Martin Compares Triplet and Quadruplet Therapies in Newly Diagnosed Multiple Myeloma

Thomas G. Martin, MD

During a virtual Targeted Oncology Case-Based Rountable, Thomas G. Martin, MD, a clinical professor of Medicine, associate director, Myeloma Program ,and coleader, Hematopoietic Malignancies Program, at the Helen Diller Family Comprehensive Cancer Center of University of California, San Francisco, discussed triplet and quadruplet combination therapies available for the treatment of multiple myeloma.

Targeted Oncology^TM: What do you consider to be the optimal induction therapy for patients such as this?

MARTIN: The NCCN [National Comprehensive Cancer Network] guidelines list several regimens used for induction.¹ I’m on the NCCN committee, and it’s surprising to me how many of these regimens are still included. The preferred regimen is bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone, or RVd. A few years ago, we used bortezomib, cyclophosphamide, and dexamethasone until the French did a randomized study that showed it’s not as good as when you use a PI [proteasome inhibitor] plus an IMiD [immunomodulatory imide drug].

Some of these other regimens are interesting: carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]; daratumumab [Darzalex], lenalidomide, bortezomib, and dexamethasone [DARA-RVd]; and an all-oral: ixazomib [Ninlaro], lenalidomide, and dexamethasone. There are [regimens] that can be useful in certain circumstances, [such as] patients with renal failure… or patients with a blood clot and you’re worried about IMiDs, or they have neuropathy to start with, and you don’t want to give them bortezomib.

What is your opinion on these poll results?

Subcutaneous daratumumab [Darzalex Faspro] is something at our practice where patients in the waiting room tell other patients they’re getting subcutaneous [daratumumab], and then everybody wants it. We were only going to switch [to subcutaneous] for a few patients to see at first, but we couldn’t stop it, so now everybody gets subcutaneous daratumumab.

In transplant-eligible patients with newly diagnosed multiple myeloma, after transplant and postconsolidation, there was very good partial remission [VGPR]…in the biggest studies we’ve heard of lately: the IFM 2009 [Intergroupe Francophone du My.lome 2009 (NCT01191060)] trial, which randomized patients to RVd or RVd plus stem cell transplant [SCT]²; the FORTE trial [NCT02203643], which randomized patients to KRd 12 cycles or KRd 8 cycles plus SCT³; the Cassiopeia trial [NCT02541383], which was VTd [bortezomib, thalidomide, and dexamethasone] versus DARA-VTd [daratumumab, bortezomib, thalidomide, and dexamethasone]⁴; and the GRIFFIN trial [NCT02874742], which was RVd versus DARA-RVd.⁵

VGPR in the RVd arm in IFM 2009 was similar to VGPR in the RVd arm in the GRIFFIN trial and was similar to VGPR in the VTd arm [in Cassiopeia]. Interestingly, KRd [in FORTE] was a little higher than in IFM 2009 in terms of VGPR or better: [about] 90% of patients achieved VGPR or better.

In the IFM trial, [nearly] 80% of patients who received RVd and SCT were MRD [minimal residual disease] negative; results for the FORTE, Cassiopeia, and GRIFFIN [studies were 58%, 64%, and 59%, respectively].^2-5 These patients had a tremendous response to current triplets. If you use a quadruplet to start, I think you only have [a few treatment options] after using 4 cycles…or 6 cycles. You could use a CAR [chimeric antigen receptor] T-cell therapy, or you could do SCT and then maintenance CAR T-cell therapy.

How did patients in the IFM 2009 trial respond to treatment overall?

In the IFM 2009 trial, if a patient received RVd alone, [the result was] was a complete response [CR] of about 50% and a VGPR [of] an additional 30%.² Three-quarters of patients had a VGPR or better. In the RVd plus SCT arm, over 80% of patients had a VGPR or better. [This is an] amazing depth when we just use RVd, SCT, a couple more cycles of RVd, and then maintenance.

The PFS [progression-free survival] in IFM heavily favored the transplant arm versus the nontransplant arm.⁶ In patients who were MRD negative at the start of maintenance-based therapy, PFS with 55 months of follow-up, was not reached. If you look at the patients after 1 year of maintenance, the curve was even better if they remained MRD negative. There was a solid PFS curve in that group of patients. These days, our goal is to achieve MRD negativity; you can check it [or not], but our goal is to achieve the deepest response possible.

What were the details of the FORTE trial in this patient population?

The FORTE trial is one of my favorite trials and a trial that keeps giving. They randomized patients initially to 3 arms.³ It was KCd [carfilzomib, cyclophosphamide, and dexamethasone] versus KRd, and they proved that KRd was better than KCd for induction therapy. Because there were 3 arms, they had a KRd transplant and a KRd no-transplant arm. The patients [received] 4 cycles of KRd and SCT, then 4 cycles of consolidation, or 4 cycles of KRd, 4 more cycles of KRd instead of SCT, and 4 more cycles of KRd. So it was really 8 KRd cycles plus SCT versus 12 KRd cycles.

What they presented at ASH [American Society of Hematology 2020 conference] is the second randomization, where they randomized these patients to receive [lenalidomide] as maintenance or carfilzomib plus [lenalidomide] as maintenancebased therapy.⁷

Some of us [think] that [carfilzomib] might be better for high-risk patients. In fact, one of the themes [from] the presentation at ASH with the FORTE trial was that [carfilzomib plus lenalidomide] for maintenance, especially in high-risk patients, is better than [lenalidomide alone] as maintenance.

How did the quadruplet therapy in Cassiopeia and GRIFFIN compare with triplet regimens?

The Cassiopeia study couldn’t be done in the United States; it could only be done in Europe. It was VTd versus VTd plus daratumumab. Patients got VTd [or DARA-VTd] for 4 cycles, autologous SCT, and then 2 cycles of VTd or DARA-VTd consolidation.⁴ [The trial] had a second randomization, and [patients] were randomized to daratumumab as maintenance or no maintenance whatsoever. That's why this trial couldn’t have been done in the United States. [Investigators can’t] do a trial where patients are randomized to no maintenance—[lenalidomide] is our standard of care.

What they saw [in Cassiopeia trial results] was a stringent CR [sCR] difference of 29% versus 20% for DARA-VTd versus VTd, respectively. It was statistically significant [P ≤ .001]. For PFS, DARA-VTd was quite good versus VTd, with improvement in PFS [HR, 0.47; 95% CI, 0.33-0.67], as well as the improvement in sCR rates.

The GRIFFIN study was a United States-based study, so it had to have a maintenance arm. Patients were either on the daratumumab arm—[receiving] DARA-RVd for 4 cycles, SCT, DARA-RVd for 2 more cycles, then daratumumab plus [lenalidomide] maintenance for about 2 years; they could go on [lenalidomide] as oral maintenance after that—or RVd for 4 cycles, SCT, 2 cycles of RVd for consolidation, then [lenalidomide] 10 mg as maintenancebased therapy. They could increase to 15 mg of lenalidomide if the patient did fine on 10 mg. This study had only about 15% of patients who were high risk, and the primary end point was sCR.⁵

The GRIFFIN study was a randomized trial of DARA-RVd versus RVd. Its primary end point was sCR, and results demonstrated a statistically significant improvement in sCR [42.4% vs 32.0%; odds ratio, 1.57; 95% CI, 0.87-2.82; P = .068].8 That means no M-proteins were detected.

If you look at MRD negativity in the DARA-RVd arm, about 50% of the patients achieved MRD negativity, whereas only about 20% of the patients on RVd achieved MRD negativity.

For essentially every characteristic [in the subgroup analysis], it was better to be on DARA-RVd versus RVd. The only characteristics that crossed the 1.00 line significantly [favoring RVd] were patients with ISS stage III disease and those who had high-risk cytogenetics.

For the PFS curve in GRIFFIN 24 months out, there wasn’t a real difference between the arms. There will probably be a difference when we get to 3 years and 4 years, but in the DARA-RVd arm, a PFS of 96% at 2 years is amazing. Only 4% of individuals relapsed in the first 2 years.

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 4.2021. Accessed January 29, 2021. https://bit.ly/36w3EKZ}

_{2. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{3. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(suppl 15):8002. doi:10.1200/JCO.2019.37.15_suppl.8002}

_{4. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1}

_{5. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab + lenalidomide, bortezomib,& dexamethasone (RVd) improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract OAB-87.}

_{6. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/blood-2018-06-858613}

_{7. Gay F, Musto P, Scalabrini DR, et al. Survival analysis of newly diagnosed transplant- eligible multiple myeloma patients in the randomized FORTE trial. Blood. 2020;136(suppl 1):35-27. doi:10.1182/blood-2020-136907}

_{8. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}