Multiple myeloma treatment decisions

 Transplantation eligible

Ref: Blood May 2022

10-15% of heme malignancies are myeloma

SOC- induction, high dose melphalan followed by aSCT, consolidation, then len maintenance

Why is transplantation under question? OS benefit has not been convincingly proved, even though PFS better with transplant in eligible patients.

Delayed ASCT can be done in  younger individuals with standard risk disease if patient prefers due to social obligations. There is a risk of secondary primary malignancies. Updated IFM trial results report 8% secondary primary tumors over 8 yr and less than 2 percent AML, not different from non ASCT arm.

Choice of induction regimen: VRD ( PETHEMA/GEM 12, CR 33%) or D-VTD ( Cassiopeia tria)

D-VRD Griffin trial 

Peripheral neuropathy rates: 9 percent ( D-VTD), 4 % VRD, D-VRD-7%

4-6 cycles of D-VRD or VRD followed by ASCT. After ASCT if standard risk__> len maintanance or consolidation followed by len maintenance

After ASCT, if high risk, tandem ASCT ( done within 6 months of ASCT -1) or VRD maintenance

High risk myeloma:

In 2016, the International Myeloma Working Group (IMWG) made an attempt to find a consensus for the definition of HR cytogenetics MM,³ identifying patients with t(4;14), t(14;16), t(14;20), del17p, gain 1q, nonhyperdiploid karyotype, del13q at conventional karyotype, and HR signature at GEP as HR and all the others being standard risk

• t(4;14) FGFR3, MMSET
• t (4;16) cMAF
• t( 14;20)
• 1p32 unfavorable
• 1q gain if  4 or more, unfavorable
• Double hit- biallelic inactivation of TP53 ( very unfavorable)
• Single hit 17p

bortezomib-based treatments have improved, or even overcome, the poor prognosis imparted by t(4;14)

Discussion:

1. In designing a treatment plan, patient factors ( age, performance status and comorbidities) were taken into consideration. Additionally disease factors indicating disease burden ( beta 2 microglobulin, LDH, renal impairment, low albumin) and disease biology ( high risk GEP, cytogenetics, FISH) and organ dysfunction. He does not have > 20% circulating plasma cell or evidence of extramedullary disease both of which are suggestive of more aggressive disease.

2. We discussed the induction chemotherapy regimen RVD-Dara. We reviewed the side effects including but not limited to cytopenias, neuropathy, risk of blood clots, infusion reactions, need for blood transfusion support and rarely, death.

3. Anticoagulation risk mitigation:≤3 Points by IMPEDE Score or <2 Points by SAVED Score--> aspirin. Otherwise 10 mg xarelto or 2.5 mg BID apixaban.

4. Bone support: 2-3 yr Bisphosphonates. This can be administered q 3 months or q 4 weekly. In patients with significant bone disease or bone pain, q monthly for 1 y r can be considered. After discussing the options, we decided on q 3months. We reviewed the side effects including hypocalcemia, renal dysfunction and osteonecrosis of jaw among the most concerning se. Ocular toxicity is also associated with significant morbidity and the patient was advised to contact our office with any vision symptoms. I recommended a baseline dental exam and clearance by dentist as well as eye exam.

5. Hypercalcemia: bisphoshphonates as per #4.

6. Anemia: ESA not indicated. Correct nutritional deficiencies. Blood transfusion support per parameters.

7. ID prophylaxis: acyclovir

Rx of high risk disease:

Quadruplet induction (MoAb + PI + IMiD + dex)
Double ASCT
Quadruplet consolidation
Two-drug maintenance (PI + IMiD) for ≥2-3 y if sustained MRD⁻ 

Template:

Diagnosis: IgG kappa myeloma, RISS- stage

Transplantation eligibility

FISH

Cytogenetics

Date of diagnosis and initial presentation:

Presentation: details

CRAB

FLC

LDH

PET

BMBX:

Treatment history:

1. Date: RVD-dara

Date of progression

Comorbidities:diabetes mellitus, hypertension, heart failure, cardiac arrhythmias, hyperlipidemia, chronic renal failure, and other cancers

Geriatric/ frailty assessment:

End organ damage: renal failure, back pain, baseline neuropathy

CML 2023

Chronic Myeloid Leukemia

CML

• Chronic phase/ Accelerated/ Blast
• Baseline : BCR-ABL % IS
• Sokal score:
• Eutos Score:

Presentation:

Date: WBC at presentation, spleen palpable below costal margin, total spleen size, symptoms, anemia or thrombocytopenia

Date	Timeline	IS %	Goal	BMBx/CBC
	Baseline		NA
	3 months		<10%
	6 months		<10%
	9 months		<1%
	12 months		<0.1% ( for TFR) otherwise < 1%

Pearls:

1.  30% of blast crisis in CML can be lymphoid rather than myeloid.

2. All the TKIs except nilotinib are FDA approved in blast crisis.

How to differentiate between CML blast crisis and de novo ph+ ALL?

FISH studies can detect the isoforms of BCR-ABL oncogene and provide important clues. The p210 isoform is commonly seen in CML, whereas the p190 isoform occurs in the majority of Ph + ALL .

 Flow cytometry  for CD 26+ which are seen on myeloid stem cells.

Dasatinib 100 mg CP, 140 mg daily AP

Monitor for hematologic and non hematologic toxicities which may require drug management including dose adjustment, briefly interrupting therapy, change of therapy and symptomatic management.

Non hematologic toxicities include: fluid retention, pleural and pericardial effusion, GI upset, rash.

Look for other causes of anemia and thrombocytopenia.

Rash: topical, systemic steroids

Hold for  hepatotoxicity at thresholds Bili 3 times, transaminases 5 times

Imatinib cramps: calcium, magnesium, L carinitine supplements

EKG, echo, diuretics for fluid overload

Adjuvant endocrine therapy

 Ref: ASCO education book 2022

1. What is the correct duration of endocrine therapy?

• 10 yr if node positive, although 7 yr may be sufficient for AI
• 10 yr for tamoxifen based on ATTOm and ATLAS trials : absolute reduction in disease recurrence of approximately 3% to 4%, and in breast cancer mortality of 2.8%

2.  Benefit of endocrine therapy

-50% recurrences happen in the first 5 yr. 2% recurrence per year LN neg, 4% per yr if LN +

-MA-17 trial showed a 4.6% absolute reduction in recurrences for patients receiving 5 additional years of letrozole after 5 years of tamoxifen, with an improvement in disease-free survival (DFS) observed in lymph node–negative and –positive disease as early as 2 years

-But OS benefit only in LN + patients

3. Role of adjuvant CDK4/6 in the adjuvant setting: who and how long?

Abema 2 yr if high risk- high risk means 4 or more LN. If 1-3 LN, for tumors > 5cm or grade 3--> IDFS benefit of 7% at 4 yr in abema group ( 85 v 76%)

Ribociclib 3 yr- intermediate or high risk: stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC 

-3 yr IDFS 90% versus 87%. Overall, the addition of ribociclib reduced the risk for recurrence by 25%

4. Premenopausal women: choice of therapy

Tamoxifen versus Tamoxifen with OFS: OS benefit with the addition of OFS to tamoxifen: reduction of recurrence by 1.4% and risk of death by 2.3% at 12 yr, SOFT trial.

-12-year OS was more than 95% in pre-menopausal women with grade 1 or 2, less than 2 cm, node neg

-12 yr OS in women who got chemo: adding OFS to tamoxifen produced an absolute reduction in distant recurrence/death of 2.6%/4.7% at 12 years (OS improved from 78.9% to 83.6%).

- ER+ HER2-negative disease who received neoadjuvant chemotherapy or were younger than age 35, absolute survival improvement was in the range of 10% for either oral endocrine agent combined with OFS compared with tamoxifen alone

- AI versus Tamoxifen in addition to OFS: distant recurrence less with AI, no survival difference so far in premenopausal women

5. Males with breast cancer

Tamoxifen or AI with GnRH agonists

Need Germline testing.

Were included in the NATALEE trial

6. Role of bisphosphonates: ASCO and Cancer Care Ontario guidelines

- Strongly consider in post menopausal women - zoledronic acid q 6 months for 3-5  yr. Clodronate may be used. Not enough data to support denosumab. No conclusive evidence that 5 yr is better than 3 yr.

-Educate about risk of ONJ, renal failure, hypocalcemia and risk of ocular complications. Monitor calcium, renal function and ask for dental issues, ocular symptoms before each treatment.

- In women age ≤ 60 years with a previous hysterectomy and ovaries left in place, luteinizing hormone, follicle-stimulating hormone, and serum estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy to receive adjuvant bisphosphonates

-In postmenopausal women, the addition of bisphosphonates led to an absolute 2.2% reduction in the risk of bone recurrence (rate ratio, 0.72) and a 3.3% reduction in the risk of breast cancer mortality (rate ratio, 0.82) with a greater effect in older women, whereas no substantial effect was observed in premenopausal patients

- addition of bisphosphonates should be considered in women who were premenopausal at breast cancer diagnosis and who receive OFS as part of their endocrine therapy

7. De-escalation of endocrine therapy: When to use BCI

-in year 4 of planned 5 yr of AI, if patient is intolerant, do BCI to see if it would help to continue

- if HER 2+ and ER+, BCI can identify low risk patients who can stop AI at 5 yr

Melanoma management

Risk calculator

https://www.melanomarisk.org.au/

 Adjuvant

1. CheckMate 238: Adjuvant Nivolumab vs Ipilimumab in Stage III-IV High-Risk Melanoma

5 year update from this study demonstrated sustained long term improvement in median RFS with nivolumab at 61.0 months vs 24.1 months (HR: 0.72). The OS data remain immature.

50% vs 39% nivo versus ipi 5 yr RFS.

2. KEYNOTE-054: Adjuvant Pembrolizumab vs Placebo for Stage III Melanoma

The 5-year RFS rates were 55% with pembrolizumab and 38% with placebo (HR: 0.61).

3. KEYNOTE-716: Adjuvant Pembrolizumab vs Placebo in High-risk, Resected, Stage II Melanoma

The 36-month RFS rate was 76.2% with pembrolizumab and 63.4% with placebo, and the median RFS was not reached in either arm. Although OS analyses remain immature, results from this study reinforce the SoC to consider adjuvant therapy with anti–PD-1 in this patient population.

4. CheckMate 76K: Adjuvant Nivolumab vs Placebo in Resected Stage IIB/IIC Melanoma

CheckMate 76K demonstrated an RFS benefit with nivolumab (HR: 0.42).

In patients with stage IIB melanoma, 12-month recurrence-free survival was 93% with adjuvant nivolumab therapy, and 84% in stage IIC melanoma (vs 84% and 72% in the placebo group).

5. COMBI-AD: Adjuvant Dabrafenib/Trametinib vs Placebo in BRAFV^600E/K-Mutant Melanoma

5 yr RFS 52% ( Dab Tram) vs 36% ( placebo)

Discussion:

Risks versus benefits of treatment, different options, duration of treatment, route of administration, chances of relapse with observation alone, patient preferences were all discussed.

Neoadjuvant

1. SWOG S1801: Adjuvant Pembrolizumab ± Neoadjuvant Pembrolizumab in Resectable Stage III-IV Melanoma

event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49%

2. OPACIN-Neo: 3 different doses of ipi nivo for stage 3 melanoma ; phase 3 ongoing. high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80% No difference between 3 arms.

3. Neoadjuvant Relatlimab + Nivolumab for Resectable Stage IIIB/C/D or IV Melanoma :phase 3 ongoing.

Metastatic 

1.  CheckMate 067: OS and PFS at 7.5-Year Follow-up

The 7.5 year follow-up of this trial found ongoing OS and PFS benefits in the nivolumab containing arms compared with ipilimumab.¹⁸ The median OS was 72.1 months, 36.9 months, and 19.9 months for nivolumab plus ipilimumab, nivolumab alone, and ipilimumab, respectively. These results reinforce the SoC for this patient population, which is using an anti–PD 1–containing regimen as upfront therapy.  

2. RELATIVITY-047: PFS by BICR

The study met its primary endpoint of an improvement in PFS with relatlimab plus nivolumab.²¹ At a median follow-up of 25.3 months, the median PFS was 10.2 months vs 4.6 months with nivolumab alone. OS not significant.

Discussion:

wild-type BRAF metastatic melanoma who is treatment naive: nivolumab in combination with either ipilimumab or relatlimab. While ipi nivo has not been compared head to head with nivo relatlimab, if the disease burden is low and patient frail,the latter combo has 10% grade 3 toxicity

3. BRAF V600 E mutated: Pooled Analysis of COMBI-d and COMBI-v Trials of Dabrafenib + Trametinib: 5-Year OS

5 year OS rate was 34% in this patient population, with a median OS of 25.9 months. The 5-year PFS rate was 19%, with a median PFS of 11.1 months

4. coBRIM: OS With Vemurafenib ± Cobimetinib in BRAF-Mutant Advanced Melanoma

Results from this study were similar to those seen with COMBI-d and COMBI-v, with a 5 year OS rate of 31% with the combination and a median OS of 22.5 months.

5. COLUMBUS:  phase III COLUMBUS study looked at encorafenib plus binimetinib in comparison with vemurafenib or encorafenib monotherapy in patients with unresectable stage IIIB/C/IV melanoma and a BRAF^V600E/K mutation.

Results similar to #3 and #4.

Metastatic melanoma treatment sequence : DREAMseq

This study established that the sequence beginning with combination nivolumab/ipilimumab resulted in a 20% absolute improvement in 2-year overall survival (72% v 52%) compared with the sequence beginning with dabrafenib/trametinib. A trend toward 2-year overall benefit was seen across all patient subsets, and other efficacy end points (progression-free survival and duration of response) also favored first-line immunotherapy

Clinical pearl: Dacarbazine is recommended in certain circumstances where patients are not eligible for immunotherapy or targeted therapy

How would you approach: BRAF wild-type melanoma who received first-line ipilimumab/nivolumab and now has progressive disease?

•  Relatlimab with Nivo
• Pembro with lenvatinib
• TIL therapy once approved or on clinical trial
• Dacarbazine

Melanoma with CNS mets

If asymptomatic -Ipi nivo

If symptomatic: steroids,local Rx and ipi nivo rather than combination BRAFMEK even for BRAF mutated melanoma

AE management BRAK MEK

• Derm: skin exam at baseline, q2 months, then upto after 6 months after stopping treatment
• Eye: baseline retinal exam, then as needed. Hold if grade 2 or higher
• Cardiac: EKG baseline, Echo baseline. At 2weeks- another EKG. At 1 month- echo. Then repeat EKG and echo q 3 m
• LFT monthly- hold if grade3 or higher
• Fever- hold, tylenol, steroids

Pearls:

1. BRAF mutant melanoma stage 4: symptomatic. Paraneoplastic are rare. Retinal manifestations may be seen. Use ipi nivo based on Dream seq data. 20% OS benefit in 2 yr.

2. MSLT II- therapeutic LND does not improve survival.

3. Steroids- small amount for short duration OK, more than 10 mg for longer term not good on IO.

4. Orthostatic hypotension in immunotherapy: rule out endocrine disturbances, but consider autonomic neuropathy. Could be directly drug induced although rare.

Generic Template

Oncology History Template

Diagnosis:

Initial diagnosis - Date ( typically date of first biopsy)

• Presentation: self palpated lump, screening mammogram, iron def anemia, bowel obstruction, abnormal weight loss, abnormal bleeding, incidentally detected elevated PSA, obstructive uropathy symptoms, dyspnea, weakness, falls
• Description of presentation:
• Imaging at presentation
• Initial diagnosis pathology and tumor markers

Treatment history:

First Progression: ( date)

• Imaging at progression ( date)
• Tumor markers at progression
• Pathology/NGS if repeated
• Treatment at progression

Second Progression: ( date)

• Imaging at progression ( date)
• Tumor markers at progression
• Pathology/NGS if repeated
• Treatment at progression

 A/P 

@age yo @gender  with 

• Diagnosis: 
• Stage: TNM ( .oncstage)
• Goals of treatment: Curative or palliative
• Menopausal status: for breast cancer
• ECOG:
• Comorbid conditions: No hx of stroke, CAD, VTE. Hx of controlled hypertension and diabetes.
• Obesity .bmi ( Specify)-NCCN recommends chemo dose for actual BMI if curative intent

Assessment:

1. Functional status/ Geriatric assessment/ 

2. Social support and additional concerns

3.  Family history and need for germline testing

4. Availability of clinical trials and patient's interest in trial participation

5. Prior organ transplant/ autoimmune conditions/ long term steroid use

6. Fertility issues if applicable: Need for Lupron

Discussion:

We discussed NCCN guidelines. Based on these, current standard of care treatment involves (neoadjuvant/ adjuvant) chemo or chemo immunotherapy.

Decision regarding treatment was made after taking into consideration disease factors such as stage, current guidelines, patient factors including comorbid conditions, patient preferences and prior treatment.

The role of chemotherapy is to eliminate micrometastases and improve survival. When chemotherapy is administered before surgery, it  often shrinks the tumor and improves the chances of negative surgical margins. Based on the final pathology report at surgery, additional treatment in the form of the same or different chemotherapy or PARP inhibitor may be indicated.

OR Discussion regarding utility of Oncotype to determine chemo

Prognosis: ( if patient requests). If stage 4, emphasize disease is not curable ( except in rare situations)

Recommendations:

1. Completion of staging work up with ( CT, PET, MRI brain, bone scan, PSMA PET). Echocardiogram, baseline EKG, baseline labs CBC, CMP, phosphorus and magnesium if indicated. NGS panel testing or PDL1if indicated.

2. Port placement

3.   Sequence of treatment reviewed: chemotherapy followed by surgery. Depending on the pathology report, if no path CR, plan for additional treatment may include more chemotherapy or PARP inhibitor. Adjuvant endocrine therapy with aromatase inhibitor, need for bone density monitoring briefly discussed.

4.Neoadjuvant/ Adjuvant /Palliative chemotherapy: 

Chemotherapy regimen  recommended: TCHP/ weekly carboplatin with taxol with pembrolizumab q 6 weeks for 12 weeks followed by DDAC.

5. We discussed side effects of the treatment.  The common side effects include fatigue, neutropenia, neutropenic fever, elevation in liver enzymes, neuropathy, hearing damage ( cisplatin), skin rash. Chemotherapy is associated with a low but well known risk of death due to complications.

Immunotherapy treatment can cause severe including life limiting side effects in 10-15% patients. 

NCCN patient hand out provided.

6. Logistics of chemo including frequency/ additional chemo teaching will be provided by RN/ pharmacist.

7.  Plan for monitoring: Review of side effects, Labs during chemo visits, CT or PET image per guidelines, echo q 3 months

8. Germline testing:  Family history reviewed. Based on NCCN guidelines, this is indicated OR not indicated.

9. Referral to Social worker for counseling

10. Supportive care

- primary VTE prophylaxis: Khorana score e.g pancreatic cancer /myeloma ASA or warfarin for myeloma. 

-antimicrobial prophylaxis support

- bone support agents

- Growth factor support

-calcium and vitamin D supplementation unless contraindicated

11. Comorbid conditions were reviewed and taken into consideration in the choice of chemo treatment

-DM

-HTN

-Atrial fibrillation/CAD

-VTE/Chronic anticoagulation :Any current anticoagulants or antiplatelet and if continued use indicated? Concerns with treatment induced thrombocytopenia

-Baseline neuropathy