We are entering the great era of immunotherapy in multiple myeloma (MM). We’ve had significant advances in the past five to 10 years, with approvals of more than 10 drugs as multiple myeloma treatment options. Most of these are derivatives from known “blockbuster” classes of drugs, including the immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and now the “naked” monoclonal antibodies—most notably, the CD38 antibodies.
An Overview of Multiple Myeloma Treatment Options
The CD38 antibodies first demonstrated activity as single agents in the relapsed/refractory MM setting and then in combination with IMiDs and PIs in less heavily pre-treated MM patients. As is typical for drug development in MM, drugs that show promise in the relapsed/refractory setting are then tested in earlier lines, including frontline therapy.
The triplet combination of daratumumab, lenalidomide, and dexamethasone has recently been tested in newly diagnosed transplant-ineligible MM patients, showing one of the longest values for progression-free survival (PFS; approximately 60 months) ever reported in a frontline MM trial (MAIA study). Additional studies are now testing quadruplet-drug therapy, combining a PI, an IMiD, a steroid, and a CD38 antibody in the frontline setting.
The GRIFFIN study enrolled transplant-eligible newly diagnosed MM patients who received four cycles of Dara-RVd (daratumumab, lenalidomide, bortezomib, and dexamethasone) induction, a single autologous transplant, two cycles of Dara-RVd consolidation, and daratumumab with lenalidomide for two years of maintenance. The initial results showed an overall response rate of 98%, with 83% of patients achieving a complete response (CR) and 64% achieving minimal residual disease (MRD) negativity (10-5). These responses appear durable, as the four-year PFS rate is 87%. These results are amazing and essentially predict that transplant-eligible patients who receive quadruplet induction therapy followed by an autologous transplant, quadruplet consolidation, and doublet maintenance therapy may have remission durations in the seven- or eight-year range, or longer, which is truly unprecedented.
We have several additional immunotherapeutics showing promise, including two chimeric antigen receptor (CAR) T-cell therapeutics that are approved for use in patients who have received four or more prior lines of therapy and who have been exposed to PIs, IMiDs, and anti-CD38 antibodies. The approved CAR T-cell therapies both target the cell surface protein B-cell maturation antigen (BCMA), which is lineage-specific and uniformly expressed on malignant plasma cells. The response rates for these CAR-T therapies range from 73% to 98%, which is also unprecedented.
Patients are experiencing deep and durable remissions, with recent data presented at the 2022 American Society for Clinical Oncology Annual Meeting showing a 27-month PFS of approximately 55% in patients receiving ciltacabtagene autoleucel. There are acute side effects, including cytokine release syndrome (CRS), neurologic toxicity, and cytopenias, which occur mainly within the first 30 days, as well as some late side effects, including infection and tremors/parkinsonism. These therapies need to be administered at a center of excellence under a mandated Risk Evaluation and Mitigation Strategy (REMS) program by the U.S. Food and Drug Administration (FDA). Overall, the side effects are manageable and reversible, and the quality of life can be quite good in responding patients. Currently, no maintenance therapy is given after CAR T-cell therapy, and patients can remain off therapy during their prolonged remission.
The bispecific T-cell redirecting or T-cell engaging antibodies are also showing promise in the relapsed/refractory setting. These agents target a cell surface protein on the malignant plasma cell and the T-cell activating receptor CD3. There are more than 10 agents being tested in phase I/II trials, some targeting BCMA and others targeting novel cell surface proteins (GPRC5D and FcRH5) on the plasma cell. Initial reports have shown impressive single-agent response rates ranging between 60% and 80%. These are some of the best response rates we’ve ever seen in heavily pre-treated patients with relapsed/refractory MM. We expect our first approval of a bispecific T-cell engaging antibody this year, and this will likely be approved in patients with relapsed/refractory MM who have received four or more prior lines of therapy.
There are side effects from T-cell engagers that include CRS, neurotoxicity, and infection. We expect that these agents will need to be initiated in the hospital and under an FDA-mandated REMS program. The CRS and neurotoxicity are generally seen during the first few doses, and this is when patients will need acute care. Generally, after the second or third dose, these agents can be given safely in the outpatient setting. Since B-cell depletion (including normal B cells) occurs with these drugs, patients on therapy need to be followed closely for signs of infection. But because these agents can be given “off the shelf” with no manufacturing required, they may be preferred for some patients. Which therapy is best for any individual patient will depend on the clinical setting.
Because these agents are so active in the late-line setting, studies are already underway investigating their use in earlier lines. Eventually, I think CARs and bispecific antibodies will be utilized in the frontline setting. There are at least two phase III, randomized trials evaluating CAR T-cell therapy as consolidation after frontline therapy in transplant-eligible patients as well as transplant-ineligible patients. In the phase III CARTITUDE-6 trial, transplant-eligible patients will be randomized to receive either ciltacabtagene autoleucel or a single autologous hematopoietic stem cell transplantation followed by lenalidomide maintenance after induction therapy. Patients receiving CAR T-cell therapy will not be taking maintenance-based therapy (“one and done”). The hope is that the impressive response and MRD negativity rates after these novel immunotherapies will allow us to stop therapy and change the paradigm of “treatment until progression” for patients with MM.
The Future of Multiple Myeloma Treatment Options
Overall, these agents offer many new avenues for multiple myeloma treatment. Our hope is that, down the road, we’re able to give quadruplet therapy induction, then either a CAR T-cell or a bispecific T-cell redirecting antibody as consolidation and then utilize a different target if the patient relapses. We hope to have multiple therapeutics targeting several different antigens such that we can go to a second CAR T-cell therapy or a second redirecting antibody therapy at the time of future relapse.
Immunotherapy has the potential to change the myeloma paradigm. A major goal for the next five to 10 years is to determine where these agents fit best (induction, consolidation, maintenance, or early relapse) and to identify the best partners for these therapeutics. The current CAR T-cell paradigm is “one and done,” no maintenance, but there may be a role for maintenance therapy after CAR T-cell therapy, and current studies are investigating this possibility. We know patients who don’t achieve a CR or a stringent CR in the first three to six months after CAR-T therapy are destined to relapse. Thus, future trials should investigate early intervention in these poor responders, with the goal of trying to mop up the residual disease.
There are additional novel immunotherapy drugs called cereblon E3 ligase modulating drugs (CELMoDs) under development, which include iberdomide and mezigdomide. These drugs appear to be more active against MM cells and more immunostimulatory to T cells than lenalidomide or pomalidomide and may be great partners for either CAR T-cells or the bispecific T-cell engagers.
We have a lot of work to do, but the end goal is to try to cure an increased fraction of patients with myeloma utilizing these amazing new novel immunotherapies. There is a push to develop regimens that can be administered for a fixed duration, so that patients can have some time off therapy, rather than the current paradigm of continuous therapy. If successful, these therapies will provide a substantial benefit in terms of quality and productivity of life. Drug costs are always of concern, but if we are successful in achieving sustained remission off therapy, I think these therapies will not only be affordable but preferred in almost all domains of the myeloma treatment paradigm.
Thomas Martin, MD, is the Clinical Research Director of Hematologic Malignancies at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.