UCSF’s Dr Thomas Martin Discusses Quadruplets vs Triplets in Multiple Myeloma

Thomas G. Martin, MD, is a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplant Program at the University of California San Francisco. He is the interim chief, Hematology, co-director of the Myeloma Program at UCSF and co-leader of the Cancer Immunology and Immunotherapy Program, Helen Diller Family Comprehensive Cancer Center. The American Journal of Managed Care® (AJMC®) asked Martin about the treatment landscape in multiple myeloma (MM) and several recent clinical trials. This interview has been edited lightly for clarity.

AJMC®:Can you provide a brief overview of the current treatment landscape in multiple myeloma, particularly the use of anti-CD38 monoclonal antibodies?

Martin: The treatment of multiple myeloma, both newly diagnosed and relapsed refractory multiple myeloma, has changed quite dramatically in the last 5 to 10 years. Much of that has been due to the introduction and success of monoclonal antibodies. We now have 3, blockbuster classes of medicines that we pair together to optimize treatment: immunomodulatory drugs [IMiDs], like lenalidomide pomalidomide; proteasome inhibitors [PI], such as bortezomib and carfilzomib; and the CD38 antibodies—daratumumab, and isatuximab. We usually combine 2 of the 3 classes together with dexamethasone, a in. triplet combination, to provide a potent anti-myeloma effect. More recently, in the newly diagnosed setting, we have been combining all 4 classes of drugs—(PI + IMiD, + CD38 monoclonal with steroids)—in attempt to enhance the depth and duration of response in the frontline setting.

The initial evaluation of a newly diagnosed patient takes into account their fitness or whether they are they well-enough to undergo an autologous transplant. This actually leads us down 1 of 2 different paths, treatment for transplant eligible or treatment for transplant ineligible. CD38 antibodies have been evaluated and have shown early success as part of frontline therapy for both transplant eligible and transplant ineligible patients.

For fit patients on the autologous transplant path, we have quite a few induction regimens we can offer but one of the most exciting, is the quadruplet of daratumumab, lenalidomide, bortezomib, and dexamethasone [dara-RVD, for Revlimid, Velcade, dexamethasone]. Dara-RVD has been tested in a recent Phase 2 trial called the GRIFFIN trial, which compared quadruplet therapy Dara-RVD to the 3 drugs RVD. At phase 2, patients were randomized to the RVD standard triplet. All patients received 4 cycles of induction [Dara-RVD or RVD and then underwent autologous transplant. After autologous transplant they received 2 cycles of consolidation [Dara-RVD or RVD] and then went on to maintenance. In the daratumumab containing arm, patients had daratumumab and lenalidomide as maintenance; in the triplet arm, they just had standard lenalidomide as maintenance—that’s what we usually do for everybody. The primary endpoint, stringent complete response (sCR rate), favored Dara-RVD vs, RVD and this met statistical significance.

Also, the number of patients who achieved MRD [minimal residual disease] negativity at the end of transplant and at the end of a year of maintenance was significantly higher in the quadruplet/daratumumab arm than it was in the triplet with lenalidomide-only, maintenance arm. The MASTERS study and other studies utilizing anti-CD38 antibody therapy with carfilzomib (Kyprolis), lenalidomide and dexamethasone [Dara-KRD, Isa-KRD] have also shown impressive overall response rates and MRD negativity rates in transplant eligible MM patients. We're all very excited about the potential, once approved, for using quadruplets as frontline therapy. For now, the standard frontline therapy for transplant eligible patients remains RVD. Sometimes, one may choose a different proteasome inhibitor called carfilzomib, and this is commonly selected in patients who have high risk disease based on cytogenetic/fish testing or R-ISS3 disease. These high-risk patients tend to have an adverse prognosis and we are very aggressive in these patients. We try to utilize transplant if transplant eligible, and use proteasome inhibitors with or without lenalidomide for maintenance. The Forte trial recently demonstrated a significant advantage for using 2-drug maintenance, KR vs. R-alone, in both high-risk as well as standard risk patients. Many of us favor using KR or VR =/- D as maintenance therapy in the high-risk patients. Overall, I think many of us will start using quadruplets once they're approved by the FDA, pre-transplant, and we are already incorporating doublet or triplet drug maintenance, especially for high-risk disease, post-transplant.

I'll switch now to frontline therapy for the transplant ineligible patients. In fact, we generally utilize similar regimens; we just don't include the autologous transplant. Probably the most utilized frontline regimen is RVD, and we also have KRD as an option. A clinical trial comparing RVD vs. KRD as frontline therapy in patients not intending to go to transplant, called the Endurance trial, recently reported nearly identical overall response rates and progression free survival (~32 months) for these two arms. Perhaps KRD was favored in patients with HR disease, and RVD favored in standard risk patients. RVD was associated with more peripheral neuropathy and KRD with more dyspnea, hypertension, heart failure and acute kidney injury, albeit significant, Gr3 or greater, in only small number of patients. Overall, the data supports the use of either regimen and it remains a matter or preference of RVD vs. KRD.

More recently, an updated analysis of the MAIA trial, presented at the European Hematology Association meeting this past summer, by Thierry Facon, which compared daratumumab plus lenalidomide and dexamethasone [Dara-RD] vs. RD as frontline therapy in transplant ineligible patients, showed an impressive progression free survival for dara-RD of 60 months. This is truly unprecedented and is the longest PFS ever reported for frontline therapy in transplant ineligible patients. I do think this is a really important study and that we should consider Dara-RD as frontline therapy for all transplant ineligible patients. It is a very potent regimen and a well-tolerated regimen as patients continued to receive Dara-R for many years. The one setting where there may be a bit of hesitation to use dara-RVD is in the high-risk cytogenetic group. In these patients, some would prefer to use a PI, bortezomib, instead of daratumumab as the third drug [so RVD]. Thus, in patients with high-risk FSH or cytogenetics—eg, those with the 17p deletion, or high-risk translocation [t(14;16) or t(14;20)], it's very reasonable to use RVD. I think jury's not in yet in terms of whether Dara-RD is as good as RVD in that setting.

Lastly in special circumstances, like frail elderly patients or those with comorbidities like renal insufficiency it may be appropriate for starting doublet therapy for frontline therapy eg VD or RD or utilizing the triplet bortezomib plus cyclophosphamide and dexamethasone (VCD). The caveat here is that if patients improve with therapy or comorbidities resolve, patients may be able to then tolerate additional drugs, so adding a third drug after a few cycles of a doublet or switching from cyclophosphamide to lenalidomide once renal insufficiency improves are reasonable strategies. 

AJMC®: And in the relapsed/refractory setting—what are the options?

Martin: Triplets are the are the mainstay for relapse or salvage-based therapy. In patients who have not received a CD38 antibody as part of frontline therapy, I prefer to use a CD38 antibody as part of initial relapse therapy. Selecting the partner drug, whether a PI or an IMiD [with dex for the triplet] is a matter of preference.We try to do class switching—for instance, many patients get either RVD or KRD as frontline therapy and then go on to maintenance; generally with single agent lenalidomide, and for patients who progress on lenalidomide maintenance, we call them lenalidomide refractory. At that point we'll often switch regimens or classes of drugs; so, we would change to a CD38 antibody, plus a proteasome inhibitor and dexamethasone as our first salvage therapy. Another option is to use a CD38 antibody with a next generation IMiD (pomalidomide) + dexamethasone.

We've had a couple of recent publications to support the use of CD38 + PI-dex for RRMM. One study called the IKEMA study, [for which UCSF was one of the study sites], compared isatuximab plus carfilzomib and [dexamethasone] vs. the doublet carfilzomib and dex in patients relapsing after 1-3 prior lines of therapy. The triplet (Isa-Kd), showed very high overall response and complete response rates, 86%, and 40% respectively, with almost a third of patients achieving MRD negativity. With a median follow-up of just over 20 months, the medium PFS has not been reached. Quite possibly, the median PFS could reach 30 months or more, potentially one of the longest PFS outcomes reported from triplet therapy in the relapsed/refractory setting.

The other CD38, daratumumab, has also been combined with carfilzomib and dexamethasone, in the CANDOR study. The CANDOR study also showed very high response rates—over 80%--as well as very high CR rates, in addition to some patients achieving MRD negativity. The PFS with Dara-Kd was just over 28 months, so again—a really amazing PFS for triplet therapy in the relapsed setting. In both IKEMA and CANDOR we would expect an even longer PFS in the subset of first relapsed patients. So again, in patients in first relapse without prior exposure to CD38 antibody therapy, the combinations of Dara-K-d, Isa-K-d, are excellent choices.

CD38 antibodies have also been combined with pomalidomide and dexamethasone for the treatment of RRMM. Isatuximab has been combined with pomalidomide + dex in the ICARIA study5, and daratumumab has been combined with pomalidomide + dex in the APOLLO study,6. Both studies were large phase 3 studies and both included a more heavily pretreated population with more than 90% of patients enrolled in both studies being lenalidomide refractory. The APOLLO study actually included approximately 10% of patients in first relapse, otherwise the patients in both studies had received 2 or more prior lines of therapy. The overall response rates and PFS were similar in both studies; PFS ~11.5 months in ICARIA and ~12.4 months in APOLLO vs. 6.6-6.9m for Pd (control arms). These data support the use of CD38 antibodies with Pd. These regimens have the benefit of being more convenient due to Pd being oral medications. Although the reported PFS values were lower in ICARIA and APOLLO than from IKEMA or CANDOR, the patient population was a bit more refractory, likely accounting fore these differences.

The other monoclonal antibody that actually performed well with pomalidomide and dexamethasone was elotuzumab, evaluated in the Phase 3 ELOQUENT 3 study; elotuzumab plus Pd vs. Pd. This study also showed higher response rates and PFS for the triplet Elo-Pd; the PFS was about 10.5 in patients having received 2 or more prior lines of therapy. This remains another option and can potentially be used in patients who have received prior anti-CD38 antibody therapy [albeit very few patients in ELOQUENT 3 had received prior CD38 therapy].

Overall, in the relapse setting, I typically use triplet based therapy and choose therapy based on treatment history, refractoriness, ongoing toxicity from prior treatment, the aggressiveness of the relapse and convenience or patient preference. In first relapse, I will use a triplet containing 2 of the 3 big classes of drugs—generally combining 2 drugs for which the patient has not had prior exposure. The goal in first relapse should be to achieve the deepest response possible. Patients generally continue the triplet therapy until disease progression allowing for dose adjustments due to emerging toxicity. The majority of patients will relapse again, and then the strategy should be to utilize another triplet regimen combining different classes of drugs [e.g. class switching]. Eventually, patients become refractory to the 3 big classes; IMiDs, PIs and CD38s; this is called triple-class refractory disease, and these our toughest patients and one of the highest unmet needs.

AJMC®: What are the choices for patients with triple-class refractory multiple myeloma?

Martin: We now have 4 agents or combinations that have been approved for use in triple-class refractory myeloma. These include 1) belantamab mafodotin, 2) selinexor + dexamethasone, 3) melphalan flufenamide + dexamethasone and 4) Idecabtagene vicleucel (Ide-cel, ABeCMATM) our first FDA approved CAR T-cell therapy targeting BCMA. Fit patients with good social support should proceed to CAR-T cell therapy as this therapy has demonstrated the highest response rate ~72%, and best PFS ~ 12 months. Each of the other treatments have unique attributes that further define treatment selection in triple class refractory patients and all these treatments play an important role in this population. In fact, patients may receive several of these options as response rates are generally lower 25%-30%, with and expected PFS of ~3-5 months. Each of these drugs have unique toxicities. Belantamab mafodotin is associated with ocular toxicity and it is mandatory to see an eye care specialist before each dose. This can be dose limiting at times, but surprisingly patients that require dose interruptions generally maintain their response even for several months while awaiting ocular toxicity to resolve. Less than 20% have a significant changes in visual acuity and this is reversible.The most common Grade 3 or greater adverse events associated with selinexor and dexamethasone are thrombocytopenia, anemia, fatigue and hyponatremia, with nausea also common (~70%) but typically Grade 1-2 in severity. Aggressive supportive care measures including dual or triple drug anti-nausea prophylaxis, salt tablets, intravenous hydration and transfusion and/or cytokine therapy is generally required. Melphalan flufenamide is mostly associated with hematologic toxicity but further development is currently suspended due to lower overall survival found in the melfufen+dex arm from the Phase 3 OCEAN study. The future of this drug remains unclear.Generally for triple class refractory patients, I try to utilize CAR T therapy in all that are eligible and then use these additional agents to improve survival and get patients further down the road in hope for additional new drug approvals.

AJMC®: Are there additional distinctions between the IKEMA and CANDOR trials? Are there more differences between the 2 trials we should know about?

Martin: In the IKEMA trial, we performed several subgroup analyses to assess which patients were most likely to benefit from ISA-Kd therapy. In fact, almost all subtypes of RRMM patients benefited from the Isa-Kd triplet including some difficult-to-treat subgroups like those with high-risk cytogenetics, with renal insufficiency, lenalidomide refractory and older patients. In addition, those that had received a prior autologous transplant as well as those with advance stage also benefited. The CANDOR trial also showed benefit in many of these subgroups. Perhaps one defining result from IKEMA was that Isa-KD showed significantly improved PFS in patients with amp 1q21 as well as in patients with 1q21 gain, independent of other high-risk cytogenetic findings. Isatuximab has also shown benefit in patients with 1q21 gain in combination with pomalidomide and dexamethasone.

AJMC®: You discussed the fact that there continue to be new therapies, including the new CAR T-cell therapy, for patients who continue to relapse. Are there any other areas of unmet need that you expect to see treatments for, as you look ahead to the next major meeting in the field, which would be the American Hematology Society meeting in December?

Martin: Yes, we will continue to see significant innovation with CAR T-cells including improvements in manufacturing, use of dual-targeted and novel-target CARs and use of novel T-subtypes like gamma-delta and NK-T cells. There will also be significant innovation with immune-activating antibodies including bispecific and tri-specific T-cell (or NK cell) engaging antibodies. Innovation for these antibodies will include targeting novel myeloma surface antigens as well as other immune cells.

The development of bispecific T cells will also expand to other stages in the MM paradigm like smoldering myeloma, as part of consolidation after induction and in early relapse. These agents are providing such a potent anti-myeloma effect in late-stage MM that earlier use of these agents may prevent the progression of SMM to active multiple myeloma and these therapeutics may increase the percentage of patients cured with multiple myeloma.

Another exciting group of agents in development are the cereblon degraders including next-generation immunomodulatory drugs and novel PROTACs. These drugs promote cereblon/ E3 ligase activity and result in degradation of Ikaros and Aiolos, two very important proteins necessary for myeloma cell survival. Current medications in development, are iberdomide and CC92480. These drugs, which are much more potent than lenalidomide or pomalidomide, will be discussed at many of our meetings for years to come and eventually will replace current immunomodulatory drugs.

Lastly, the BCL2 inhibitor venetoclax has demonstrated significant activity together with dexamethasone +/- PIs in patients withtranslocation (t(11;14). Venetoclax is approved for use in myeloma leukemias/MM, but should be considered in patients with t(11;14) who have evidence of relapsed disease. It’s use as part of frontline therapy is being studied and we look forward to seeing.

AJMC®: Is there anything else you’d like to add?

Martin: The treatment of myeloma has changed dramatically over the past 10 years and it will continue to change significantly over the next 10 years. That said, we will always have patients that continue to relapse even with our best drugs and these patients will represent an ongoing unmet medical need. Thus, we need to innovate and continue to develop additional novel therapeutics in myeloma. There are many avenues being pursued with immunotherapeutics including cellular therapies and immune activating antibodies. These therapeutics are currently our most potent agents, and incorporating alternative sources of CARs like NK CARs (natural killer CARs), gamma delta T cells or other allogeneic/third party immune cells—may enhance the use of these agents in the relapsed refractory setting. But we also need additional drugs with novel mechanisms of action. We are only beginning to target specific molecular changes within malignant plasma cells and there is hope that this will improve outcomes. The future of therapeutics for patients with myeloma is bright and we continue to develop strategies aimed at enhancing survival and potentially curing this disease.