomalidomide and dexamethasone, so it dealt with the 2 together, or it could be a quadruplet,” Martin explained. “There is a whole other half of that study with the GPRC5D specific bispecific T-cell engager talquetamab plus daratumumab, so that is looking at daratumumab plus talquetamab or daratumumab plus talquetamab and pomalidomide/dexamethasone. We have patients on that on that trial also, and that is in the multiple relapsed/refractory population.”

P-BCMA-101 Tscm CAR-T Cells in the Treatment of Patients With Multiple Myeloma (MM; NCT03288493)

P-BCMA-101 CAR T cells, which are autologous T stem cell memory CAR T cells, are being tested in patients with relapsed/refractory multiple myeloma in this open-label, phase 1/2 trial. The phase 1 study is using a novel BCMA-directed, CAR T-cell therapy that uses a novel way to do gene transfer using a transpose on technology, Martin said.

“Their manufacturing process is likely to enhance the number of early T cells that are in the final product; they call it central memory T cells or stem cell sensory memory T cells. We will see about those and if those actually provide longer persistence of the CARs after the CAR T-cell therapy, and whether that can provide a better long-term response. We're still assessing that in this trial.

There are also cohorts that are using rimiducidin in addition to this to try to decrease the chance that the patient may develop some anti-CAR antibodies. Sometimes, the patient's own immune system tries to fight off the CAR; you might be able to prevent that by using rimiducidin as a prevention of the anti-CAR antibodies.

We had always said that CAR T cells were ‘one and done,’ but now this study will test whether additional therapy post–CAR T-cell therapy might be important to the long-term persistence of the CARs and the long-term effects. The CAR T-cell therapy does require a longer hospital stay; for most of these bispecifics T-cell engagers, patients are in the hospital for maybe a week for their initial step-up dosing, and then it's all outpatient thereafter, whereas the [CAR T-cell therapy is longer].

For us, it's more time invested in the hospital; most of the time, it's 2 weeks in the hospital and patients need to stay in San Francisco for the first month. Some patients select the CAR T-cell therapy because they want to invest that month and then be done with a lot of [their treatment]. Then, other patients say, ‘I don't really have a caregiver that can stay in San Francisco for a month, and I'm more a little worried about the toxicity because there is perhaps a little bit more cytokine release syndrome and the potential for neurotoxicity. I'd rather go with the bispecific and just come back and forth.’ It is patient preference for sure, that drives some of this.”