Vij Highlights Benefits of Quadruplet Therapy for Patients With Multiple Myeloma

Ravi Vij, MD, MBA

Ravi Vij, MD, MBA

During a Targeted Oncology™ case-based peer perspectives live discussion, Ravi Vij, MD, MBA, professor, Department of Medicine, Oncology Division, Bone Marrow Tranplantation & Leukemia, Washington University School of Medicine in St. Louis spoke with a group of oncologists about best practices for treating patients with multiple myeloma. The ideas he presented were based on a real case of a male patient with multiple myeloma.

• A 51-year-old man presented with worsening fatigue on exertion and pallor.
• Hemoglobin: 9.2 g/dL
• Blood urea nitrogen/creatinine/calcium: within normal limits
• Creatinine clearance: 95 mL/min
• Lactate dehydrogenase: within normal limits
• Serum b₂-macroglobulinemia: 4.1 mg/L
• Serum albumin: 3.2 mg/dL
• Serum M-protein: 1.5 g/dL
• l Free light chains: 110
• Bone marrow biopsy: 66% plasma cells
• Fluorescence in situ hybridization (FISH) showed deletion (del) in chromosome 13q.
• Urine protein electrophoresis: M-spike of 400 mg of l light chains in 24 hours
• PET/CT: lytic lesions in ribs and L3, no increased standard uptake value
• Immunoglobulin G positive in urine and serum free light chains
• Adequate liver and heart function
• ECOG performance status: 1
• Diagnosis: multiple myeloma, standard risk, stage II by multiple myeloma International Staging System (ISS) and Revised ISS

​​​​​​TARGETED ONCOLOGY: What do these laboratory values tell you about the patient at presentation?

VIJ: The biopsy here shows 66% plasma cells. These days, to begin a bone marrow biopsy, we often get 3 readings on the plasma cells. You get the flow cytometry; you get the plasma cell percentage, [which is] where you get the 66%; then you get the third item, your immunohistochemistry of the core [needle biopsy]; and that is the best way to evaluate plasma cells.

[Testing for] the CD38 in the core…is the best way to evaluate plasma cells because when you do flow cytometry, it’s all going to be undercounted. It’s the core [where] you do see CD38. The flow cytometry done in most labs is not useful for the enumeration of plasma cells. The flow cytometry that is being talked about more and more is the MRD [minimal residual disease] flow. I know that it’s hard to figure out if you are using MRD.

About 50% of patients will show del(13q) on FISH testing. When you pick it up on cytogenetics, it’s bad. When you pick it up on FISH, it loses its significance unless it is associated with another abnormality. The FISH battle in most institutions these days includes transformation partners chromosome 14 (including t[4;14], t[11;14], and t[14;20]). Of these, t(11;14) is [considered] neutral these days, whereas the others indicate poor prognosis. [The treatment of] t(4;14) has gotten to be better since the advent of protease inhibitors. It’s not as bad as the t(14;16) and the t(14;20).

Now, del(17p) has got to be the worst factor and is also now under some scrutiny because it is found now that when you do next-generation sequencing [NGS], the only patients with del(17p) who do poorly are those who have mutations in the other allele. Twenty-five percent of patients with del(17p) are going to have a mutation on the other allele. That means for 75% of the patients with del(17p) [whom] we are telling…have a bad prognosis, it is probably not correct. It’s just that NGS is not part of our current commercial assays, so we are not able to discern for most [patients], unless they are on a research study, whether their del(17P) is associated with a 17p mutation on the other allele.

Now, because we can’t do NGS on every patient, we treat everyone with del(17p) as if they are high risk. We give them dual immunotherapy. It is something that is probably overtreatment for the majority of patients based on what we are learning now, but it is the way we practice.

What do you do about the imaging with multiple myeloma?

PET scans are getting a bit more difficult; peer to peer is required. Most [patients] in the United States, if they are getting a screening test, get a skeletal survey. The International Myeloma Working Group recommendations that [were] published earlier this year…recommend doing a whole-body CT.¹Now, a whole-body CT is faster than getting a skeletal survey, it’s less radiation, and it’s cheaper than getting a skeletal survey. The only reason we are not able to do it in the United States is the lack of a billing code. In Europe, they have been doing it for years now.

Medicare allows for 3 PET scans during a patient’s life span, so that’s another complicat[ing] factor that you have to deal with. As far as the issue of doing skeletal surveys on everybody goes, I think it’s a little dependent on whom you speak to. The International Myeloma Working Group does [recommend] that a PET/CT be considered in patients for prognostic purposes. Now, if you have a skeletal survey that shows ligate lesions, at least getting a PET/CT does not change the management in most cases.

The number of kidney and thyroid cancers I pick up when I do a PET scan for myeloma is a fair number. I’m not saying that you should do a PET/CT just to pick up kidney and thyroid cancers, but there is an incidence out there.

Suppose this patient did not have multiple myeloma but, rather, smoldering myeloma. What would you do?

I think there’s a lot of controversy. [Results of a study by the Spanish Myeloma Group showed] that giving Revlimid [lenalidomide] and dexamethasone [Rd] for 2 years improved not only PFS [progression-free survival] but OS [overall survival] as well.²That study was not adopted in the United States because of 2 reasons. One is that they gave it to high-risk patients, but they defined high risk based on flow characteristics using a panel of antibodies that nobody uses in the United States. The second thing is if you look at the graph [for PFS], the patients on the placebo arm fell off. They probably had a lot of patients with myeloma in there and did not do any PET scans or MRIs on those patients. That is what we call inadequate staging.

Now ECOG just repeated the study with some variation and presented it at the ASCO [American Society of Clinical Oncology] Annual Meeting.³They didn’t give Rd; they gave lenalidomide alone, [and] instead of giving it for 2 years, they gave it until progression. As with the Spanish study, [they showed that] progression was delayed by the introduction of lenalidomide. They did not show a survival advantage, but the HR for PFS was similar to the Spanish study. They claim that now we should start treating everybody with high-risk smoldering multiple myeloma.

What is the definition ofhigh-risk smoldering myeloma?

For the high-risk smoldering, it’s the 20/20/2 criteria. Twenty percent plasma cells, free light chain ratio >20, and M-protein >2 g/dL.⁴If you have 2 of these 3 criteria, then they are high risk. Those are the patients [for whom] you could make an argument to treat, but if you talk to a number of [clinicians] who treat smoldering myeloma in mass quantities, there is no consensus on this issue because most…feel that they all have [patients] in their practice who [have smoldering myeloma], and they have been seeing them for years.

You have now decided that you are going to treat this patient because he has multiple myeloma. What are the options for induction therapy?

As far as the induction regimen goes, everybody gives 3 drugs. I think that we know that 3 drugs are better than 2 when it comes to the depth of the response. That is the standard of care today. Whether [to use] KRd [carfilzomib (Kyprolis) plus Rd] or VRd [bortezomib (Velcade) plus Rd] is…a debate that continues to go on. There are no randomized data. They usually say KRd is used for high-risk and VRd for standard-risk patients. We tend to prefer KRd, but the fact is if a patient gets started on VRd, I don’t change it to KRd, and if a [patient] has difficulty getting insurance approval for KRd, I don’t insist on giving KRd.

The reason I give KRd, [besides] the efficacy data, is because of the neuropathy with bortezomib. KRd does have a 5% to 7% chance of cardiopulmonary adverse effects [AEs], and with those patients, you do regret ever using KRd. But I can tell you even with once-a-week bortezomib, the majority of patients do have some degree of neuropathy, and about 20% of patients have it so bad that you regret having used it.

This patient is going to have transplant, so what do you do for maintenance?

We usually recommend [using maintenance until disease] progression. The honest answer is we don’t know the right duration of maintenance. The studies [with results that show] a survival advantage gave maintenance until progression. The other thing is even if you plan to give it until progression, about 50% stop because of AEs before 2 years because you can’t push [push them to stay on the drug]. If the patient is having cytopenia, diarrhea, or extreme fatigue, they can’t think clearly.

Clinicians want to give it for shorter periods. In Europe, they give it for 1 to 2 years, and that is mainly based on their risk of primary disease. But if you look at the data—look at event-free survival, including progression and secondary disease as an event—far more [patients] benefit, and there is that 7% change to secondary malignancies. For the vast majority, the benefit outweighs that risk.

What regimen do you favor for maintenance therapy?

I think because 3 drugs are better than 2, 4 seem to be better than 3 rationally because there is going to be better response. For myeloma, there are two 4-drug regimens that are FDA approved: One is for nontransplant patients, which is VMP [bortezomib, melphalan, and prednisone] plus daratumumab [Darzalex],⁵and the other is for transplant-eligible patients, which is daratumumab plus VTd [bortezomib, thalidomide, and dexamethasone].⁶VTd is not a standard regimen in the United States, but it is the European standard.

How do the GRIFFIN study data compare with these regimens?

This was first presented by Peter Voorhees, MD, at the ASH [American Society of Hematology] Annual Meeting & Exposition last year. This is a phase II trial adding daratumumab to the VRd backbone [D-VRd]. What we saw was in a small number of patients, it was not showing much toxicity over and above what you get with VRd.⁷

Phase of Treatment

D-VRd

VRd

End of induction

12.1%

7.2%

End of ASCT

21.2%

14.4%

End of consolidation

42.4%

32.0%

Clinical cutoff

62.6%

45.4%

The question is, with longer-term follow-up with more data, do you get deeper responses? GRIFFIN data were updated at [ASH this year]. What we saw with more updated data is the response is much better with D-VRd than with VRd [alone][TABLE].⁸TABLE. Stringent Complete Responses Observed in the Updated GRIFFIN Study Data⁸ASCT indicates autologous stem cell transplant; D-RVd, daratumumab, lenalidomide, bortezomib, and dexamethasone; RVd, lenalidomide, bortezomib, and dexamethasone.What are the primary safety concerns of quadruplet therapy compared with standard triplet therapy?

We know that daratumumab is an immunosuppressant. We see more infections with daratumumab.

Physiologically, I think that is important mostly in patients who are ≥75 years and eligible for a transplant. It doesn’t have much in the way of organ toxicity, so even if you have a relativity moderately compromised cardiac function or pulmonary function, it’s not going to be a major deterrent. If a patient is eligible for a transplant, even if a patient is on dialysis, that’s fine.

References

1. Hillengass J, Usmani S, Rajkumar SV, et al. International Myeloma Working Group consensus recommendations on imaging in monoclonal plasma cell disorders [erratum in Lancet Oncol. 2019;20(7):e346. doi: 10.1016/S1470-2045(19)30423-1]. Lancet Oncol. 2019;20(6):302-312. doi: 10.1016S1470-2045(19)30309-2.
2. Mateos MV, Hernández MT, Giraldo P,et al.Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.Lancet Oncol.2016;17(8):1127-1136 doi: 10.1016/S1470-2045(16)30124-3.
3. Lonial S, Jacobus SJ, Weiss M, et al. E3A06: randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma.J Clin Oncol. 2019;37(suppl 15; abstr 8001). doi: 10.1200/JCO.2019.37.15_suppl.800.
4. Lakshman A, Rajkumar SV, Buadi FK,et al.Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria.Blood Cancer J.2018;8(6):59. doi: 10.1038/s41408-018-0077-4.
5. ASCO Poststaff. FDA approves daratumumab/VMP combination for newly diagnosed multiple myeloma.ASCO Postwebsite. ascopost.com/issues/may-25-2018/fda-approves-daratumumab-vmp-combination/. Published May 25, 2018. Accessed December 10, 2019.
6. FDA approves daratumumab for transplant-eligible multiple myeloma. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-transplant-eligible-multiple-myeloma. Published September 26, 2019. Accessed December 10, 2019.
7. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara‐Vrd) vs. Vrd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT).Blood. 2019;132(suppl 1; abstr 653):15 doi: 10.1182/blood-2018-151.
8. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update.Blood. 2019;134(suppl 1; abstr 691). doi: 10.1182/blood-2019-123456.