Maisel Reviews Treatment Options for Multiple Myeloma in 2 Case Studies

Christopher Maisel, MD

Christopher Maisel, MD

During aTargeted Oncologylive case-based peer perspectives program, Christopher Maisel, MD, recently discussed the treatment options and considerations he makes when treating patients with multiple myeloma. Maisel, a hematologist and oncologist at the Charles A. Sammons Cancer Center, Texas Oncology-Baylor, explained his treatment decisions and recent data that could impact his decisions based on 2 case scenarios.

Case 1

A 77-year-old Caucasian man presented to his primary care physician complaining of fatigue. His past medical history revealed osteoarthritis with limited mobility. A physical exam showed pallor, hypertrophic changes at distal and proximal interphalangeal joints, poor grip strength, and bilateral swelling in shoulder joints.

His blood work indicated anemia (hemoglobin [Hb], 10.2 g/dL), hypercalcemia (corrected serum calcium [csCa]: 12.9 mg/dL), and slightly elevated creatinine (1.5 mg/dL); his creatinine clearance (CrCl) levels were 50 mL/min. Based on these findings, the patient was referred to hematology for further evaluation.

The patient’s laboratory findings were notable for the following: peripheral blood smear showed rouleaux formation; Hb, 10.3 g/dL; creatinine, 1.3 mg/dL; CrCl, 61 mg/dL; M-protein, 1.4 g/dL; lambda free light chains, 4.43 mg/dL; lactate dehydrogenase, 186 U/L;β2 microglobulin (B2M): 3.8 mcg/mL; bone marrow biopsy showed 43% plasma cells; fluorescence in situ hybridization (FISH), t(14;16).

He was later diagnosed with multiple myeloma, high-risk and it was noted that he had an ECOG performance status of 1.

Based on the case, what are your initial concerns for this patient?

We see patients like this all the time at our practice. By modern American standards, we would not call him exceptionally elderly. The FISH t(14;16) for this patient concerns me because it is a high-risk cytogenetic feature. Additionally, his csCa is almost 13 mg/dL, which is an item of concern that needs to be immediately addressed. This patient needs treatment.

Can you identify the current treatment options for frontline multiple myeloma?

There is no right or wrong answer here, and it can be debated at some length. The category 1 preferred regimens from the National Comprehensive Cancer Network (NCCN) guidelines are: bortezomib (Velcade), lenalidomide (Revlimid), plus dexamethasone (RVD); lenalidomide plus low-dose dexamethasone (RD); bortezomib, cyclophosphamide, plus dexamethasone; and daratumumab (Darzalex) with bortezomib, melphalan, and prednisone (VMP). Other NCCN recommendations are a bit outside of label indications and they include: carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRD); carfilzomib, cyclophosphamide, and dexamethasone; and ixazomib (Ninlaro), lenalidomide, and dexamethasone.¹Additionally, the doublet of bortezomib plus dexamethasone is used a fair amount in certain circumstances.

Would you consider a double or a triplet regimen for this patient?

The SWOG S0777 trial [considered this comparison] and mainly represented an older population, but all age groups were included.²The patients in the study had newly diagnosed multiple myeloma without the intention for immediate autologous stem cell transplant (autoSCT). This could include patients with comorbidities, as well as older patients. These are patients who fit our patient demographic. They were stratified 1:1 to receive induction with the triplet RVD versus RD. In the triplet regimen, the lenalidomide dose was 25 mg, which is our highest starting dose. Intravenous (IV) bortezomib was given, and this is something that we do not really do anymore. The comparative arm had the same doses of lenalidomide and dexamethasone. After 6 months of therapy, the patient went on to maintenance therapy until progressive disease or unacceptable toxicity. The maintenance therapy was also a very high dose of lenalidomide.

The primary endpoint was progression-free survival (PFS). The median PFS for the triplet regimen was 43 months versus 30 months for the doublet. That is a substantial difference, with a 2-sidedPvalue of .004. In this trial, RVD significantly improved PFS. Additionally, overall survival (OS) was significantly improved, with a 2-sidedPvalue of .03. In oncology, getting OS data in a study takes bigger power and a longer-duration follow-up. The median OS was 75 months with the triplet versus 64 months with the doublet. This tells us that the triplet up front seems to be have a better OS than the doublet.

What toxicities should oncologists be aware of with the triplet-regimen RVD?

In the SWOG study, rates of grade 3 or higher neurological toxicities for the RVD regimen were a lot higher, in addition to rates for pain, sensory, and gastrointestinal toxicities. This would be expected with the IV administration of bortezomib. With subcutaneous administration, neurotherapy and other associated toxicities are much less. In the case of our 77-year-old patient, using IV bortezomib twice a week could lead to a substantial change of neuropathy.

Could RVD-lite be a better option for this patient?

With RVD-lite, we are giving lenalidomide at a lower dose of 15 mg, and we are giving bortezomib once weekly subcutaneously. With RVD-lite there is an overall response rate (ORR) of 86% and a very good partial response (VGPR) or better rate of 66%.³This modified regimen seems to be less toxic, while preserving the ORR of the [full-dose] 3-drug regimen. With this regimen, I would say about 80% of my patients will experience fatigue; however, the peripheral neuropathy rate is only 2% grade 3 or higher. It is most likely the preferred option for this patient.

Are there other treatment regimens entering the landscape based on recent data?

The phase III MAIA study included transplant-ineligible newly diagnosed patients with multiple myeloma, with several stratifications.⁴The patients in this trial were randomized to either daratumumab, lenalidomide, plus dexamethasone or standard RD. There were about 370 patients in each arm, and the primary endpoint was PFS. In this study, the intent was that patients would not go on to autoSCT. The median age was 73 years, and more of these patients resided in Europe rather than the United States.

At 30 months, the PFS rate was 71% with the addition of daratumumab versus 56% for RD. ThePvalue was statistically significant. These are very recent data supporting the use of daratumumab in the up-front setting without a melphalan-containing regimen. The median PFS was not reached with the triplet compared with 31.9 months [with RD]. We do not have enough data to determine OS; however, the ORR is 93% versus 81%, respectively, and there were more VGPRs and 3 times as much minimum residual disease (MRD) negativity among those treated with the triplet.

In terms of adverse events (AEs), there is a little bit more neutropenia, the same amount of anemia, and a little more lymphopenia, pneumonia, and potential for infection. This is not a significant difference compared to RD alone.

The phase III ALCYONE study was more recently published, and daratumumab plus VMP now has an FDA approval.⁵This study compared a very standard regimen of VMP, which is mostly used in Europe, with or without daratumumab in patients with untreated multiple myeloma who were not transplant candidates. We do not want to give melphalan for patients who may be collecting stem cells at some point. These patients had a good performance status and CrCl, with no preexisting neuropathy because they were going to get bortezomib.

Bortezomib was given subcutaneously in cycle 1 twice a week. Afterwards, it was given once a week. Melphalan and prednisone were given at the standard doses. The standard dose of daratumumab was also given at your standard dosing. It was given for 9 cycles and then it was either stopped or daratumumab was given for cycles 10 plus every 4 weeks until progressive disease.

The primary endpoint was PFS, and the secondary endpoints included OS. There was a fair number of patients who were included, with about 350 patients in each arm. The median PFS for the daratumumab-containing regimen was not yet reached. At 24 months, 63% of patients were progression free. This was compared to those who had VMP, where the median PFS was 19 months. This is a significant difference, with a median follow-up of 27.8 months. ThePvalue was very statistically significant. All subgroups were favored, and the AEs were comparable in both arms, with more infection in the daratumumab arm.

Personally, I do not like giving melphalan and I find it to be challenging. I had a patient who was given a melphalan-containing regimen who experienced secondary myelodysplasia that was evolving in the leukemia. I think most American practitioners would agree with me that they do not use it. This is considered category 1 in the NCCN guidelines; however, it is a regimen that has not had a lot of uptake in the United States in the up-front setting.

How does MRD status affect your treatment decisions in multiple myeloma?

They briefly touched upon this in highlights of the American Society of Hematology, and MRD in myeloma is starting to get more traction. In the MAIA study, for patients who were MRD-negative, the percent surviving without progression is nearly 100% with the triplet regimen. In patients treated with RD who were MRD-negative, there was an 80% PFS rate up to 30 months. However, those who were MRD-positive at 30 months, the PFS rate is maybe 50%. Higher MRD-negativity rates are achieved with the triplet-containing regimen in the MAIA study.

The patient received continuous lenalidomide 15 mg plus low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL and therapy with single-agent lenalidomide was continued.

Two years after diagnosis, the laboratory values were notable for the following: Hb, 11.4 g/dL; Creatinine, 1.0 mg/dL; M-protein rose from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. He also reported feeling tired. One month later, the patient complained of increasing back pain, fatigue, and weakness. Laboratory findings showed: M-protein, 2.1 g/dL; serum B2M, 6.2 mg/L; albumin, 2.1 g/dL; CrCl, 32 mL/min.

His PET/CT scan showed a new lytic lesion and new compression fracture in the L4/L5 vertebrae. Additionally, a bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, confirmed by CD138+ immunohistochemistry stain. It was noted that he had an ECOG performance status of 2.

What factors do you consider when choosing the next therapy for this patient?

This patient received continuous RD. After 9 cycles of this doublet, his M-spike plateaued at 0.6. He achieved what we would call a PR, but not a VGPR. Then he was given single-agent lenalidomide. He [was] on this for 2 years after his diagnosis; however, his M-protein [rose] again and he reported feeling tired. I would have changed therapy at this point; however, they did not do this in this case. A month later, he [continued] to progress, and we [wanted] to give him new therapy. When deciding on my next choice of therapy, I would consider his renal function, performance status, the fact that he is lenalidomide-refractory, and he is now 80 years old.

Which backbone would you consider, and what AEs are of concern in an older patient such as this?

Infection is always a concern for the older population. We are probably less concerned about neuropathy. If we decide to treat this patient with bortezomib, we would use it once a week subcutaneously and it wouldn’t be a problem. In general, this is someone who needs a proteasome inhibitor [PI]. He has had immunomodulatory therapy, he has become refractory to lenalidomide, and he has high-risk cytogenetics. A PI backbone would be the proper choice for this patient.

Case 2

July 2011

A 61-year-old Caucasian women was diagnosed with stage II multiple myeloma and her genetic testing showed t(11;14). At the time, she was treated with RVD induction therapy, followed by autoSCT. With this therapy, she achieved a complete remission and was placed on lenalidomide maintenance therapy.

Are you using MRD testing today, and if so, how do you use it?

I would like to use it; however, we do not yet have routine capability. There are data that show PFS and OS are significantly improved for patients who are MRD-negative versus MRD- positive.⁶This gives us further incentive for MRD testing, but we also should consider if insurance will pay for it.

August 2016

On routine follow-up, the patient reported having mild fatigue, but continued to work full time. It was noted that she had grade 1 neuropathy. Her laboratory values showed: M-protein, 1.4 g/dL; light chain levels continued to rise; Hb, 10.3 g/dL; creatinine, 1.3 mg/dL.

Are you aware of any new data supporting regimens in the setting of relapsed disease?

Although it is not new, the phase III POLLUX trial studied the comparison of daratumumab, lenalidomide, and dexamethasone (DRd) versus RD in patients who were not lenalidomiderefractory.⁷There was a significant improvement in PFS for patients treated with DRd. It would not be an ideal regimen for this patient, however, because she had lenalidomide in the up-front setting, lenalidomide in the maintenance setting, and then progressed. For this patient, we would likely choose a PI as the backbone of therapy.

The phase III ARROW study compared once- versus twice-weekly dosing of carfilzomib plus dexamethasone in patients with relapsed/refractory multiple myeloma with 2 to 3 prior lines of therapy.⁸The once-weekly dose of carfilzomib was 70 mg after an initial dose of 20 mg. The twice-weekly dose of carfilzomib was the standard 27 mg after an initial dose of 20 mg. In the trial, the PFS was significantly improved with the once-weekly dosing, 11.2 months versus 7.6 months. ThePvalue was also statistically significant.

If you look at the subgroup of this study, patients who were younger than 65 years seemed to benefit more in terms of PFS with the once-weekly dosing. For patients with high-risk cytogenetics, there was also a trend to benefit and patients who were refractory to lenalidomide also tended to benefit more than those who were not.

The ELOQUENT study compared elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone versus pomalidomide and dexamethasone alone for patients who progressed on lenalidomide.⁹The drug was given 10 mg IV every week for cycles 1 and 2, and then every 4 weeks it was given at 20 mg. Pomalidomide was given at a dose of 4 mg orally on days 1 through 21, and dexamethasone was at a dose of 40 mg every week.

The median PFS with the addition of elotuzumab was 10.3 months versus 2.7 months with pomalidomide and dexamethasone alone. In many cases, elotuzumab does not have any single-agent activity. For patients who have failed lenalidomide, the prior use for elotuzumab was not there. However, these data now show that if you are going to give your patient pomalidomide and dexamethasone, the addition of elotuzumab would be reasonable.

References:

1. NCCN clinical practice guidelines in multiple myeloma. NCCN website. nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Published November 16, 2018. Accessed February 1, 2019.
2. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S077): a randomised, open-label, phase 3 trial.Lancet. 2017;389(10068): 519-527. doi: 10.1016/S0140-6736(16)31594-X.
3. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma.Br J Heamatol. 2018;182(2):222-230. doi: 10.1111/bjh.15261.
4. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Presented at: ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract LBA-2.Blood. 2018;132(suppl; abtr LBA-2). ash.confex.com/ash/2018/webprogram/Paper120737.html
5. Mateos MV, Dimopoulos MA, Cavo M, et al; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018;378(6):518-528. doi: 10.1056/NEJMoa1714678.
6. Lahuerta JJ, Paiva B, Vidriales MB, et al; GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group. Depth of response in multiple myeloma: a pooled analysis of three PETHEMA/GEM clinical trial.J Clin Oncol. 2017;35(25):2900-2910. doi: 10.1200/JCO.2016.69.2517.
7. Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.
8. Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study.Lancet Oncol. 2018;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1.
9. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma.N Engl J Med. 2018;379(19):1811-1822. doi: 10.1056/NEJMoa1805762.